WO2017073743A1 - Composé tricyclique - Google Patents

Composé tricyclique Download PDF

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WO2017073743A1
WO2017073743A1 PCT/JP2016/082100 JP2016082100W WO2017073743A1 WO 2017073743 A1 WO2017073743 A1 WO 2017073743A1 JP 2016082100 W JP2016082100 W JP 2016082100W WO 2017073743 A1 WO2017073743 A1 WO 2017073743A1
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disease
compound
syndrome
optionally substituted
pharmaceutically acceptable
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Japanese (ja)
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道寛 前本
正森 菅原
宏道 小坂
健至 上森
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協和発酵キリン株式会社
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed 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
    • A61K31/5365—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 ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a tricyclic compound having anticancer activity or the like, or a pharmaceutically acceptable salt thereof, and a DHODH inhibitor containing the tricyclic compound or pharmaceutically acceptable salt as an active ingredient, etc. .
  • Ewing sarcoma family tumors are primarily adolescents and children due to fusion genes caused by chromosomal translocations between EWSR1 genes and ETS family genes (e.g., FLI1, ERG, ETV1, E1AF, FEV, etc.) It is a sarcoma that occurs.
  • This fusion gene also called oncoprotein, functions mainly as an abnormal transcription factor, and induces Ewing sarcoma by activating various pathways such as the cell cycle, anti-apoptotic pathway, and DNA repair pathway. It is considered to be.
  • the most common fusion gene is the transcription factor EWS / FLI1 generated by translocation between the EWSR1 gene and the FLI1 gene, which is detected in about 85% of Ewing sarcoma.
  • vincristine, doxorubicin, ifosfamide, cyclophosphamide, actinomycin, etoposide, etc. are used in combination for chemotherapy treatment of Ewing sarcoma.
  • the 5-year survival rate is said to be about 10-23% [J. Clin. Oncol., 2005, Vol. 23, No. 19, p.4354-4362]. Accordingly, there is a need for new antitumor agents with a mechanism of action different from existing therapeutic agents.
  • talazoparib (BMN-673) (Current Opinion Oncology), 2014, Vol. 26, No. 4, p.428-433 And Olaparib [Cancer Research (Res.), 2012, Vol. 72, No. 7, p.1608-1613].
  • Dihydroorotate dehydrogenase promotes the synthesis of pyrimidine necessary for cell growth in the body. That is, by inhibiting the action of DHODH, it is possible to suppress the growth of cells that proliferate pathologically quickly.
  • DHODH inhibitory activity for example, 3,4,9-tetrahydro-2H-pyrido [3,4-b] indole derivatives (Non-patent Document 1) and the like are known.
  • DHODH inhibitors also include, for example, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcerative Inflammatory bowel diseases such as colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, allergy Inflammatory eye symptoms such as conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarthritis, hemangioma, ocular neovascularization, macular degeneration, HIV infection, hepatitis infection, sepsis, septic shock
  • tricyclic compounds examples include 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole derivatives (Patent Document 1), which are VEGF production inhibitors, and sodium iodide cotransporter inhibition 1,3,4,9-tetrahydropyrano [3,4-b] indole derivatives (Patent Document 2) and 1,3,4,5-tetrahydro- [1,2] oxazino [4,5- b] Indole derivatives (Non-patent Document 2) and the like are known.
  • Patent Document 1 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole derivatives
  • Patent Document 2 1,3,4,5-tetrahydro- [1,2] oxazino [4,5- b] Indole derivatives
  • the present invention relates to the following (1) to (46).
  • DHODH Dihydroorotate dehydrogenase
  • R 3a and R 3b are the same or different and each has a hydrogen atom, optionally substituted lower alkyl, optionally substituted cycloalkyl, or optionally substituted.
  • R 4 represents an optionally substituted aromatic Heterocyclic group, aryl which may have a substituent, aliphatic heterocyclic group which may have a substituent, cycloalkyl which may have a substituent or a substituent
  • R 4 represents an optionally substituted aromatic Heterocyclic group, aryl which may have a substituent, aliphatic heterocyclic group which may have a substituent, cycloalkyl which may have a substituent or a substituent
  • Z represents an oxygen atom, a sulfur atom or NR Z1 (wherein R Z1 represents a hydrogen atom or an optionally substituted lower alkyl group)
  • R 5 represents a hydrogen atom, halogen, hydroxy, or a substituent.
  • X and Y are the same or different and each represents a nitrogen atom or CR Z2 (wherein R Z2 is a hydrogen atom, halogen, hydroxy, optionally substituted lower group) Alkyl, optionally substituted cycloalkyl, optionally substituted lower alkoxy, optionally substituted lower alkylamino or optionally substituted di-lower R 6 represents an alkylamino, and when X and Y are CR Z 2 at the same time, two R Z2 may be the same or different, and R 6 represents an optionally substituted lower alkyl or halogen.
  • a 1 represents an oxygen atom or a nitrogen atom
  • B 1 is CR 2a R 2b (wherein R 2a and R 2b are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl, a substituent Represents an optionally substituted cycloalkyl, an optionally substituted lower alkoxy, an optionally substituted lower alkylamino or an optionally substituted dilower alkylamino.
  • R 1 does not exist, When A 1 is a nitrogen atom, B 1 is an oxygen atom or CR 2c R 2d (wherein R 2c and R 2d are the same or different and each represents a hydrogen atom or a lower alkyl optionally having substituent (s)); , Optionally substituted cycloalkyl, optionally substituted lower alkoxy, optionally substituted lower alkylamino or optionally substituted dilower alkyl R 1 represents a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted lower alkanoyl, an optionally substituted lower alkoxycarbonyl, Aroyl which may have a substituent, Aromatic heterocyclic carbonyl which may have a substituent, Aryloxycarbonyl which may have a substituent, Lower alkyl which may have a substituent Aminocarbonyl or It may have a substituent represents an di-lower alkylaminocarbonyl.
  • DHODH-related diseases are rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarthritis, he
  • DHODH-related diseases are rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, u
  • DHODH Diseases involving DHODH are rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarthritis, hemangio
  • DHODH Diseases involving DHODH are rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarth
  • A is a nitrogen atom
  • B is an oxygen atom
  • R 1 is a hydrogen atom
  • a lower alkyl optionally having a substituent
  • a lower alkanoyl optionally having a substituent
  • a substituent Optionally substituted lower alkoxycarbonyl, optionally substituted aroyl, optionally substituted aromatic heterocyclic carbonyl, optionally substituted aryloxycarbonyl, substituted
  • the tricyclic compound or the pharmaceutical thereof according to any one of (10) to (18), which is a lower alkylaminocarbonyl which may have a group or a dilower alkylaminocarbonyl which may have a substituent Acceptable salt.
  • a medicament comprising the tricyclic compound or a pharmaceutically acceptable salt thereof according to any one of (10) to (20) as an active ingredient.
  • a cancer preventive or therapeutic agent comprising the tricyclic compound or a pharmaceutically acceptable salt thereof according to any one of (10) to (20) as an active ingredient.
  • the preventive or therapeutic agent according to (22), wherein the cancer is Ewing sarcoma.
  • a method for the prevention and / or treatment of cancer comprising: (25) The method according to (24), wherein the cancer is Ewing sarcoma.
  • DHODH-related diseases include rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarthritis, hemangioma, ocular neovascularization, macular degeneration, HIV infection, hepatitis infection, sepsis, septic shock, end
  • a method for preventing and / or treating a disease involving DHODH comprising: (33) Diseases involving DHODH include rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet'
  • DHODH-related diseases include rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarthriti
  • DHODH Diseases involving DHODH include rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteop
  • DHODH-related diseases are rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarthritis, he
  • Diseases involving DHODH are rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarthritis, heman
  • a pharmaceutical composition comprising the tricyclic compound according to any one of (10) to (20) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of a disease involving DHODH .
