WO2014157382A1 - Inhibiteur de sphingosine kinase - Google Patents

Inhibiteur de sphingosine kinase Download PDF

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WO2014157382A1
WO2014157382A1 PCT/JP2014/058631 JP2014058631W WO2014157382A1 WO 2014157382 A1 WO2014157382 A1 WO 2014157382A1 JP 2014058631 W JP2014058631 W JP 2014058631W WO 2014157382 A1 WO2014157382 A1 WO 2014157382A1
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optionally substituted
alkyl
hydrogen atom
mono
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敦彦 早川
佳奈 岩▲崎▼
諒平 横山
郁美 白石
直之 福地
香織 久保
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味の素株式会社
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Definitions

  • the present invention relates to a compound having sphingosine kinase inhibitory activity and useful as a pharmaceutical, particularly a prophylactic and / or therapeutic agent for hyperproliferative disease, inflammatory disease or autoimmune disease.
  • Sphingolipid has recently attracted attention as one of the lipids that play an important role in vivo. It has been found that sphingolipids function not only as a major component of cell membranes but also as important signal molecules. Diseases called dyslipidemia are caused by the accumulation of certain sphingolipids in the body. Sphingolipids present on the cell membrane function to regulate cell proliferation, participate in cell growth and differentiation, act on nerves, and are associated with cell infections and malignancies. Many physiological roles of sphingolipids have not yet been elucidated, but recently, various sphingolipid metabolites such as ceramide have become known to have physiological activities such as induction of apoptosis and stimulation of cell proliferation. The possibility that lipid metabolic enzymes are closely related to the causes of various pathological conditions has been suggested (Non-patent Document 1).
  • S1P sphingosine-1-phosphate
  • S1P can be reversibly inactivated via dephosphorylation by some phosphatases, or it can be irreversibly inactivated by S1P lyase.
  • S1P is produced by intracellular organelles and the plasma membrane and then secreted. The newly produced S1P is then secreted and bound extensively by albumin and other plasma proteins.
  • GPCRs G protein coupled receptors
  • S1P via S1P1-5R have diverse biological functions including inflammatory response, cell proliferation, apoptosis, cell migration, lymphocyte migration and cell senescence Is adjusted (Non-patent Document 2).
  • S1P has been found to be an important mediator of angiogenesis and tumorigenesis.
  • One method of modulating S1P levels is to target sphingosine kinase, thereby affecting S1P biosynthesis.
  • Sphingosine kinase has been shown to promote cell proliferation in vitro and forms tumors in vivo.
  • Sphingosine kinase also confers resistance to radiation therapy and chemotherapy and is elevated in some solid tumors.
  • Sphingosine kinase inhibitors have been shown to have anticancer effects in vivo. These effects are due to inhibition of S1P production. Therefore, reducing the level of S1P by inhibiting sphingosine kinase means that it is useful for the treatment of hyperproliferative diseases such as cancer.
  • S1P has been shown to have several important effects on cells that mediate immune function. Platelets, monocytes and mast cells promote the inflammatory cascade at the site of tissue damage and secrete S1P upon activation. Activation of sphingosine kinase is required for signaling reactions because the ability of TNF- ⁇ to induce adhesion molecule expression upon activation of NF ⁇ B is mimicked by S1P and blocked by the sphingosine kinase inhibitor dimethyl sphingosine (Non-Patent Literature) 3).
  • S1P mimics TNF- ⁇ 's ability to induce COX-2 expression and PGE 2 synthesis, and SK knockdown by RNA interference blocks these responses to TNF- ⁇ (not S1P) (Non-Patent Document 4).
  • S1P also causes production of superoxide and other toxic radicals, and is also a mediator of Ca 2+ influx during neutrophil activation by TNF- ⁇ and other stimuli (Non-Patent Document 5).
  • Sphingosine kinase exists as two isoforms, sphingosine kinase 1 and sphingosine kinase 2.
  • Sphingosine kinase 1 has been shown to be activated by cytokines including TNF- ⁇ and interleukin 1 ⁇ (IL-1 ⁇ ).
  • IL-1 ⁇ interleukin 1 ⁇
  • Sphingosine kinase 1 and S1P have also been implicated in a variety of immune cell functions including mast cell degranulation, neutrophil migration, lymphocyte migration and maturation.
  • Non-patent Documents 6 and 11 Recently, it has been reported that the expression of sphingosine kinase and sphingosine kinase 1 is increased in the intestinal tracts of Crohn's disease patients and ulcerative colitis patients, respectively.
