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WO2017129069A1 - Composés bicycliques liés à la tétrahydroquinoléine et leurs utilisations - Google Patents

Composés bicycliques liés à la tétrahydroquinoléine et leurs utilisations Download PDF

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WO2017129069A1
WO2017129069A1 PCT/CN2017/071997 CN2017071997W WO2017129069A1 WO 2017129069 A1 WO2017129069 A1 WO 2017129069A1 CN 2017071997 W CN2017071997 W CN 2017071997W WO 2017129069 A1 WO2017129069 A1 WO 2017129069A1
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sulfonyl
tetrahydroquinolin
fluorophenyl
cancer
methyl
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PCT/CN2017/071997
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English (en)
Chinese (zh)
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许�永
罗小雨
王蕊
邢艳丽
吴锡山
薛晓纤
张岩
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中国科学院广州生物医药与健康研究院
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Publication of WO2017129069A1 publication Critical patent/WO2017129069A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero 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
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the technical field of chemical medicine, in particular to the preparation and application of a tetrahydroquinoline-related bicyclic compound.
  • Retinoic acid receptor-related orphan receptor is an important orphan receptor in the nuclear receptor family.
  • the receptor family includes three subtypes, ROR ⁇ , ROR ⁇ and ROR ⁇ .
  • ROR ⁇ is widely expressed in the liver, skeletal muscle, skin, lung, fat cell tissue, kidney, thymus, and brain. The expression of ROR ⁇ is very limited and is only expressed in the central nervous system. ROR ⁇ is expressed in liver, skeletal muscle, and adipocyte tissues, particularly in key cells in the immune system.
  • T H 17 helper T cell 17
  • T H 17 cells is a key regulator of immune pathology, thus regulating T H 17 cells capable of modulating an immune system response.
  • Interleukin-17 (IL-17) is a key pro-inflammatory cytokine in the development of inflammation and various autoimmune diseases, and is closely related to multiple sclerosis (MS) and rheumatoid arthritis (RA).
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • ROR ⁇ directly regulate IL-17 production and secretion of cytokines, it is a key factor in the development of T H 17 cells.
  • ROR family proteins inhibiting effective to inhibit T H 17 cells, thereby regulating immune response, the drug multiple sclerosis, rheumatoid arthritis, psoriasis, clone disease, asthma, inflammatory bowel disease, lung disease and other diseases develop has great significance. It has been reported in the literature that ROR may be involved in the development and progression of inflammation and related tumors.
  • ROR is also able to regulate gene transcription in the absence of endogenous ligand ligation, and it has been found in the crystal structure test of the ligand binding domain of ROR that cholesterol and cholesterol sulfonate can enter the ligand pocket. Soon, a series of hydroxycholesterol derivatives were found to regulate the transcriptional activity of ROR. However, it is unclear whether these cholesterol derivatives are endogenous ligands for ROR. Subsequent studies have shown that a synthetic small molecule, T1317, binds to ROR ⁇ and ROR ⁇ and regulates their activity, but this compound also interacts with at least four other nuclear receptors (LXR ⁇ / ⁇ , FXR, PXR). Thereby limiting its development as a drug for the treatment of immune diseases.
  • LXR ⁇ / ⁇ , FXR, PXR nuclear receptors
  • a selective inverse agonist SR3335 of ROR ⁇ , a reverse agonist SR1001 with dual effects on ROR ⁇ and ROR ⁇ , and selective inverse agonists SR2211 and SR1555 of ROR ⁇ , which can inhibit interleukin-17 cells, are currently found.
  • GlaxoSmithKline has published a series of patents that mention a class of aromatic amines that inhibit ROR receptors. It has also been reported that the natural products digoxin and ursolic acid can be used as selective regulators of ROR ⁇ and can inhibit the differentiation of interleukin-17 cells. However, further studies have shown that digoxin has strong side effects, and ursolic acid also has a role in the glucocorticoid receptor. These studies have shown that selective inhibitors of synthetic ROR have great potential as drugs for inhibiting the expression of interleukin-17.
  • One of the technical problems to be solved by the present invention is to provide a novel tetrahydroquinoline-related bicyclic compound having a novel structure.