  • DHODH-related diseases include rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcer Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, Inflammatory eye symptoms such as allergic conjunctivitis, Behcet's syndrome, conjunctivitis, uveitis, osteoporosis, osteoarthritis, hemangioma, ocular neovascularization, macular degeneration, HIV infection, hepatitis infection, sepsis, septic shock, end
  • the present invention provides a tricyclic compound having anticancer activity or the like, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a DHODH inhibitor containing a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Lower alkyl and lower alkoxy, lower alkanoyl, lower alkylamino, di-lower alkylamino, lower alkoxycarbonyl, lower alkylaminocarbonyl and lower alkyl moiety of di-lower alkylaminocarbonyl include, for example, linear or branched carbon atoms of 1 to 10 alkyls, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.
  • the two lower alkyl moieties of di-lower alkylamino and di-lower alkylaminocarbonyl may be the same
  • cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • aryl and the aryl moiety of aroyl and aryloxycarbonyl include aryl having 6 to 14 carbon atoms, and more specifically, phenyl, naphthyl, azulenyl, anthryl and the like.
  • aliphatic heterocyclic group for example, a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are condensed
  • aromatic heterocyclic group part of the aromatic heterocyclic group and the aromatic heterocyclic carbonyl examples include, for example, a 5-membered or 6-membered monocyclic fragrance containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Halogen means fluorine, chlorine, bromine and iodine atoms.
  • Lower alkyl optionally having substituent, lower alkoxy optionally having substituent, lower alkanoyl optionally having substituent, lower alkylamino optionally having substituent, substituted A di-lower alkylamino optionally having a group, a lower alkoxycarbonyl optionally having a substituent, a lower alkylaminocarbonyl optionally having a substituent and a dialkyl optionally having a substituent.
  • substituent in the lower alkylaminocarbonyl are the same or different, for example, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C 3-8 cycloalkyl, C 6-14 aryl, having 1 to 3 substituents, Aliphatic heterocyclic group, aromatic heterocyclic group optionally having a substituent (as the substituent in the aromatic heterocyclic group optionally having a substituent, C 1-10 alkyl and the like if example), C 1-10 alkoxy, C 3-8 cycloalkoxy, C 6-14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 Aroyloxy, C 1-10 alkylsulfanyl, —NR X R Y (wherein R X and R Y are the same or different and represent a hydrogen atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl)
  • substituent in the heterocyclic carbonyl and the optionally substituted aroyl include the same or different, for example, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, and substituent having 1 to 3 substituents.
  • the substituent of the C 1-10 alkyl optionally also have a good C 1-10 alkyl [the substituent group have, for example, hydroxy, C 1-10 alkoxy, C 1-10 alkylsulfonyl, C 1-10 alkylamino, di-C 1-10 alkylamino and the like], trifluoromethyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, substituent Have Good C 1-10 alkoxy (The substituent of the C 1-10 alkoxy optionally having said substituent, for example C 1-10 alkoxy, etc.), C 3-8 cycloalkoxy, C 6- 14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, —NR Xa R Ya where R Xa and R Ya are the same or different , Hydrogen atom, C 1-10 alkyl, C
  • substituents in the optionally substituted cycloalkyl and the optionally substituted aliphatic heterocyclic group are the same or different, for example, oxo, halogen, hydroxy, having 1 to 3 substituents.
  • C 1-10 alkyl as shown here and C 1-10 alkoxy, C 2-11 alkanoyloxy, C 1-10 alkylsulfanyl, C 1-10 alkylsulfonyl, C 1-10 alkylamino, di-C 1-10 alkyl
  • Examples of the C 1-10 alkyl moiety of amino, C 2-11 alkanoyl, C 1-10 alkoxycarbonyl, C 1-10 alkylcarbamoyl and diC 1-10 alkylcarbamoyl include the groups exemplified in the above-mentioned lower alkyl. Illustrated.
  • the two C 1-10 alkyl moieties in diC 1-10 alkylamino and diC 1-10 alkylcarbamoyl may each be the same or different.
  • the C 3-8 cycloalkyl and C 3-8 cycloalkyl moiety cycloalkoxy, e.g. groups listed illustrative of the cycloalkyl are exemplified.
  • Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples.
  • Examples of the aryl moiety of C 7-16 aralkyloxy, C 7-16 aralkyl and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above aryl examples, and examples of the alkyl moiety include C 1-10 Examples thereof include alkylene, and more specifically, a group in which one hydrogen atom has been removed from the groups exemplified in the above-mentioned lower alkyl.
  • the aliphatic heterocyclic group, aromatic heterocyclic group and halogen are as defined above.
  • R 3a and R 3b are hydrogen atoms, n is 0 or 1, when n is 0, R 4 is an aromatic heterocyclic group which may have a substituent; when n is 1, Z is an oxygen atom, R 4 is an optionally substituted lower alkyl, R 5 is a hydrogen atom, X and Y are CH, R 6 is a halogen, A 1 is a nitrogen atom, B is CH 2 and R 1 may have a substituent.
  • aryloxycarbonyl is mentioned.
  • Pharmaceutically acceptable salts of the compounds (I), (II) and (IIa) used in the present invention include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acids Includes addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compounds (I), (II) and (IIa) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate and phosphate, acetic acid Organic salts such as salts, oxalates, maleates, fumarate, citrates, benzoates, methanesulfonates, and the like.
  • Examples of pharmaceutically acceptable metal salts include sodium salts.
  • Alkali metal salts such as potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like.
  • pharmaceutically acceptable ammonium salts include ammonium and tetramethylammonium.
  • pharmaceutically acceptable organic amine addition salt include addition salts such as morpholine and piperidine.
  • pharmaceutically acceptable amino acid addition salt include lysine, Lysine, phenylalanine, aspartic acid, addition salts of glutamic acid and the like.
  • A is an oxygen atom
  • B is CR 2a1 R 2b1 [wherein R 2a1 and R 2b1 are the same or different and each represents a hydrogen atom (deuterium atom)]
  • Compound (Ia) in which R 3a and R 3b are the same or different and each is a hydrogen atom (deuterium atom) can be produced according to the following steps. (Wherein, R a represents a lower alkyl group, and R 4 , R 5 , R 6 , X and Y are as defined above)
  • Compound (a-4) is obtained by reacting Compound (a-1) with 1 to 10 equivalents of Compound (a-2) for 5 minutes to 72 hours at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used. 1 to 20 equivalents to compound (a-1) in the presence of 1 to 20 equivalents of base to compound (a-1) at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used. It can be produced by reacting with compound (a-3) for 5 minutes to 72 hours.
  • Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like.
  • solvent examples include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), 1,4-dioxane, pyridine and the like. These may be used alone or in admixture.
  • Compound (a-1), compound (a-2) and compound (a-3) can be obtained as commercial products.
  • Compound (a-5) is produced by reacting compound (a-4) with 2 to 10 equivalents of a reducing agent at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours. Can do.
  • Examples of the reducing agent include sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, or their deuterium
  • examples of the solvent include toluene, diethyl ether, THF, DME, 1,4-dioxane and the like can be mentioned, and these can be used alone or in combination.
  • sodium borohydride or lithium borohydride for example, methanol, ethanol, or the like may be used as the solvent.
  • Compound (Ia) is obtained by reacting Compound (a-5) with 1 to 10 equivalents of Compound (a-6) for 5 minutes at a temperature between room temperature and the boiling point of the solvent used in the presence of 0.1 to 20 equivalents of an additive. It can be produced by reacting for ⁇ 72 hours.
  • additives include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, aluminum chloride, bismuth trifluoromethanesulfonate, bismuth chloride, ytterbium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride, Examples thereof include boron trifluoride.
  • solvent examples include dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,4-dioxane, THF, DME, diethyl ether, diisopropyl
  • solvent examples include dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,4-dioxane, THF, DME, diethyl ether, diisopropyl
  • examples include ether, benzene, toluene, xylene, pyridine, N-methyl-2-pyrrolidone (NMP), water, and the like. These may be used alone or in combination.
  • Compound (a-6) can be obtained as a commercial product or a known method [for example, Experimental Chemistry Course, 5th edition, Volume 15, p.p1, Maruzen Co., Ltd. (2005), WO2012 / 062730, Synthesis, 44: 735-746, 2012, etc.] or the like.