  • Non-patent Document 7, Patent Document 1 regulating or chemically suppressing sphingosine kinase 1 and S1P levels can cause inflammatory diseases (such as rheumatoid arthritis, inflammatory bowel disease (IBD: Crohn's disease, ulcerative colitis)), and autoimmunity. It can be said that this is an effective method for treating a disease (Non-patent Document 7, Patent Document 1).
  • the object of the present invention is to have sphingosine kinase inhibitory activity, particularly effective inhibitory activity against sphingosine kinase 1, and useful as a medicament, particularly a prophylactic and / or therapeutic agent for hyperproliferative diseases, inflammatory diseases or autoimmune diseases Is to provide such a compound.
  • Ring A represents an optionally substituted 5- or 6-membered aromatic ring group
  • R 1a , R 1b And R 1c Each independently, and two of them may be bonded to the same carbon atom, and may be a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, or a substituted group.
  • An optionally substituted mercapto group, an optionally substituted amino group or an acyl group, and R 1a , R 1b And R 1c At least one of is a hydroxy group or hydroxy C 1-3 Represents an alkyl group;
  • R 2a And R 2b Each independently represents a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group, or R 2a And R 2b Together with the carbon atom to which they are attached may form an optionally substituted cyclic group;
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group;
  • R 4 Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted mercapto group;
  • R 5 , R 6 And R 7 Each independently represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, an optionally substituted hydrocarbon group
  • Ring A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group;
  • R 1a , R 1b And R 1c Each independently, and two of them may be bonded to the same carbon atom, and may be a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group, an optionally substituted amino group, or an optionally substituted group.
  • R 2a And R 2b Each independently represents a hydrogen atom, a halogen atom or an optionally substituted C 1-6 An alkyl group;
  • R 3 Is a hydrogen atom, optionally substituted C 1-6 An alkyl group or an acyl group;
  • R 4 Is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 An alkyl group or optionally substituted C 1-6 An alkoxy group;
  • R 5 , R 6 And R 7 Are each independently a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 Alkyl group,
  • X 1 But CR 8 Is; X 2 And X 3 Each independently represents a nitrogen atom or CR 8 Is; R 8 Is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 Alkyl group, optionally substituted C 1-6 An alkoxy group, an amino group, or an optionally substituted mono- or di-C 1-6 An alkylamino group; n is 0, 1, 2 or 3; and the compound or salt thereof according to the above [1], wherein m is 1, 2 or 3; [17] Ring A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group; R 1a , R 1b And R 1c Each independently, and two of them may be bonded to the same carbon atom, and may be a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group, an optionally substitute
  • R 2a And R 2b Each independently represents a hydrogen atom, a halogen atom or an optionally substituted C 1-6 An alkyl group;
  • R 3 Is a hydrogen atom, optionally substituted C 1-6 An alkyl group or an acyl group;
  • R 4 Is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 An alkyl group or optionally substituted C 1-6 An alkoxy group;
  • R 5 , R 6 And R 7 Are each independently a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 Alkyl group,
  • Ring A is a group selected from the group consisting of a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thienyl group, and a thiazolyl group; R 1a , R 1b And R 1c Each independently, and two of them may be bonded to the same carbon
  • Ring A is a phenyl group or a pyridyl group;
  • R 1a , R 1b And R 1c Are each independently a hydrogen atom, a hydroxy group, or a hydroxymethyl group, and R 1a , R 1b And R 1c At least one of is a hydroxy group or a hydroxymethyl group;
  • R 2a And R 2b Are both hydrogen atoms;
  • R 3 Is a hydrogen atom or a methyl group;
  • R 4 Is a hydrogen atom;
  • R 5 , R 6 And R 7 Are each independently a hydrogen atom, a fluorine atom, C 3-10 A cycloalkyl group, C 3-10 C optionally substituted by a cycloalkyl group 1-6 Alkoxy group, C 2-6 Alkenyl group, oxo group or C 1-6 C optionally substituted by an alkyl group 3-10 Cycloalkenyl group, C 1-6 A 6-membered non-aromatic heterocycl
  • Ring A is a phenyl group, a pyridyl group or a pyrimidinyl group;
  • R 1a , R 1b And R 1c Are each independently a hydrogen atom, a hydroxy group, or a hydroxymethyl group, and R 1a , R 1b And R 1c At least one of is a hydroxy group or a hydroxymethyl group;
  • R 2a And R 2b Are both hydrogen atoms;
  • R 3 Is a hydrogen atom or a methyl group;
  • R 4 Is a hydrogen atom;
  • R 5 , R 6 And R 7 One of which is a tert-butyl group, a mono (tert-butyl) carbamoyl group, a cyclobutyloxymethyl group, a cyclopentyloxymethyl group, a cyclopentylthiomethyl group, a cyclohexen-1-yl group, a cyclopenten-1-yl group, or A
  • a pharmaceutical composition comprising the compound or a salt thereof according to any one of [1] to [26] above, and a pharmaceutically acceptable carrier, [30]
  • the pharmaceutical composition according to [30] above, wherein the inflammatory disease is inflammatory bowel disease, arthritis, rheumatism, asthma, allergy, inflammatory kidney disease, chronic obstructive pulmonary disease, periodontal disease or dermatitis , [32] The pharmaceutical composition according to [30] above, wherein the inflammatory disease is inflammatory bowel disease or rhe
  • compound (I) Since compound (I) has a sphingosine kinase inhibitory action, it is useful as a prophylactic and / or therapeutic agent for hyperproliferative diseases, inflammatory diseases or autoimmune diseases.