  • X is selected from: C, O or N;
  • Y is selected from: CO or SO 2 ;
  • n is selected from: 0, 1 or 2;
  • R 1 is optionally selected from the group consisting of: C 0 to C 6 alkylene-R 3 ;
  • R 2 is optionally selected from the group consisting of: C 0 to C 6 alkylene-R 3 ;
  • R 3 is optionally selected from the group consisting of: H, cycloalkyl or heterocyclic;
  • the above cycloalkyl group is optionally selected from a saturated or unsaturated ring composed of 3 to 7 carbon atoms, and the cycloalkyl group is selected from 0, 1, 2 or 3, selected from halogen, C 1 -C 6 alkane.
  • the above heterocyclic group is optionally selected from 1 to 3 of a 5- or 6-membered heterocyclic ring selected from N, O or S heteroatoms, and the heterocyclic group is selected from 0, 1, 2 or 3 Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy, cyano, -N(R 4 )(R 5 ), -C 1 -C 6 alkylene-N(R 4 )( R 5 ), -C 0 -C 6 alkylene-alkoxy, -C 0 -C 6 alkylene-COOR 6 , -OC 1 -C 6 alkylene-N(R 4 )(R 5 ) -OC 0 -C 6 alkylene-COOR 6 -COR 4 , -OR 4 , -N(R 4 )COR 6 , -N(R 4 )COOR 6 , -SO 2 N(R 4 )(R 5 Or a -N
  • R 1 and R 2 are independently selected from any one of the following groups:
  • R 3 is independently selected from: H, cycloalkyl or heterocyclic; the cycloalkyl is selected from cyclobutane, cyclopentane , cyclohexane, cycloheptane, phenyl, naphthyl, benzyl, etc., wherein the cycloalkyl group is selected from the group consisting of fluorine, chlorine, bromine, iodine, and C 1 -C 6 alkane.
  • the compound is selected from the group consisting of compounds of the formula IA or formula IB:
  • X is selected from: C, O or N;
  • Y is selected from: CO or SO 2 ;
  • n is selected from: 0; 1 or 2;
  • R 1 and R 2 are independently selected from the group consisting of methyl, ethyl, propyl, butyl or C 0 -C 6 alkylene-R 3 ; said R 3 is independently selected from: H, cycloalkyl or a heterocyclic group; the cycloalkyl group is optionally selected from the group consisting of cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl or benzyl; the cycloalkyl group is 0, 1, 2 or Three are selected from the group consisting of fluorine, chlorine, bromine, iodine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy, cyano, -N(R 4 )(R 5 ), -C 1 -C 6 alkylene-N(R 4 )(R 5 ), —C 0 —C 6 alkylene-alkoxy,
  • R 5 (R 5 ), -C 1 -C 6 alkylene-N(R 4 )(R 5 ), -C 0 -C 6 alkylene-alkoxy, -C 0 -C 6 alkylene-COOR 6 , -OC 1 -C 6 alkylene-N(R 4 )(R 5 ), -OC 0 -C 6 alkylene-COOR 6 -COR 4 , -OR 4 , -N(R 4 )COR 6 , -N(R 4 )COOR 6 , -SO 2 N(R 4 )(R 5 ) or -N(R 4 )SO 2 -C 1 -C 6 alkyl group substituted; wherein R 4 , R 5 are Selected from H, methyl, ethyl, propyl or butyl; R 6 is selected from H, methyl, ethyl, propyl or butyl;
  • X is selected from: C, O or N;
  • Y is selected from: CO or SO 2 ;
  • n is selected from: 0; 1 or 2;
  • R 1 and R 2 are independently selected from the group consisting of methyl, ethyl, propyl, butyl or C 0 -C 6 alkylene-R 3 ; said R 3 is independently selected from: H, cycloalkyl or a heterocyclic group; the cycloalkyl group is optionally selected from the group consisting of cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl or benzyl; the cycloalkyl group is 0, 1, 2 or Three are selected from the group consisting of fluorine, chlorine, bromine, iodine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy, cyano, -N(R 4 )(R 5 ), -C 1 -C 6 alkylene-N(R 4 )(R 5 ), —C 0 —C 6 alkylene-alkoxy,
  • R 5 (R 5 ), -C 1 -C 6 alkylene-N(R 4 )(R 5 ), -C 0 -C 6 alkylene-alkoxy, -C 0 -C 6 alkylene-COOR 6 , -OC 1 -C 6 alkylene-N(R 4 )(R 5 ), -OC 0 -C 6 alkylene-COOR 6 -COR 4 , -OR 4 , -N(R 4 )COR 6 , -N(R 4 )COOR 6 , -SO 2 N(R 4 )(R 5 ) or -N(R 4 )SO 2 -C 1 -C 6 alkyl group substituted; wherein R 4 , R 5 are It is selected from H, methyl, ethyl, propyl or butyl; R 6 is selected from H, methyl, ethyl, propyl or butyl.