  • A is an oxygen atom
  • R 2a2 and R 2b2 are the same or different, each represents a hydrogen atom or a lower alkyl group
  • B is CR 2a2
  • R 2b2 is
  • R Compound (Ib) in which 3a and R 3b are the same or different and each is a hydrogen atom (deuterium atom) can be produced according to the following steps.
  • V 1 is, for example, chlorine atom, represents a leaving group such as bromine atom
  • P 1 for example represents acetyl, benzoyl, a hydroxyl-protecting group such as benzyl
  • R 2a2 and R 2b2 are the same or different
  • Each represents a hydrogen atom or a lower alkyl group, and R 4 , R 5 , R 6 , X and Y are as defined above
  • Process 4 Compound (a-8) is compounded with 1 to 10 equivalents of compound (a-7) at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used in the presence of 1 to 20 equivalents of a base. It can be produced by reacting for 5 minutes to 72 hours.
  • Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like.
  • solvent examples include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, and these are used alone or in combination.
  • Compound (a-7) can be obtained as a commercial product, or a known method [for example, Experimental Chemistry Course, 5th Edition, Volume 13, p. 341, Maruzen Co., Ltd. (2005), Journal of Medicinal Chemistry, 19, 654-662, 1976, etc.] or the like.
  • Process 6 Compound (a-5-1) can be produced in the same manner as in production method 1, step 2 using compound (a-9).
  • Process 7 Compound (Ib) can be produced in the same manner as in production method 1, step 3 using compound (a-5-1).
  • A is an oxygen atom
  • B is CR 2a3 R 2b3 [wherein R 2a3 and R 2b3 represent a hydrogen atom (deuterium atom)]
  • R 3a and R 3b are Compound (Ic) which is a hydrogen atom can be produced according to the following steps. (Wherein R a represents lower alkyl, and R 4 , R 5 , R 6 , X and Y are as defined above)
  • Process 8 Compound (a-5-2) can be produced in the same manner as in production method 1, step 2 using compound (a-11).
  • Compound (a-11) can be obtained as a commercial product, or can be produced according to a known method (for example, Journal of Medicinal Chemistry, 50, 10-20, 2007, etc.).
  • Step 9 Compound (Ic) can be produced in the same manner as in production method 1, step 3 using compound (a-5-2).
  • compound (Id) in which A is a nitrogen atom, B is an oxygen atom, and R 3a and R 3b are hydrogen atoms (deuterium atoms) can be produced according to the following steps. .
  • P 2 represents an amino-protecting group such as tert-butyloxycarbonyl, benzyl, etc.
  • V 2 and V 2A are the same or different and each represents, for example, a chlorine atom, bromine atom, iodine atom, trifluoro
  • Compound (a-14) is obtained by using, for example, Protective Groups in Organic Synthesis, TW Greene, John Wiley & It can be produced according to the method for introducing a protecting group described in, for example, John Wiley & Sons Inc. (1981).
  • Compound (a-13) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 5th Edition, Volume 15, p.1, Maruzen Co., Ltd. (2005), Journal of the Chemical Society, 3493 -3494, 1958 etc.] or the like.
  • Step 11 Compound (a-15) can be produced in the same manner as in production method 1, step 2 using compound (a-14).
  • Compound (a-16) can be prepared by a known method using compound (a-15) [for example, Experimental Chemistry Course, 5th Edition, Volume 13, p. 341, Maruzen Co., Ltd. (2005), Bioorg. Med. Chem. Lett., 11, 5059-5068, 2003, etc.], or the like.
  • Compound (a-18) is prepared by reacting compound (a-16) without solvent or in a solvent, optionally in the presence of 1 to 30 equivalents of a base, at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used. It can be produced by reacting with ⁇ 10 equivalents of compound (a-17) for 5 minutes to 72 hours.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, potassium tert-butoxide, diisopropylethylamine, DBU and the like.
  • solvent examples include dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, acetone, water, and the like. These are used alone or in combination.
  • Compound (a-17) can be obtained as a commercial product.
  • Process 14 Compound (a-19) can be obtained by using, for example, Protective Groups in Organic Synthesis, TW Greene, John Wiley & It can be produced by a deprotection reaction of phthalimide as described in, for example, John Wiley & Sons Inc. (1981).
  • Process 15 Compound (a-21) is obtained by reacting compound (a-19) in the presence of 1 to 20 equivalents of a base in a solvent at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used. It can be produced by reacting with a-20) for 5 minutes to 72 hours.
  • Examples of the base include potassium acetate, sodium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate, diisopropylethylamine, 1,8-diazabicyclo [5.4. .0] -7-Undecene (DBU) and the like.
  • DBU 1,8-diazabicyclo [5.4. .0] -7-Undecene
  • solvent examples include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, NMP, acetone, water, and the like. These may be used alone or in combination.
  • Compound (a-20) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course, 5th Edition, Volume 13, p. 341, Maruzen Co., Ltd. (2005)] or the like. be able to.
  • Step 16 Compound (a-22) can be produced in the same manner as in production method 1, step 3 using compound (a-21).
  • Step 17 Compound (Id) can be obtained using Compound (a-22), for example, Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons, It can be produced according to the method for removing a protecting group described in, for example, John Wiley & Sons Inc. (1981).
  • Manufacturing method 5 Compound (a-22) of Production Method 4 can also be produced according to the following steps. (Wherein P 3 represents an amino-protecting group such as 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl, etc., and R 1 , R 4 , R 5 , R 6 , P 2 , V 2 , X And Y are as defined above)
  • Process 18 Compound (a-23) is obtained using, for example, Protective Groups in Organic Synthesis, Green (TW Greene), using Compound (a-19) obtained in Step 14 of Production Method 4. ) By John Wiley & Sons Inc. (1981), etc.
  • Step 19 Compound (a-24) can be produced in the same manner as in production method 1, step 3 using compound (a-23).
  • Compound (a-25) can be obtained by using, for example, Protective Groups in Organic Synthesis, TW Greene, John Wiley & It can be produced according to the protecting group removal method described in, for example, John Wiley & Sons Inc. (1981).
  • Step 21 Compound (a-22) can be produced in the same manner as in production method 4, step 15 using compound (a-25).
  • the intermediates and target compounds in each of the above production methods should be isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Can do.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • Some of the compounds (I), (II) and (IIa) used in the present invention may have stereoisomers such as geometric isomers and optical isomers, tautomers and the like.
  • the invention includes all possible isomers, including these, and mixtures thereof.
  • a part or all of each atom in the compound (I), (II) or (IIa) used in the present invention may be replaced by a corresponding isotope atom, and the present invention relates to these isotope atoms. It also includes substituted compounds.
  • a part or all of the hydrogen atoms in the compound (I), (II) or (IIa) used in the present invention may be a hydrogen atom having an atomic weight of 2 (deuterium atom).
  • a compound in which part or all of each atom in the compound (I), (II) or (IIa) used in the present invention is replaced with a corresponding isotope atom is obtained by using a commercially available building block. It can be manufactured by a method similar to the manufacturing method.
  • a compound in which part or all of the hydrogen atoms in the compound (I) are replaced with deuterium atoms is, for example, 1) a method of deuterating carboxylic acid or the like under basic conditions using deuterium peroxide (For example, see US Pat. No. 3,849,458), 2) A method of deuterating alcohol, carboxylic acid, etc.
  • compound (I), (II) or (IIa) used in the present invention when it is desired to obtain a salt of compound (I), (II) or (IIa) used in the present invention, when compound (I), (II) or (IIa) is obtained in the form of a salt, it may be purified as it is. When obtained in a free form, the compound (I), (II) or (IIa) used in the present invention is dissolved or suspended in a suitable solvent, and an acid or base is added to form a salt. Isolated and purified.
  • the pharmaceutically acceptable salt of compound (I), (II) or (IIa) used in the present invention may exist in the form of an adduct with water or various solvents. Products are also encompassed by the present invention.