  • compound (I) effectively inhibits sphingosine kinase, preferably sphingosine kinase 1, and exhibits enteritis suppression action through cytokine production suppression action, it can be a novel therapeutic agent for inflammatory bowel disease (IBD). .
  • IBD inflammatory bowel disease
  • FIG. 2 is a graph showing the cytokine (TNF- ⁇ ) production inhibitory effect of compound (I).
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the “hydrocarbon group” in the “optionally substituted hydrocarbon group” includes, for example, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a C 3 And -10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group and the like.
  • the C 1-10 alkyl group means a linear or branched alkyl having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, etc. Is mentioned. Of these, a C 1-6 alkyl group is preferable, and a C 1-4 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl, etc.) is particularly preferable.
  • a C 1-6 alkyl group is prefer
  • the C 2-10 alkenyl group means a straight or branched alkenyl having 2 to 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl. 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5 -Hexenyl, 1-heptenyl, 1-octenyl and the like. Of these, a C 2-6 alkenyl group is preferable.
  • the C 2-10 alkynyl group means a straight or branched alkynyl having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Of these, a C 2-6 alkynyl group is preferable.
  • Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Among them, a C 3-8 cycloalkyl group is preferable, a C 3-6 cycloalkyl group is more preferable, and a cyclopentyl group is particularly preferable.
  • Examples of the C 3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Of these, a C 3-6 cycloalkenyl group is preferable.
  • the C 3-10 cycloalkyl group and the C 3-10 cycloalkenyl group may each be condensed with a benzene ring to form a condensed ring group.
  • Examples of such a condensed ring group include indanyl, Dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
  • the C 3-10 cycloalkyl group and the C 3-10 cycloalkenyl group may be a C 7-10 bridged hydrocarbon group.
  • Examples of the C 7-10 bridged hydrocarbon group include bicyclo [2.2.1] heptyl (norbornyl), bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3. 2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like.
  • C 3-10 cycloalkyl and C 3-10 cycloalkenyl groups mentioned may also form a C 3-10 cycloalkane or C 3-10 cycloalkene and spirocyclic groups, respectively.
  • C 3-10 cycloalkane and C 3-10 cycloalkene ring are exemplified corresponding to C 3-10 cycloalkyl group and C 3-10 cycloalkenyl groups described above. Examples of such a spiro ring group include spiro [4.5] decan-8-yl.
  • Examples of the C 6-14 aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Among them, a C 6-12 aryl group is preferable, a C 6-10 aryl group is preferable, and phenyl is particularly preferable.
  • Examples of the C 7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like. Among them, a C 7-11 aralkyl group is preferable, and benzyl is particularly preferable.
  • Examples of the C 8-13 arylalkenyl group include styryl and the like.
  • hydrocarbon group may have 1 to 7 (preferably 1 to 3) substituents at substitutable positions.
  • the “5- or (or) 6-membered aromatic ring group” means a 5- or 6-membered monocyclic conjugated unsaturated ring group exhibiting aromaticity.
  • examples of the aromatic hydrocarbon group include a phenyl group
  • examples of the aromatic heterocyclic group include one or two nitrogen atoms defined below as an “aromatic heterocyclic group”.