  • the compound is selected from any of the following compounds:
  • the present invention also provides a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate or solvate of the above compound.
  • the cancer is selected from the group consisting of: acoustic neuroma, acral melanoma, acromegaly, acute eosinophilic leukemia, acute red leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute mononuclear cells.
  • Leukemia acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumor, adrenocortical carcinoma, adrenal tumor, adult T cell leukemia/lymphoma, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma , ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical deformity rod-shaped tumor, B-cell chronic lymphocytic leukemia, B-cell Prolymphocytic leukemia, B cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone tumor, brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma in situ, chondroma, teeth Osteosarcoma, my
  • the inflammatory disease or autoimmune disease is selected from the group consisting of: inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, encephalomyelitis, myocarditis, nephritis, osteomyelitis, myositis , hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, asthma, allergic rhinitis, chronic Obstructive pulmonary disease, autoimmune disease, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenia, pulmonary hemorrhagic nephritis Syndrome, atherosclerosis, Addison's disease
  • the compounds of the present invention can be applied to various routes of administration when used, including but not limited to the following routes, oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, through lumbar puncture, menstrual Urethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intra-abdominal, intrathecal, surgical implantation).
  • a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate, solvate thereof, and optionally pharmaceutically acceptable Carrier or excipient.
  • a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, isomer, racemate, prodrug co-crystal complex, hydrate, solvate thereof, together with one or more Other therapeutically active agents, and optionally pharmaceutically acceptable carriers or excipients.
  • Such other therapeutically active agents include, but are not limited to: (1) inhibitors of TNF-[alpha]; (2) non-selective COX-1 / COX-2 inhibitors; (3) COX-2 inhibitors; 4) Other inflammatory and autoimmune diseases for treatment, including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus, penicillium Amine, bucillamine, akitali, imidazoribine, clofibrate, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide , Lymphostat-B, BAFF/APRIL inhibitors, such as belimizumab; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP)
  • compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration employed.
  • the compositions of the present invention can be administered by oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposome, and the like.
  • Oral compositions can be solid, gel or liquid.
  • solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, a flavoring agent and the like.
  • binders include, but are not limited to, microcrystalline cellulose, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste;
  • examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate And stearic acid;
  • examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate;
  • examples of glidants include, but are not limited to, silica;
  • examples of disintegrants include, but are not limited to, Sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar and carboxymethyl cellulose.
  • compositions of the invention are administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection.
  • the injection can be formulated into any conventional form, such as a liquid solution or suspension, a solid form or emulsion suitable for dissolution or suspension in a liquid prior to injection.
  • pharmaceutically acceptable carriers which can be used in the injection of the present invention include, but are not limited to, aqueous carriers, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents And other pharmaceutically acceptable substances.
  • aqueous carrier examples include sodium chloride injection, lin format injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection;
  • examples of the non-aqueous carrier include fixed oil of plant origin, Cottonseed oil, corn oil, sesame oil and peanut oil;
  • examples of the antimicrobial agent include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.;
  • isotonic agents include sodium chloride and glucose; buffers include phosphate And citrate.
  • compositions of the invention may also be prepared as sterile lyophilized powders in which the compound is dissolved in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by standard solutions under standard conditions known to those skilled in the art. The bacteria are filtered, followed by lyophilization to give the desired preparation.