  • Compound (I), (II) or (IIa) or a pharmaceutically acceptable salt thereof used in the present invention is used for diseases associated with DHODH (for example, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple Sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcerative colitis and other inflammatory bowel diseases, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis, transplantation Unilateral host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, Behcet's syndrome, conjunctivitis and other inflammatory eye symptoms, uveitis, osteoporosis, osteoarthritis , Hemangioma, ocular neovascularization
  • a dihydroorotate dehydrogenase (DHODH) inhibitor containing the tricyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be provided.
  • the compound (I), (II) or (IIa) or a pharmaceutically acceptable salt thereof used in the present invention can be administered alone as it is, but is usually provided as various pharmaceutical preparations. desirable. These pharmaceutical preparations are used for animals or humans, but are preferably used for humans.
  • the pharmaceutical preparation according to the present invention comprises a compound (I), (II) or (IIa) or a pharmaceutically acceptable salt thereof alone or as a mixture with any other therapeutic active ingredient as an active ingredient It can contain as.
  • These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (for example, diluents, solvents, excipients, etc.). Manufactured by any method.
  • administration route it is desirable to use the most effective route for treatment, and oral or parenteral such as intravenous administration can be mentioned.
  • administration forms include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution, or a mixed solution of a saline solution and a glucose solution.
  • a diluent or a solvent such as a salt solution, a glucose solution, or a mixed solution of a saline solution and a glucose solution.
  • the dose and frequency of administration of the compound (I), (II) or (IIa) or a pharmaceutically acceptable salt thereof used in the present invention are determined depending on the dosage form, patient age, body weight, nature of the condition to be treated or Although it depends on the severity, etc., in the case of oral administration, it is usually administered once or several times a day in the range of 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult. In the case of parenteral administration such as intravenous administration, 0.001 to 1000 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.
  • a disease involving a dihydroorotate dehydrogenase comprising a tricyclic compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • DHODH dihydroorotate dehydrogenase
  • Prophylactic and / or therapeutic agents are provided.
  • Prevention refers to substantially reducing the likelihood or severity of a disease state or biological sign thereof, or delaying the onset of such a disease state or biological sign, and the like. The same applies to the following prevention.
  • an effective amount of a tricyclic compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject (preferably a subject in need thereof).
  • a method of preventing and / or treating a disease involving dihydroorotate dehydrogenase (DHODH) is provided, comprising a step.
  • This subject includes animals other than humans, but preferably humans. The same applies to the following objects.
  • the tricyclic compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of diseases involving dihydroorotate dehydrogenase (DHODH) Salt is provided.
  • a tricyclic compound of formula (I) or a pharmaceutical thereof in the manufacture of a medicament for the prevention and / or treatment of a disease involving dihydroorotate dehydrogenase (DHODH), a tricyclic compound of formula (I) or a pharmaceutical thereof An acceptable salt is provided.
  • DHODH dihydroorotate dehydrogenase
  • a pharmaceutical composition comprising a tricyclic compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of diseases involving DHODH Things.
  • the pharmaceutical composition is prepared as an oral preparation or a parenteral preparation according to a conventional method using additives that are acceptable for formulation.
  • the pharmaceutical is an oral preparation, it should be in the form of a solid preparation such as a tablet, powder, fine granule, granule, capsule, pill or sustained release, or a liquid preparation such as a solution, suspension or emulsion. Can take.
  • additives that are acceptable for formulation include, for example, excipients, stabilizers, preservatives, wetting agents, emulsifiers, lubricants, sweeteners, coloring agents, fragrances, buffers, antioxidants. Agents, pH adjusters and the like. The same applies to the following pharmaceutical compositions.
  • a tricyclic compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of diseases involving DHODH.
  • a medicament containing a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof for use as a medicament there is provided a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of a disease involving DHODH A pharmaceutical composition comprising a salt is provided.
  • a prophylactic or therapeutic agent for cancer comprising as an active ingredient a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof.
  • an effective amount of a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof is administered to a subject (preferably requiring it).
  • a method of preventing and / or treating cancer comprising the step of administering to a subject).
  • a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of cancer Is provided.
  • a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and / or treatment of cancer is provided.
  • the cancer is preferably Ewing sarcoma.
  • a dihydroorotate dehydrogenase comprising a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • DHODH dihydroorotate dehydrogenase
  • an effective amount of a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof is administered to a subject (preferably requiring it).
  • DHODH dihydroorotate dehydrogenase
  • a tricyclic compound represented by formula (II) or formula (IIa) for use in prevention and / or treatment of a disease involving dihydroorotate dehydrogenase (DHODH) Or a pharmaceutically acceptable salt thereof is provided.
  • a tricycle represented by formula (II) or formula (IIa) in the manufacture of a medicament for the prevention and / or treatment of a disease involving dihydroorotate dehydrogenase (DHODH) There is provided the use of a sex compound or a pharmaceutically acceptable salt thereof.
  • a tricyclic compound represented by formula (II) or formula (IIa) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of a disease involving DHODH The use of salt is provided.
  • the disease involving DHODH is not particularly limited as long as it can be prevented and / or treated by inhibiting DHODH, but preferably rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus , Multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, ulcerative colitis and other inflammatory bowel diseases, Crohn's disease, Reiter syndrome, fibromyalgia, chronic pancreatitis , Graft-versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, Behcet's syndrome, conjunctivitis and other inflammatory eye symptoms, uveitis, osteoporosis, deformity Osteoarthritis, hemangioma, ocular neo
  • Example 1 6-Chloro-1- (4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl) -1,3,4,9-tetrahydropyrano [3,4-b] indole (Compound 1)
  • 2- (5-Chloro-1H-indol-3-yl) ethanol (100 mg, 0.511 mmol) was dissolved in toluene (1 mL) and dioxane (1 mL), and commercially available 4- (5-methyl-1, 2,4-oxadiazol-3-yl) benzaldehyde (106 mg, 0.562 mmol) and tris (trifluoromethanesulfonic acid) bismuth (III) (33.5 mg, 0.0511 mmol) were added, and the mixture was stirred at 50 ° C.
  • Example 2 6-Chloro-1- (4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl) -1,3,4,9-tetrahydropyrano [3,4-b] indole (Compounds 2a and 2b)
  • CHIRALPAK registered trademark
  • Example 3 Process 1 4- (1,3-Dioxolan-2-yl) benzonitrile (Compound 3-1) 4-Formylbenzonitrile (5.0 g, 38 mmol) was dissolved in toluene (100 mL), and ethylene glycol (7.20 g, 114 mmol) and p-toluenesulfonic acid (0.065 g, 0.38 mmol) were added. Stir for 16 hours.
  • Process 2 4- (1,3-Dioxolan-2-yl) -N'-hydroxybenzimidoamide (Compound 3-2)
  • Compound 3-1 (6.5 g, 37 mmol) was dissolved in ethanol (100 mL), triethylamine (25 mL, 185 mmol) and hydroxylamine hydrochloride (12.8 g, 185 mmol) were added, and the mixture was heated at 80 ° C. for 4 hours. Stir. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 3-2 (7.50 g, 36 mmol, 97%).
  • Process 3 3- (4- (1,3-Dioxolan-2-yl) phenyl) -5-((methylthio) methyl) -1,2,4-oxadiazole (Compound 3-3)
  • Methylthioacetic acid (1.5 g, 14.15 mmol) was dissolved in dichloromethane (40 mL), DMF (1 drop) and oxalyl chloride (8.9 g, 70.7 mmol) were added, and the mixture was stirred at room temperature for 2 hr.
  • the reaction solution was evaporated under reduced pressure, the obtained residue was dissolved in pyridine (2 mL), compound 3-2 (1.5 g, 12.1 mmol) was added, and the mixture was stirred at 80 ° C. for 6 hr.
  • Process 4 3- (4- (1,3-Dioxolan-2-yl) phenyl) -5-((methylsulfonyl) methyl) -1,2,4-oxadiazole (Compound 3-4)
  • Compound 3-3 (0.70 g, 9.68 mmol) was dissolved in dichloromethane (30 mL), m-chloroperbenzoic acid (1.08 g, 6.29 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 3-4 (0.35 g, 1.12 mmol, 44%).