  • examples thereof include a 5- or 6-membered aromatic heterocyclic group, a 5-membered aromatic heterocyclic group containing one sulfur atom, and the like.
  • the “5- or (or) 6-membered aromatic ring group” is preferably, for example, a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thienyl group, and a thiazolyl group. Particularly preferred.
  • heterocyclic group in the “optionally substituted heterocyclic group” include an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • the aromatic heterocyclic group includes, for example, 4 to 7 members (preferably 5 or 5) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms.
  • 6-membered) monocyclic aromatic heterocyclic group and condensed aromatic heterocyclic group examples include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
  • Monocyclic aromatic heterocyclic groups such as furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyrazinyl, imidazopyridyl, thienopyridyl,
  • non-aromatic heterocyclic group examples include 3 to 7 members (preferably 4 to 7 members) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring-constituting atoms. , More preferably 5 or 6-membered) monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group.
  • fused non-aromatic heterocyclic group include a ring corresponding to the 3- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 or 2 nitrogen atoms.
  • 1 or 2 rings selected from a heterocyclic ring eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a heterocyclic ring eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocyclic ring containing 1 sulfur atom eg, thiophene
  • benzene ring examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.
  • non-aromatic heterocyclic group Azetidinyl, pyrrolidinyl, piperidyl, morpholinyl (eg, morpholino), thiomorpholinyl, piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, dioxolyl, dioxolanyl, pyrhydronylpyrazyl
  • Monocyclic non-aromatic heterocyclic groups such as tetrahydrothiopyranyl, tetrahydrofuryl, pyrazolidinyl, pyrazolinyl, tetrahydropyrimidinyl, dihydrotriazolyl, tetrahydrotriazolyl; Dihydroindolyl, dihydroisoindolyl, di
  • the non-aromatic heterocyclic group may be cross-linked.
  • Preferable examples of the bridged non-aromatic heterocyclic group include (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl.
  • heterocyclic group in the “optionally substituted heterocyclic group” may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • examples of the “optionally substituted hydroxy group” include a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, which may be substituted, respectively. Substitution selected from a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-13 aralkyl group, a C 8-13 arylalkenyl group, an acyl group, an optionally substituted silyl group, a heterocyclic group, etc. Examples thereof include a hydroxy group which may be substituted with a group.
  • the 13 arylalkenyl group include those exemplified as the “hydrocarbon group” in the aforementioned “optionally substituted hydrocarbon group”.
  • heterocyclic group examples include those similar to the “aromatic heterocyclic group” and “non-aromatic heterocyclic group” exemplified as the “heterocyclic group” in the “optionally substituted heterocyclic group”. .
  • Preferable examples of the “optionally substituted hydroxy group” include a C 1-10 alkoxy group, a C 3-10 cycloalkyloxy group, a C 6-12 aryloxy group, or a C 7-13 aralkyloxy group.
  • C 1-6 alkoxy groups C 3-6 cycloalkyloxy groups (eg, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy etc.), C 6-10 aryloxy groups (eg, phenoxy etc.) Or a C 7-11 aralkyloxy group (eg, benzyloxy, phenethyloxy, naphthylmethyloxy, biphenylylmethyloxy, etc.).
  • Particularly preferred is a C 1-4 alkoxy group (eg, methoxy, ethoxy, isopropoxy, isobutoxy etc.), a C 5-6 cycloalkyloxy group (eg, cyclopentyloxy, cyclohexyloxy) or phenoxy.
  • a C 1-4 alkoxy group eg, methoxy, ethoxy, isopropoxy, isobutoxy etc.
  • a C 5-6 cycloalkyloxy group eg, cyclopentyloxy, cyclohexyloxy
  • examples of the “optionally substituted mercapto group” include, for example, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, each of which may be substituted, C 3-10 cycloalkenyl group, C 6-14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group, acyl group (eg, C 1-10 alkyl-carbonyl group, C 6-14 aryl- A carbonyl group, a C 1-10 alkylsulfonyl group, a C 6-14 arylsulfonyl group, etc.), an optionally substituted silyl group (eg, tri C 1-4 alkylsilyl group, etc.), a heterocyclic group, etc.
  • the mercapto group which may be substituted by the substituent is mentioned.
  • Preferable examples of the “optionally substituted mercapto group” include a C 1-10 alkylthio group, a C 3-10 cycloalkylthio group, a C 6-12 arylthio group, a C 7-13 aralkylthio group, and the like.