  • the present invention provides a novel structure of tetrahydroquinoline-related bicyclic compounds, which have a very good inhibitory effect on ROR ⁇ protein and can be used to develop new ROR ⁇ protein inhibitors; Such compounds are useful in the preparation of ROR gamma receptor inhibitors; or in the preparation of a medicament for the treatment of cancer, inflammatory diseases and autoimmune diseases.
  • Figure 1 is a graph showing the inhibitory activity of the compounds of Examples 1-68 on the ROR ⁇ protein.
  • Figure 2 is a graph showing the inhibitory activity of the compounds of Examples 1-68 on the level of ROR ⁇ cells.
  • any variable e.g. R 1, R 2, etc.
  • R 1, R 2, etc. any variable
  • combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring.
  • alkyl and alkylene as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the definition of “C 1 -C 6 " in “C 1 -C 6 alkyl” includes a group having 1, 2, 3, 4, or 5 carbon atoms arranged in a straight chain or a branched chain.
  • C 1 -C 6 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
  • heteroaryl denotes a stable monocyclic ring of up to 6 atoms in the ring or up to 6 atomic bicyclic carbocyclic rings in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 Heteroatoms of O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, imidazolyl, triazolyl, pyrazolyl, indolyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl , pyrimidinyl, pyrrolyl.
  • Heteroaryl is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group for the definition of the following heteroaryl.
  • the heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
  • heterocycle refers to a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups. group.
  • Heterocyclyl thus includes the heteroaryl groups mentioned above, as well as the dihydrogenated and tetrahydrogenated analogs thereof.
  • heterocyclyl include, but are not limited to, imidazolyl, oxazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyridyl Azinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l,4-dioxin Alkyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, Dihydropyridyl, di
  • the heterocyclic group is selected from the group consisting of imidazolyl, pyridyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidinone, 2-pyrrolidone, thienyl, oxazolyl, triazolyl, isomerism Azolyl.
  • halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be considered unsubstituted or substituted.
  • (C 1 -C 6 )alkyl may be substituted by one, two or three selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like. Substituted.
  • the invention includes the free forms of the compounds of formula I, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form" refers to an amine compound in a non-salt form.
  • the pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • Free form The solubility of the formula in certain physical properties, such as in polar solvents, is somewhat different from its respective salt form, but for the purposes of the present invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as Arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxylamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine Azine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine,
  • the acidic moiety such as a carboxyl group
  • a cationic moiety such as tetravalent
  • the compounds of the invention are potential internal salts or zwitterions.
  • the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituents are attached to a compound which allows multiple substituents under the definition of formula I above.
  • Y is SO 2
  • the definitions of R 1 , R 2 , n, and X are the same as defined above, and can be prepared by the following method (1):
  • Example 1 4-Chloro-2-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (4 -chloro-2-fluoro-N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide)
  • Example 42 4-(N-(1-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid (4-( Preparation of N-(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzoic acid)
  • Example 47 3-((7-(2,4-Difluorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid (3-((7) -(2,4-difluorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoic acid)
  • Example 54 Methyl 2-((7-(2,6-dichlorophenylsulfonylamino)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate (methyl 2- Preparation of ((7-(2,6-dichlorophenylsulfonamido)-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)benzoate)
  • the present invention uses the AlphaScreen detection technique to verify the inhibitory ability of the compounds of the invention.
  • the inhibitory activity of the compound of the present invention against the ROR ⁇ protein was determined.
  • the final concentration of the target protein ROR ⁇ was 100 nM; assay buffer (10 ⁇ ) MOPS (500 mM) pH 7.4, CHAPS (0.5 mM), NaF (500 mM), BSA (1 mg/ml); final concentration of donor microbeads in the kit 50 ⁇ g/mL, the final concentration of the receptor microbeads was 50 ⁇ g/mL; the co-agonistic factor of ROR ⁇ , the short peptide bSRC1-4 (Biotin-QKPTSGPQTPQAQQKSLLQQLLTE) was at a final concentration of 20 nM.
  • reaction system ROR ⁇ : 15 ⁇ L, assay buffer: 15 ⁇ L, deionized water: 60 ⁇ L, small molecule compound: 15 ⁇ L, donor microbead: 15 ⁇ L, acceptor microbead: 15 ⁇ L; positive inhibitor: T1317 (purchased, The product name is T0901317 and the brand is cayman).