  • Process 5 4- (5-((methylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) benzaldehyde (Compound 3-5)
  • Compound 3-4 (0.30 g, 0.968 mmol) was dissolved in 2 mol / L hydrochloric acid (15 mL) and stirred at 70 ° C. for 2 hours.
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography to obtain compound 3-5 (0.25 g, 0.93 mmol, 84%).
  • Example 4 Process 1 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) benzonitrile (Compound 4-1) 2- (5-Bromo-1H-indol-3-yl) ethan-1-ol (1.00 g, 4.16 mmol) was dissolved in toluene (6 mL) and 4-cyanobenzaldehyde (0.6 g, 4.5 mmol) and trifluoro Bismuth (III) lomethanesulfonate (0.273 g, 0.413 mmol) was added and stirred at 100 ° C. for 6 hours.
  • Process 2 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N'-hydroxybenzimidoamide (Compound 4-2)
  • Compound 4-1 (0.40 g, 1.13 mmol) is dissolved in ethanol (5 mL), hydroxylamine hydrochloride (0.39 mg, 1.02 mmol) and triethylamine (0.76 ml, 5.68 mmol) are added, and the mixture is stirred at 70 ° C. for 6 hours. did.
  • Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 4-2 (0.35 g, 0.909 mmol, 80%).
  • Process 3 3- (3- (4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) phenyl) -1,2,4-oxadiazole- 5-yl) propan-2-yl acetate (compound 4-3)
  • Compound 4-2 (0.15 g, 0.389 mmol) was dissolved in pyridine (2 mL), 2-acetoxyisobutyryl chloride (0.067 g, 0.405 mmol) was added, and the mixture was stirred at 80 ° C. for 6 hr.
  • Process 4 2- (3- (4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) phenyl) -1,2,4-oxadiazole- 5-yl) propan-2-ol (compound 4)
  • Compound 4-3 (0.06 g, 0.123 mmol) was dissolved in ethanol (5 mL) and water (0.5 mL), lithium hydroxide monohydrate (0.06 g, 1.48 mmol) was added, and the mixture was stirred at room temperature for 4 hours. . Water was added to the reaction solution, and the organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 4 (0.024 g, 0.053 mmol, 44%).
  • Example 5 Process 1 3- (4-Bromo-2-fluorophenyl) -5-methyl-1,2,4-oxadiazole (Compound 5-1) 4-Bromo-2-fluoro-benzonitrile (1.00 g, 5.00 mmol) was dissolved in ethanol (5 mL), 50% aqueous hydroxylamine solution (0.631 mL, 10.0 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hr. The reaction solution was evaporated under reduced pressure, the residue was dissolved in pyridine (5 mL), acetyl chloride (0.711 mL, 10.0 mmol) was added to the mixture, and the mixture was stirred at 80 ° C. for 1 hour.
  • Example 6 Process 1 3- (4-Bromo-3-methylphenyl) -5-methyl-1,2,4-oxadiazole (Compound 6-1) 4-Bromo-3-methyl-benzonitrile (1.50 g, 7.65 mmol) was dissolved in ethanol (5 mL), 50% aqueous hydroxylamine (0.939 mL, 15.3 mmol) was added, and the mixture was refluxed for 1 hour. The reaction solution was evaporated under reduced pressure, the residue was dissolved in pyridine (5 mL), acetyl chloride (1.09 mL, 15.3 mmol) was added under ice cooling, and the mixture was refluxed for 2 hours.
  • Example 7 Process 1 2-Chloro-5- (1,3-dioxolan-2-yl) pyridine (Compound 7-1) Dissolve 6-chloronicotinaldehyde (3.00 g, 21.2 mmol) in toluene (20 mL), add ethylene glycol (4.73 mL, 85 mmol) and tosylic acid monohydrate (403 mg, 2.12 mmol), and mix. The solution was refluxed overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 7-1 (3.29 g, 84%).
  • Process 4 3- (5- (1,3-Dioxolan-2-yl) pyridin-2-yl) -5-methyl-1,2,4-oxadiazole (Compound 7-4)
  • Compound 7-3 (536 mg, 2.13 mmol) is dissolved in acetonitrile (5 mL), 1 mol / L THF solution (2.13 mL, 2.13 mmol) of tetrabutylammonium fluoride is added, and the mixture is refluxed for 2 hours. It was. Water was added to the mixture, and the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 7-4 (470 mg, 94%).
  • Process 5 6- (5-Methyl- (1,2,4-oxadiazol-3-yl) nicotinaldehyde (Compound 7-5)
  • Compound 7-4 (470 mg, 2.02 mmol) was dissolved in THF (5 mL), 1 mol / L hydrochloric acid (5.04 mL, 5.04 mmol) was added, and the mixture was stirred at room temperature overnight.
  • the organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give compound 7-5 (313 mg, 82%).
  • Example 8 6-Bromo-1- (4- (5-methyl-1,3,4-oxadiazol-3-yl) phenyl) -1,3,4,9-tetrahydropyrano [3,4-b] indole (Compound 8)
  • compound 8 was obtained using 4- (5-methyl-1,3,4-oxadiazol-2-yl) benzaldehyde.
  • Example 9 Process 1 2-Chloro-N'-hydroxyacetimidoamide (Compound 9-1) 2-Chloroacetonitrile (5.00 g, 66.6 mmol) is dissolved in water (15 mL), hydroxylamine hydrochloride (4.85 g, 69.9 mmol) and sodium carbonate (3.52 g, 33.3 mmol) are added at 0 ° C, and at room temperature. Stir for 1 hour. The organic layer was extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product compound 9-1 (4.80 g, 44.4 mmol, 66%).
  • Process 3 4- (3- (Chloromethyl) -1,2,4-oxadiazol-5-yl-benzaldehyde (Compound 9-3)
  • the crude product compound 9-2 (0.50 g, 2.08 mmol) was dissolved in DMF (5 mL) and stirred at 120 ° C. for 3 hours.
  • the reaction mixture was opened in ice, and the precipitate was collected by filtration to give compound 9-3 (0.32 g, 1.46 mmol, 70%).
  • Compound 9-3 (0.75 g, 3.37 mmol) was dissolved in toluene (20 mL), and ethylene glycol (0.57 mL, 10.13 mmol) and p-toluenesulfonic acid (0.06 g, 0.337 mmol) were added. Stir for hours.
  • Process 5 5- (4- (1,3-Dioxolan-2-yl) phenyl) -3- (methylthio) methyl-1,2,4-oxadiazole (Compound 9-5)
  • the crude product compound 9-4 (1.00 g, 3.74 mmol) was dissolved in DMF (15 mL), sodium methanethiol (1.31 g, 18.72 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the deposited precipitate was collected by filtration to give compound 9-5 (0.80 g, 2.87 mmol, 77%).
  • Process 6 5- (4- (1,3-Dioxolan-2-yl) phenyl) -3-((methylsulfonyl) methyl) -1,2,4-oxadiazole (Compound 9-6)
  • Compound 9-5 (0.80 g, 2.87 mmol) was dissolved in dichloromethane (30 mL), m-chloroperbenzoic acid (0.99 g, 5.75 mmol) was added, and the mixture was stirred at room temperature for 18 hours.
  • the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 9-6 (0.70 g, 2.25 mmol, 78%).
  • Process 7 4- (3-((methylsulfonyl) methyl) -1,2,4-oxadiazol-5-yl) benzaldehyde (Compound 9-7)
  • Compound 9-6 (0.70 g, 2.25 mmol) was dissolved in THF (10 mL), 2 mol / L hydrochloric acid (7 mL) was added, and the mixture was stirred at 75 ° C. for 2 hr. Water was added to the reaction mixture, and the precipitate was collected by filtration to give compound 9-7 (0.50 g, 1.87 mmol, 84%).
  • LCMS (MM): m / z 267 [M + H] + .
  • Example 10 6-Bromo-1- (4- (3-((ethylsulfonyl) methyl) -1,2,4-oxadiazol-5-yl) phenyl) -1,3,4,9-tetrahydropyrano [3 , 4-b] indole (compound 10)
  • compound 10 was obtained.