  • a C 1-4 alkylthio group eg, methylthio,
  • the "acyl group" for example, a formyl group, an optionally substituted C 1-6 alkyl - carbonyl group, an optionally substituted C 1-6 alkoxy - carbonyl group, substituted Optionally substituted C 3-10 cycloalkyl-carbonyl group, optionally substituted C 3-10 cycloalkyloxy-carbonyl group, optionally substituted C 7-13 aralkyl-carbonyl group, optionally substituted A good C 7-13 aralkyloxy-carbonyl group, an optionally substituted C 6-14 aryl-carbonyl group, an optionally substituted C 6-14 aryloxy-carbonyl group, a carbamoyl group (—CONH 2 ), optionally substituted mono- or di -C 1-6 alkyl - carbamoyl group optionally mono- or di -C be substituted 3- 0 cycloalkyl - carbamoyl group, an optionally substituted mono- or di - aromatic heterocycl
  • acyl group an optionally substituted C 1-6 alkyl-carbonyl group (eg, pivaloyl), an optionally substituted C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) ), A C 3-10 cycloalkyl-carbonyl group, a C 3-10 cycloalkyloxy-carbonyl group, an optionally substituted C 1-6 alkyl group, and a carbamoyl group (eg, Mono tert-butylcarbamoyl), an optionally substituted mono- or di-non-aromatic heterocyclic carbamoyl group (eg, tetrahydrofuranylcarbamoyl etc.), an optionally substituted C 3-10 cycloalkyl group mono- or di- Optionally substituted carbamoyl groups (eg, mono (cyclohexyl) carbamoyl, mono (cyclopentyl) calcyl Moil, etc.),
  • heterocyclic ring of the “heterocyclic carbonyl group” examples include the “aromatic heterocyclic group” and the “non-aromatic heterocyclic group” exemplified as the “heterocyclic group” in the “optionally substituted heterocyclic group”. Can be mentioned.
  • cyclic aminocarbonyl group is a group in which a carbonyl is bonded to a nitrogen atom constituting a nitrogen-containing non-aromatic heterocyclic group (hereinafter also referred to as a cyclic amino group).
  • examples of the “optionally substituted amino group” include, for example, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, each of which may be substituted, An amino group which may be mono- or di-substituted with a substituent selected from a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-13 aralkyl group, a C 8-13 arylalkenyl group, an acyl group and the like Is mentioned.
  • the 13 arylalkenyl group include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group”, and among them, a C 1-4 alkyl group (eg, methyl, tert-butyl). Etc.) and C 5-6 cycloalkyl groups (eg, cyclopentyl, cyclohexyl, etc.) are preferred.
  • the 14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group and acyl group each may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • acyl group exemplified as the substituent of the “optionally substituted amino group” include the same as the above “acyl group”, and among them, the optionally substituted C 1-6 alkyl- A carbonyl group (eg, pivaloyl), an optionally substituted C 1-6 alkylsulfonyl group (eg, methylsulfonyl) and the like are preferable.
  • the “optionally substituted amino group” is preferably a mono- or di-C 1-6 alkylamino group (eg, mono-C such as methylamino group, ethylamino group, propylamino group, isopropylamino group).
  • 1-6 alkylamino groups di-C 1-6 alkylamino groups such as dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, etc., cyclic amino groups (eg, azetidinyl group, pyrrolidinyl group, piperidyl group) , Morpholinyl group, etc.), and mono- or di-acylamino groups (eg, acetylamino group, pivaloylamino group, trifluoroacetylamino group, benzoylamino group, methanesulfonylamino group, tert-butylsulfonylamino group, etc.).
  • cyclic amino groups eg, azetidinyl group, pyrrolidinyl group, piperidyl group
  • Morpholinyl group etc.
  • mono- or di-acylamino groups eg, ace
  • nitrogen-containing heterocyclic ring means “aromatic heterocyclic group” and “non-aromatic heterocyclic group” exemplified as “heterocyclic group” in the “optionally substituted heterocyclic group”.
  • the ring constituent atom may contain at least one nitrogen atom, and may further contain one or two heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Means a heterocycle of members.
  • nitrogen-containing heterocycle examples include pyrrole, pyridine, pyrazine, imidazole, pyrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, Piperazine, morpholine, thiomorpholine and the like can be mentioned.
  • the nitrogen-containing heterocycle may have 1 to 5 (preferably 1 or 2) substituents at substitutable positions.
  • the “cyclic group” means a saturated or unsaturated cyclic hydrocarbon group or a saturated or unsaturated heterocyclic group.