  • the detection wavelength is 680 nm and the emission wavelength is 520-620 nm.
  • the inhibitory activity data of the compounds of the present invention 1-68 (compounds prepared in Examples 1-68, respectively) against the RORy protein are shown in Fig. 1.
  • Table 1 IC 50 values of inhibitory activity of the more active compounds of the invention against ROR ⁇ protein
  • the experimental results show that the compound of the present invention has a very good inhibitory effect on the ROR ⁇ protein, particularly the inhibitory activity of the compound 30 (representing the compound prepared in Example 30, the same below), 31, 33, 34, 38, 39 on the ROR ⁇ protein. Better than the comparator T1317.
  • the present invention uses the Luciferase detection technique to verify the inhibitory ability of the compounds of the invention.
  • the inhibitory activity of the compounds of the invention against nuclear receptor RORy cell levels was determined.
  • Human renal epithelial cell line 293T cells Human renal epithelial cell line 293T cells; DMEM medium containing 10% fetal bovine serum; 96-well plate transparent plate; double reporter gene detection kit; Opti-MEM reagent; Lipo-fectamine 2000 transfection reagent; recombinant plasmid: Gal4- ROR ⁇ LBD: 25 ng, RORE_Luc: 25 ng, pG5-luc, Renilla; positive inhibitor: T1317 (purchased, product name T0901317, brand cayman).
  • Human renal epithelial cell line 293T cells were cultured in DMEM medium containing 10% fetal calf serum. The day before transfection, cells were prepared in 96-well plates with a cell density of 1.5x10 4 cells / well. Transient transfection was carried out 24 hours after adherent growth, using a double reporter gene co-transfection method, the transfection reagent was Lipo-fectamine2000, and the transfection reagent and plasmid were diluted with Opti-MEM reagent, respectively. Gal4-ROR ⁇ LBD was 25 ng per well; pG5-luc gene was 25 ng per well; Renilla was 5 ng per well. After transfection for 24 hours, different concentrations of compounds were added. After incubation for 24 hours, the Luciferase double reporter assay kit was used to detect the luminescent signal. 3 replicate wells per sample.
  • IC 50 values for the inhibitory activity of the more active compounds of the present invention against ROR gamma cell levels are shown in Table 2 below:
  • IC 50 of the inhibitory activity of the active compound is preferably on the cellular level ROR ⁇
  • the experimental results show that the compound of the present invention has a very good inhibitory effect on the ROR ⁇ cell level test, and in particular, the inhibitory activity of the compound 31 on the ROR ⁇ protein is better than that of the control drug.
  • the inhibitory activity of compounds 22 and 24 on the ROR ⁇ protein was comparable to that of the control drug.
  • the compound of the present invention has the advantages of novel structure and easy preparation compared with the control drug.

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Abstract

La présente invention tombe dans le domaine des techniques pharmaceutiques chimiques, et en particulier décrit la préparation d'un composé bicyclique lié à la tétrahydroquinoléine et son utilisation, où le composé présente la structure telle que présentée dans la formule I. Le composé et un sel de qualité phamaceutique, un isomère, un racémate, un complexe promédicament co-cristal, un hydrate et son solvate peuvent efficacement réguler les récepteurs ROR, et peuvent être utilisés pour préparer des médicaments destinés au traitement de maladies apparentées régulées par les récepteurs ROR, ou peuvent être utilisés pour préparer des médicaments destinés au traitement des cancers, des maladies inflammatoires et des maladies auto-immunes.
PCT/CN2017/071997 2016-01-29 2017-01-21 Composés bicycliques liés à la tétrahydroquinoléine et leurs utilisations WO2017129069A1 (fr)

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CN110511182B (zh) * 2019-09-03 2023-01-17 上海昕凯医药科技有限公司 一种连续流反应合成7-硝基-1,2,3,4-四氢喹啉的方法
CN110724096B (zh) * 2019-09-30 2021-06-04 海南大学 一种具有免疫抑制活性的四氢喹啉类生物碱Malaysiensin及其制备方法和应用
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