  • LCMS (MM): m / z 503 [M + H] + .
  • Example 11 Process 1 5- (4- (1,3-Dioxolan-2-yl) phenyl) -3-methoxymethyl-1,2,4-oxadiazole (Compound 11-1) Compound 11-1 (0.06 g, 0.229 mmol, 61%) was obtained using sodium methoxide in the same manner as in Step 5 of Example 9.
  • Example 12 Process 1 6-Bromo-1- (4- (3- (chloromethyl) -1,2,4-oxadiazol-5-yl) phenyl) -1,3,4,9-tetrahydropyrano [3,4- b] indole (compound 12-1)
  • compound 12-1 (0.25 g, 0.272 mmol, 68%) was obtained using compound 9-3.
  • Process 2 1- (5- (4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) phenyl) -1,2,4-oxadiazole- 3-yl) -N, N-dimethylmethanamine (Compound 12)
  • Compound 12-1 (0.20 g, 0.45 mmol) was dissolved in THF (3 mL), 2 mol / L THF solution (2.20 mL, 4.50 mmol) of dimethylamine was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the deposited precipitate was collected by filtration to obtain Compound 12 (0.13 g, 0.286 mmol, 64%).
  • Example 13 Process 1 2- (5-Bromo-1H-indol-3-yl) ethane-1,1-d 2 -1-ol (Compound 13-1) 2- (5-Bromo-1H-indol-3-yl) acetic acid (500 mg, 1.97 mmol) is dissolved in methanol (5 mL), concentrated sulfuric acid (10.5 ⁇ L, 0.197 mmol) is added, and the mixture is mixed with 3 Reflux for hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 14 Process 1 1- (5-Bromo-1H-indol-3-yl) -2-hydroxyethanone (Compound 14-1) 5-Bromo-1H-indole (2.00 g, 10.2 mmol) was dissolved in dioxane (30 mL), acetoxyacetyl chloride (4.39 mL, 40.8 mmol) was added under ice cooling, and the mixture was stirred at 100 ° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, the organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 14-1 (573 mg, 22%).
  • Example 15 Process 1 2- (5-Bromo-1H-indol-3-yl) -N-methoxy-N-methylacetamide (Compound 15-1) 2- (5-Bromo-1H-indol-3-yl) acetic acid (500 mg, 1.97 mmol) was dissolved in DMF (5 mL), N, O-dimethylhydroxylamine hydrochloride (384 mg, 3.94 mmol), Triethylamine (0.549 mL, 3.94 mmol), EDC hydrochloride (754 mg, 3.94 mmol) and 1-hydroxybenzotriazole monohydrate (603 mg, 3.94 mmol) were added and the mixture was stirred at room temperature for 3 hours.
  • Process 2 1- (5-Bromo-1H-indol-3-yl) propan-2-ol (Compound 15-2)
  • Compound 15-1 (582 mg, 1.96 mmol) was dissolved in THF (10 mL), and a 1 mol / L THF solution (5.94 mL, 5.88 mmol) of methylmagnesium bromide was added at ⁇ 78 ° C. under an argon atmosphere. Stir for hours. Water was added to the reaction solution, and the organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 16 Process 1 2-Fluoro-4- (pyrimidin-2-yl) benzaldehyde (Compound 16-1) 4-Bromo-2-fluorobenzaldehyde (200 mg, 0.985 mmol) dissolved in toluene (5 mL), lithium chloride (418 mg, 9.85 mmol), 2- (tributylstannyl) pyrimidine (436 mg, 1.182 mmol) And bis (triphenylphosphine) palladium (II) chloride (69.1 mg, 0.099 mmol) were added and the mixture was refluxed for 2 hours.
  • Example 17 Process 1 4- (3-Fluoropyridin-2-yl) benzaldehyde (Compound 17-1) 4-Formylphenylboronic acid (0.5 g, 2.875 mmol) was dissolved in DME (10 mL) and water (2 mL), tetrakis (triphenylphosphine) palladium (0.033 g, 0.0287 mmol) and cesium carbonate (1.4 g, 4.28 mmol) was added and the mixture was stirred at 80 ° C. for 2 hours. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to give compound 17-1 (0.25 g, 1.24 mmol, 53%).
  • Example 18 Process 1 4- (pyrimidin-2-ylamino) propyl benzoate (Compound 18-1) 4-Aminobenzoic acid (1.00 g, 5.58 mmol) is dissolved in 2-propanol (15 mL), and 2-chloropyrimidine (767 mg, 6.70 mmol) and concentrated hydrochloric acid (0.349 mL, 4.18 mmol) are added. The reaction was performed at a set temperature of 120 ° C. for 2 hours using a wave synthesizer. Water was added to the reaction solution, and the organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give compound 18-1 (1.29 g, 90%).
  • Process 2 4- (Pyrimidin-2-ylamino) phenylmethanol (Compound 18-2)
  • Compound 18-1 (1.70 g, 6.61 mmol) was dissolved in toluene, and a 1 mol / L toluene solution (13.3 mL, 13.2 mmol) of isobutylaluminum hydride was added at ⁇ 78 ° C. under an argon atmosphere, followed by stirring for 1 hour.
  • a saturated aqueous Rochelle salt solution was added to the reaction solution, and the organic layer was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography to give compound 18-2 (273 mg, 21%).
  • Process 3 4- (Pyrimidin-2-ylamino) benzaldehyde (Compound 18-3) Compound 18-2 (273 mg, 1.36 mmol) was dissolved in chloroform (5 mL), desmartin periodinane (633 mg, 1.49 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 18-3 (165 mg, 61%).
  • Example 19 6-Bromo-1- (2-morpholinopyrimidin-5-yl) -1,3,4,9-tetrahydropyrano [3,4-b] indole (Compound 19) Compound 19 (21 mg, 17%) was obtained using commercially available 2-morpholinopyrimidine-5-carbaldehyde in the same manner as in Step 6 of Example 3.
  • Example 20 Process 1 6-Bromo-1- (4-nitrophenyl) -1,3,4,9-tetrahydropyrano [3,4-b] indole (Compound 20-1) 2- (5-Bromo-1H-indol-3-yl) ethan-1-ol (1.00 g, 4.16 mmol) was dissolved in toluene (30 mL) and 4-nitrobenzaldehyde (0.63 g, 4.16 mmol) and Ytterbium (III) trifluoromethanesulfonate (0.25 g, 0.416 mmol) was added, and the mixture was stirred at 100 ° C. for 6 hours.
  • Example 22 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N- (pyridin-3-ylmethyl) aniline (compound 22) In the same manner as in Example 20, compound 22 was obtained using 3-pyridinecarboxaldehyde. ESI-MS m / z: 433 (M + H) +
  • Example 23 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N- (pyridin-4-ylmethyl) aniline (Compound 23) In the same manner as in Example 20, compound 23 was obtained using 4-pyridinecarboxaldehyde. ESI-MS m / z: 433 (M + H) +
  • Example 24 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N- (thiophen-2-ylmethyl) aniline (Compound 24) In the same manner as in Example 20, compound 24 was obtained using 2-thiophenecarboxaldehyde. ESI-MS m / z: 439 (M + H) +
  • Example 25 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N- (thiophen-3-ylmethyl) aniline (Compound 25) In the same manner as in Example 20, compound 25 was obtained using 3-thiophenecarboxaldehyde. ESI-MS m / z: 439 (M + H) +
  • Example 26 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N- (furan-2-ylmethyl) aniline (Compound 26) In the same manner as in Example 20, compound 26 was obtained using 2-furancarboxaldehyde. ESI-MS m / z: 423 (M + H) +
  • Example 27 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N- (furan-3-ylmethyl) aniline (compound 27) In the same manner as in Example 20, compound 27 was obtained using 3-furancarboxaldehyde. ESI-MS m / z: 423 (M + H) +
  • Example 28 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N-((1-methyl-1H-pyrazol-4-yl) methyl) Aniline (Compound 28) In the same manner as in Example 20, compound 28 was obtained using 1-methyl-1H-pyrazole-4-carboxaldehyde. ESI-MS m / z: 437 (M + H) +
  • Example 29 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N- (cyclopentylmethyl) aniline (Compound 29)
  • compound 29 was obtained using cyclopentanecarboxaldehyde.