  • the cyclic hydrocarbon group include a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, etc.
  • a 3- to 10-membered cyclic hydrocarbon group (C 3-10 cycloalkyl group, C 3 ⁇ 10 cycloalkenyl group or C 6-10 aryl group) is preferable, and a 3- to 6-membered cyclic hydrocarbon group (C 3-6 cycloalkyl group, C 3-6 cycloalkenyl group or phenyl group) is more preferable.
  • heterocyclic group examples include the groups described above, and among them, a dihydrofuranyl group, a pyrrolidinyl group or an imidazolyl group is preferable, a dihydrofuranyl group or a pyrrolidinyl group is more preferable, and a dihydrofuranyl group is particularly preferable.
  • optionally substituted silyl group refers to a silyl group substituted with three identical or different hydrocarbon groups (eg, C 1-10 alkyl group, C 6-12 aryl group, etc.).
  • a tri-C 1-4 alkylsilyl group such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group; a tert-butyldiphenylsilyl group; a triphenylsilyl group And the like, and a tri-C 1-4 alkylsilyl group is particularly preferable.
  • “optionally substituted” means that it may have one or more substituents unless otherwise specified.
  • substituents ( 1) a halogen atom, (2) a hydroxy group, (3) a carboxy group, (4) a nitro group, (5) a cyano group, (6) a C 1-6 alkyl group optionally substituted by a halogen atom, (7 ) C 3-10 cycloalkyl group, (8) C 3-10 cycloalkenyl group, (9) C 2-6 alkenyl group, (10) C 2-6 alkynyl group, (11) C 1-6 alkoxy group, (12) C 1-6 alkylenedioxy group, (13) C 6-14 aryloxy group, (14) C 7-14 aralkyloxy group, (15) C 6-14 aryl group, (16) C 7- 14 aralkyl group, (17) a formyl group, (18) halogen C 1-6 alkyl optionally substituted by atom - carbonyl group
  • halogen atom hydroxy group, nitro group, cyano group, C 1-4 alkyl group (methyl, ethyl, isopropyl, isobutyl, tert-butyl etc.), trifluoromethyl group, methoxymethyl group, C 3-10 cycloalkyl Groups (eg, cyclopentyl, cyclohexyl, adamantyl, etc.), C 1-4 alkoxy groups (eg, methoxy, ethoxy, isopropoxy, isobutoxy, tert-butoxy, etc.), C 3-10 cycloalkyloxy groups (eg, cyclopentyloxy, etc.) ), C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), C 3-10 cycloalkyloxy-carbonyl group (eg, cyclopentyloxycarbonyl), formyl group, C 1-6 alkyl-carbonyl group (eg, methyl, e
  • the above substituent may be further substituted with the above substituent.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • the substituent may further include a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 1-6 alkoxy group, C 3-10 cycloalkyloxy group, C 6-14 aryl group, C 6-14 aryloxy group, C 7-13 aralkyl group, C 7-13 aralkyloxy group, heterocyclic group, halogen atom, hydroxy group, carboxy Group, amino group, carbamoyl group, cyano group, nitro group, oxo group and the like.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
  • the compound of the present invention is a compound represented by the following formula (I) (sometimes referred to as the present compound or compound (I)).
  • Ring A represents an optionally substituted 5- or 6-membered aromatic ring group
  • R 1a , R 1b and R 1c are each independently, and two of them may be bonded to the same carbon atom, and may be a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, or a substituted group.
  • R 1a , R 1b and R 1c is a hydroxy group or a hydroxy C 1;
  • -3 represents an alkyl group;
  • R 2a and R 2b each independently represent a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group, or R 2a and R 2b are substituted together with the carbon atom to which they are attached.
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group
  • R 4 represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted mercapto group
  • R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, or a substituted group.
  • the two adjacent groups may together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered cyclic group
  • X 1 , X 2 and X 3 each independently represent a nitrogen atom or C—R 8 ;
  • R 8 represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, or an optionally substituted amino group;
  • n represents 0, 1, 2 or 3; and m represents 1, 2 or 3.
  • Ring A in formula (I) is an optionally substituted 5- or 6-membered aromatic ring group.
  • Ring A is preferably an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyrazolyl group, or an optionally substituted thienyl.
  • the “optionally substituted” of the “optionally substituted 5- or 6-membered aromatic ring group” represented by ring A means an additional substituent separately from the groups R 5 , R 6 and R 7. It means that you may have.