  • Example 30 4- (6-Bromo-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -N- (cyclopropylmethyl) aniline (Compound 30) Compound 30 was obtained using cyclopropanecarboxaldehyde in the same manner as in Example 20. ESI-MS m / z: 397 (M + H) +
  • Example 33 4-chlorophenyl 8-bromo-4- (4- (pyrimidin-2-yl) phenyl) -4,5-dihydro- [1,2] oxazino [4,5-b] indole-3 (1H ) -Carboxylate (compound 33)
  • Compound 3A (0.126 g, 0.254 mmol) obtained in Reference Example 3 was dissolved in dichloromethane (2 mL), 4- (pyrimidin-2-yl) benzaldehyde (0.056 g, 0.305 mmol), boron trifluoride-ethyl ether complex.
  • Example 34 Methyl 8-chloro-4- (4- (4-methoxypyrimidin-2-yl) phenyl) -4,5-dihydro- [1,2] oxazino [4,5-b] indole-3 (1H) -Carboxylate (Compound 34) Using 5-chloro-1H-indole-3-carbaldehyde, in the same manner as in Reference Example 1, tert-butyl 5-chloro-3-((((methoxycarbonyl) amino) oxy) methyl) -1H-indole- 1-carboxylate was obtained, and compound 34 (0.0207 g, 16%) was obtained in the same manner as in Example 1 using 4- (4-methoxypyrimidin-2-yl) benzaldehyde.
  • Example 35 Process 1 3- (4- (1,3-Dioxolan-2-yl) phenyl) -5- (trichloromethyl) -1,2,4-oxadiazole (Compound 35-1)
  • Compound 3-3 (0.5 g, 2.40 mmol) obtained in Step 3 of Example 3 was dissolved in pyridine (15 mL), 2,2,2-trichloroacetyl chloride was added, and the mixture was refluxed for 3 hours.
  • the reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 35-1 (0.315 g, 39%).
  • Process 2 3- (4- (1,3-Dioxolan-2-yl) phenyl) -5- (2-methoxyethoxy) -1,2,4-oxadiazole (Compound 35-2)
  • Compound 35-1 (0.300 g, 0.894 mmol) was dissolved in DMF (3 mL), 2-methoxyethanol (0.127 mL, 1.61 mmol) and sodium hydride (0.054 g, 1.34 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Stir.
  • Process 3 4- (5- (2-methoxyethoxy) -1,2,4-oxadiazol-3-yl) benzaldehyde (Compound 35-3) Compound 35-2 (0.169 g, 0.578 mmol) is dissolved in methanol (1 mL) and THF (1 mL), 2 mol / L-hydrochloric acid (0.029 mL, 0.058 mmol) is added, and the mixture is stirred at room temperature for 1 hour. Stir.
  • Example 36 Methyl 8-chloro-4- (4- (5-methoxy-1,2,4-oxadiazol-3-yl) phenyl) -4,5-dihydro- [1,2] oxazino [4,5 -b] indole-3 (1H) -carboxylate (compound 36)
  • Compound 36 (0.0256 g, 21%) was obtained in the same manner as in Example 35 except that 2-methoxyethanol and sodium hydride in Step 2 of Example 35 were replaced with sodium methoxide.
  • Example 37 Process 1 4- (5-Methoxypyrimidin-2-yl) benzaldehyde (Compound 37-1) Compound 37-1 was obtained from 2-chloro-5-methoxypyrimidine in the same manner as in Example 14 described in US6613747B2.
  • Example 38 Process 1 3-Methyl-4- (4-methylpyrimidin-2-yl) benzaldehyde (Compound 38-1) Compound 38-1 was obtained in the same manner as in Example 14 described in US6613747B2, using 2-chloro-3-methylpyrimidine and (4-formyl-2-methylphenyl) boronic acid.
  • Example 39 Process 1 3-((9H-Fluoren-9-yl) methyl) 5-tert-butyl 8-bromo-4- (4- (4-methylpyrimidin-2-yl) phenyl)-[1,2] oxazino [ 4,5-b] indole-3,5 (1H, 4H) -dicarboxylate (Compound 39-1)
  • Compound 4A (0.5 g, 0.887 mmol) obtained in Reference Example 4 was dissolved in acetonitryl (7 mL), 4- (4-methylpyrimidin-2-yl) benzaldehyde (0.229 g, 1.15 mmol), iodinated Sodium (0.399 g, 2.66 mmol) and trimethylchlorosilane (0.34 mL, 2.66 mmol) were added at ⁇ 40 ° C., and the mixture was stirred for 3.5 hours while slowly warming to room temperature.
  • Process 4 1- (8-Bromo-4- (4- (4-methylpyrimidin-2-yl) phenyl)-[1,2] oxazino [4,5-b] indole-3 (1H, 4H, 5H) -Yl) propan-1-one (compound 39)
  • Compound 39-3 (0.013 g, 0.023 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.087 mL, 1.13 mmol) was added, and the mixture was stirred at room temperature for 14 hours.
  • Example 41 Process 1 4- (1,2,4-Triazin-3-yl) benzaldehyde (Compound 41-1) 4- (Tributylstayl) benzaldehyde (2.05 g, 5.19 mmol) was dissolved in 1,2-dimethoxyethane (20.0 mL), and copper (I) bromide dimethyl sulfide complex (1.07 g, 5.19 mmol), 3- (Methylthio) -1,2,4-triazine (0.300 g, 2.36 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.272 g, 0.236 mmol) were added and stirred at 100 ° C.
  • Example 42 Process 1 3-((9H-Fluoren-9-yl) methyl) 5-tert-butyl 8-bromo-4- (4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl )-[1,2] oxazino [4,5-b] indole-3,5 (1H, 4H) -dicarboxylate (compound 42-1)
  • Compound 4A (2.7 g, 4.79 mmol) obtained in Reference Example 4 was dissolved in acetonitryl (25 mL) and commercially available 4- (5-methyl-1,2,4-oxadiazol-3-yl) Benzaldehyde (1.08 g, 5.75 mmol), sodium iodide (2.16 g, 14.4 mmol) and trimethylchlorosilane (1.84 mL, 14.4 mmol) were added at ⁇ 40 ° C., and the mixture was stirred for 3 hours while slowly warming to room temperature.
  • Example 43 (8-Bromo-4- (4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl)-[1,2] oxazino [4,5-b] indole-3 (1H, 4H, 5H) -yl) (furan-2-yl) methanone (Compound 43)
  • Compound 43 was obtained in the same manner as in Example 40, using Compound 42-2 and Furan-2-carbonyl chloride.
  • Example 44 1- (8-Bromo-4- (4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl)-[1,2] oxazino [4,5-b] indole -3 (1H, 4H, 5H) -yl) -2,2,2-trifluoroethanone (Compound 44)
  • Compound 44 was obtained in the same manner as Example 40 using Compound 42-2 and trifluoroacetic anhydride.
  • Example 45 8-Bromo-4- (4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl) -1,3,4,5-tetrahydro- [1,2] oxazino [ 4,5-b] indole (compound 45)
  • Compound 42-2 (0.03 g, 0.059 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.452 mL, 5.87 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • To the mixture was added saturated aqueous sodium hydrogen carbonate, and the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 48 Process 1 3- (4- (1,3-Dioxolan-2-yl) phenyl) -5-isopropyl-1,2,4-oxadiazole (Compound 48-1)
  • Compound 3-2 (0.800 g, 3.84 mmol) obtained in Step 2 of Example 3 was dissolved in pyridine (10 mL), isobutyryl chloride (0.815 g, 7.69 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. .
  • Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 48-1 (0.500 g, 1.92 mmol, 50%).
  • Process 2 4- (5-Isopropyl-1,2,4-oxadiazol-3-yl) benzaldehyde (Compound 48-2) Compound 48-1 (0.500 g, 1.92 mmol) was dissolved in 2 mol / L hydrochloric acid and stirred at 80 ° C. for 5 hours. After allowing to cool, the reaction solution was neutralized by adding saturated aqueous sodium hydrogen carbonate, and the organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. -2 (0.300 g, 1.38 mmol, 72%) was obtained.
  • Example 49 Methyl 8-bromo-4- (4- (5-ethyl-1,2,4-oxadiazol-3-yl) phenyl) -4,5-dihydro- [1,2] oxazino [4,5 -b] indole-3 (1H) -carboxylate (compound 49)
  • compound 49 was obtained from 4- (5-ethyl-1,2,4-oxadiazol-3-yl) benzaldehyde.
  • Example 50 Methyl 8-bromo-4- (4- (5- (tert-butyl) -1,2,4-oxadiazol-3-yl) phenyl) -4,5-dihydro- [1,2] oxazino [4,5-b] indole-3 (1H) -carboxylate (compound 50)
  • compound 50 was obtained using 4- (5- (tert-butyl) -1,2,4-oxadiazol-3-yl) benzaldehyde.
  • Example 52 Methyl 8-bromo-4- (4- (3- (methoxymethyl) -1,2,4-oxadiazol-5-yl) phenyl) -4,5-dihydro- [1,2] oxazino [ 4,5-b] indole-3 (1H) -carboxylate (Compound 52)
  • Compound 52 was obtained in the same manner as in Example 31 using Compound 11-2 obtained in Step 2 of Example 11.
  • Example 54 Methyl 8-bromo-4- (4- (5-((ethylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) phenyl) -4,5-dihydro- [1,2 ] Oxazino [4,5-b] indole-3 (1H) -carboxylate (Compound 54)
  • Process 1 4- (5-((Ethylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) benzaldehyde (Compound 54-1) In the same manner as in Step 1 to Step 5 of Example 3, Compound 54-1 was obtained.
  • Example 55 Formulation Example 1 (tablet) A tablet having the following composition is prepared by a conventional method. Compound 1 (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, and 10% aqueous solution (120 g) of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Magnesium stearate (1.2 g) was added to this, mixed, and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a 8 mm diameter punch to produce tablets (20 active ingredients per tablet). mg). Formulation Compound 1 20 mg Lactose 143.4 mg Potato starch 30 mg Hydroxypropylcellulose 6 mg Magnesium stearate 0.6 mg 200 mg
  • Example 56 Formulation Example 2 (Injection) An injection having the following composition is prepared by a conventional method. Compound 1 (1 g) and D-mannitol (5 g) are added to and mixed with distilled water for injection. Further, hydrochloric acid and sodium hydroxide aqueous solution are added to adjust the pH to 6, and then with distilled water for injection. Bring the total volume to 1000 mL. The resulting mixture is aseptically filled in 2 mL glass vials to give an injection (containing 2 mg of active ingredient per vial). Formulation Compound 1 2 mg D-mannitol 10 mg Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount distilled water for injection appropriate amount 2.00 mL
  • Test Example 1 Evaluation of cell viability of human Ewing sarcoma cell line
  • Human Ewing sarcoma cell line A-673 (purchased from ATCC) having the EWS / FLI1 fusion gene was suspended in the culture medium so that there were 5000 cells per mL.
  • a 96-well plate was inoculated with 0.1 mL per well and cultured at 37 ° C. under 5% CO 2 for 24 hours.
  • a compound dissolved in DMSO was diluted with DMSO to prepare a solution having a concentration 1000 times the final concentration.
  • the prepared DMSO solution was diluted with a medium to prepare a solution having a concentration 10 times higher than the final concentration, and 0.011 mL per well was added to a plate seeded with cells.
  • the cells were cultured at 37 ° C. under 5% CO 2 for 120 hours. After completion of the culture, the cell viability of each well was determined.
  • the survival rate of the wells to which the compound was added was determined by setting the wells in which only DMSO was added to the cells as the survival rate of 100% and the wells in which the cells were not added as the survival rate of 0%. For each compound, the survival rate was evaluated at 8 concentrations or more, using a 4-parameter logistic model, Fitting was performed using the following formula to determine the 50% inhibitory concentration (IC 50 ). In the above formula, x means compound concentration, A means minimum asymptote, B means Hill coefficient, C means inflection point, and D means maximum asymptote. The results are shown in Table 3.
  • compound (I), (II) or (IIa) or a pharmaceutically acceptable salt thereof is considered useful for the prevention and / or treatment of cancer such as Ewing sarcoma.
  • Mitochondrial fractions were prepared from A-673 Ewing sarcoma cells using Q proteome Mitochondria Isolation Kit.
  • the prepared mitochondrial fraction was diluted with a phosphate buffer (pH 7.4) to a protein concentration of 0.25 mg / mL, and an evaluation compound or acetonitrile (control) was added up to 1.25 vol%.
  • 40 ⁇ L of this solution was added to a 96-well plate and preincubated at 37 ° C. for 2 minutes.
  • L-dihydroorotic acid was adjusted to 500 ⁇ mol / L with phosphate buffer (pH 7.4), and the reaction was started by adding 10 ⁇ L to each well.
  • acetonitrile containing 3 ⁇ mol / L of 5-fluoroorotic acid (internal standard) was added to stop the reaction. After stirring, the mixture was allowed to stand on ice for about 10 minutes and centrifuged (5,000 ⁇ g, 5 minutes, 4 ° C.). 120 ⁇ L of the supernatant was collected, 20 ⁇ L of which was diluted with 180 ⁇ L of 70 vol% acetonitrile.
  • the amount of orotic acid (OA) produced by the enzymatic reaction was determined by LC / MS / MS analysis. The production rate of OA was calculated according to the following formula.
  • IC 50 values were calculated by fitting the OA production rate to the Xlfit model 205 sigmoid dose response (4-parameter logistic model). The results are shown in Table 4.

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Abstract

La présente invention concerne : un inhibiteur de DHODH qui contient un composé tricyclique représenté par la formule (I) : ou un sel pharmaceutiquement acceptable de celui-ci ou un composé similaire comme principe actif ; et d'autres. [Dans la formule, R3a et R3b représentent indépendamment un atome d'hydrogène ou un groupe similaire ; R4 représente un groupe hétérocyclique aromatique qui peut porter un substituant ou un groupe similaire ; R5 représente un atome d'hydrogène ou un groupe similaire ; X et Y représentent indépendamment un atome d'azote ou un groupe similaire ; Z représente un atome d'oxygène ou un groupe similaire ; n représente 0 ou 1 ; R6 représente un groupe alkyle inférieur qui peut porter un substituant ou un groupe similaire ; A représente un atome d'oxygène ou un groupe similaire ; B représente CR2aR2b (dans lequel R2a et R2b représentent indépendamment un atome d'hydrogène ou un groupe similaire) ou un groupe similaire ; et R1 est absent ou représente un atome d'hydrogène ou un groupe similaire.]
PCT/JP2016/082100 2015-10-30 2016-10-28 Composé tricyclique WO2017073743A1 (fr)

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WO2021226478A1 (fr) * 2020-05-08 2021-11-11 Ptc Therapeutics, Inc. Inhibiteur de dhodh pour le traitement de la covid-19
US11427600B2 (en) 2014-06-27 2022-08-30 Nogra Pharma Limited Aryl receptor modulators and methods of making and using the same
US11458126B2 (en) 2017-08-01 2022-10-04 Ptc Therapeutics, Inc. DHODH inhibitor for use in treating hematologic cancers
US11613538B2 (en) 2009-05-27 2023-03-28 Ptc Therapeutics, Inc. Method of inhibiting or reducing a viral infection

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Publication number Priority date Publication date Assignee Title
US11613538B2 (en) 2009-05-27 2023-03-28 Ptc Therapeutics, Inc. Method of inhibiting or reducing a viral infection
US11427600B2 (en) 2014-06-27 2022-08-30 Nogra Pharma Limited Aryl receptor modulators and methods of making and using the same
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WO2021226478A1 (fr) * 2020-05-08 2021-11-11 Ptc Therapeutics, Inc. Inhibiteur de dhodh pour le traitement de la covid-19

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