  • substituents include the above-mentioned “substituents”, preferably a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a C 6-10 aryl group, or a halogen atom. And more preferably a halogen atom (eg, fluorine atom).
  • Ring A particularly preferably has no substituents other than the groups R 5 , R 6 and R 7 .
  • Ring A is preferably a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thienyl group or a thiazolyl group, and more preferably a phenyl group or a pyridyl group.
  • R 1a , R 1b and R 1c in formula (I) are each independently, and two of them may be bonded to the same carbon atom, and may be a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon.
  • a group, an optionally substituted hydroxy group, an optionally substituted mercapto group, an optionally substituted amino group or an acyl group, and at least one of R 1a , R 1b and R 1c is hydroxy Group or a hydroxy C 1-3 alkyl group.
  • R 1a , R 1b and R 1c include R 1a , R 1b and R 1c are each independently, and two of them may be bonded to the same carbon atom, and may be a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group or an optionally substituted amino group.
  • group, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkylthio group may be an acyl group or a substituted A C 6-10 aryl group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxy C 1-3 alkyl group;
  • R 1a , R 1b and R 1c , R 1a , R 1b and R 1c are each independently substituted with a hydrogen atom, a halogen atom, a hydroxy group, a C 1-3 alkoxy group, or a hydroxy group or a 5- or 6-membered nitrogen-containing aromatic heterocyclic group.
  • An optionally substituted C 1-3 alkyl group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxy C 1-3 alkyl group.
  • R 1a , R 1b and R 1c , R 1a , R 1b and R 1c are each independently a hydrogen atom, a hydroxy group or a hydroxymethyl group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxymethyl group .
  • R 2a and R 2b in formula (I) are each independently a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group, or R 2a and R 2b are a carbon atom to which they are bonded. Together, they form a cyclic group (eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, etc.) that may be substituted.
  • a cyclic group eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, etc.
  • R 2a and R 2b are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group.
  • R 2a and R 2b are both hydrogen atoms.
  • R 3 in the formula (I) is a hydrogen atom, an optionally substituted hydrocarbon group (eg, a C 1-6 alkyl group) or an acyl group.
  • R 3 is a hydrogen atom, a C 1-3 alkyl group or a C 1-3 alkylsulfonyl group.
  • R 3 is a hydrogen atom or a C 1-3 alkyl group.
  • R 3 is a hydrogen atom or a methyl group.
  • R 4 in Formula (I) is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, or an optionally substituted mercapto group.
  • R 4 is a hydrogen atom.
  • R 5 , R 6 and R 7 in formula (I) are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, an optionally substituted hydrocarbon group, or an optionally substituted hydroxy group.
  • R 5 , R 6 and R 7 , R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkenyl group, optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 3-10 cycloalkenyl group, an optionally substituted C 7-13 aralkyl group, an optionally substituted C 1- 6 an alkoxy group, an optionally substituted C 3-10 cycloalkyloxy group, an optionally substituted C 7-13 aralkyloxy group, an optionally substituted C 1-6 alkylthio group, an optionally substituted An optionally substituted C 3-10 cycloalkylthio group, an optionally substituted C 7-13 aralkylthio group, an optionally substituted C 1-6 alkylsulfonyl group, an optionally substituted Mono- or di
  • R 5 , R 6 and R 7 , R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a C 7-13 aralkyl group optionally substituted by a C 1-6 alkoxy group, a C 3-10 cycloalkyl group, C C1-6 alkoxy optionally substituted by a group C 7-13 aralkyloxy group, C 3-10 cycloalkyl groups by an optionally substituted C 1-6 alkoxy group, C 3-10 cycloalkyloxy group, C 1-6 alkylthio group, C 1-6 alkylsulfonyl group, mono C 1-6 alkyl-carbonylamino group, mono or di-C 1-6 alkylamino group, phenyl group, phenoxy group, mono or di- (C 1-6 alkyl) -carbamoyl group, mono (C 3-10 cycloalkyl) carbamoyl group, mono- or di- (
  • R 5 , R 6 and R 7 , R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a C 3-10 cycloalkyl group, a C 1-6 alkoxy group optionally substituted by a C 3-10 cycloalkyl group, C 3-10 cycloalkyloxy group, C 1-6 alkylthio group, di (C 1-6 alkyl) amino group, mono C 1-6 alkyl-carbonylamino group, phenyl group, phenoxy group, mono- or di-C 1 -6 alkyl-carbamoyl group, mono (C 3-10 cycloalkyl) carbamoyl group, mono- or di-C 1-6 alkylsulfamoyl group, 6-membered non-substituted optionally by C 1-6 alkyl group C which may be substituted by an aromatic heterocyclic group, a tri C 1-4 alkylsilyl group, a
  • R 5 , R 6 and R 7 , R 5 , R 6 and R 7 are each independently a hydrogen atom, a fluorine atom, a C 3-10 cycloalkyl group (eg, adamantyl etc.), a C 3-10 cycloalkyl group which may be substituted 1-6 alkoxy groups (eg, cyclopentylmethoxy, cyclopentylethoxy, etc.), C 2-6 alkenyl groups (eg, 3,3-dimethylbuten-1-yl, etc.), oxo groups, or C 1-6 alkyl groups
  • An optionally substituted C 3-10 cycloalkenyl group eg, cyclohexen-1-yl, cyclopenten-1-yl, 4,4-dimethylcyclohex-1-one-2-en-2-yl
  • C 1 -6 alkyl non-aromatic Hajime Tamaki may 6 membered optionally substituted by group (eg, 3,6-
  • R 5 , R 6 and R 7 is a tert-butyl group, a mono (tert-butyl) carbamoyl group, a cyclobutyloxymethyl group, a cyclopentyloxymethyl group, a cyclopentylthiomethyl group, a cyclohexene-1; -Yl group, cyclopenten-1-yl group or 4,4-dimethylcyclohex-1-one-2-en-2-yl group (more preferably, mono (tert-butyl) carbamoyl group, cyclopentyloxymethyl group, Cyclohexen-1-yl group or 4,4-dimethylcyclohex-1-one-2-en-2-yl group), and the remaining two groups are each independently a hydrogen atom or a methyl group. is there.
  • X 1 , X 2 and X 3 in the formula (I) are each independently a nitrogen atom or C—R 8 .
  • X 1 is C—R 8 ;
  • X 2 and X 3 are each independently a nitrogen atom or C—R 8 .
  • X 1 is C—R 8 ;
  • X 2 and X 3 are both C—R 8 , or one of X 2 and X 3 is a nitrogen atom and the other is C—R 8 .
  • R 8 in formula (I) is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, or an optionally substituted amino group. It is a group.
  • R 8 is a hydrogen atom.
  • N in the formula (I) is 0, 1, 2, or 3.
  • N is preferably 0, 1, or 2.
  • n it is 0 or 1.
  • N is 1 as a particularly preferred embodiment.
  • M in the formula (I) is 1, 2 or 3.
  • m it is 1 or 3.
  • m it is 1.
  • Ring A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group;
  • R 1a , R 1b and R 1c are each independently, and two of them may be bonded to the same carbon atom, and may be a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group or an optionally substituted amino group.
  • R 1a , R 1b and R 1c are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group
  • R 3 is a hydrogen atom, an optionally substituted C 1-6 alkyl group or an acyl group
  • R 4 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 1-6 alkoxy group
  • R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, or an optionally substituted
  • X 1 is C—R 8 ;
  • X 2 and X 3 are each independently a nitrogen atom or C—R 8 ;
  • R 8 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an amino group or an optionally substituted mono- or di -C A 1-6 alkylamino group;
  • Compound (I) wherein n is 0, 1, 2 or 3; and m is 1, 2 or 3.
  • Ring A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group;
  • R 1a , R 1b and R 1c are each independently, and two of them may be bonded to the same carbon atom, and may be a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group or an optionally substituted amino group.
  • R 1a , R 1b and R 1c are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group
  • R 3 is a hydrogen atom, an optionally substituted C 1-6 alkyl group or an acyl group
  • R 4 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 1-6 alkoxy group
  • R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted
  • X 1 is C—R 8 ;
  • X 2 and X 3 are each independently a nitrogen atom or C—R 8 ;
  • R 8 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an amino group or an optionally substituted mono- or di -C A 1-6 alkylamino group;
  • Compound (I) wherein n is 0, 1, 2 or 3; and m is 1, 2 or 3.
  • Ring A is a group selected from the group consisting of a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thienyl group, and a thiazolyl group;
  • R 1a , R 1b and R 1c are each independently, and two of them may be bonded to the same carbon atom, and a hydrogen atom, a halogen atom, a hydroxy group, a C 1-3 alkoxy group, or a hydroxy group Or a C 1-3 alkyl group which may be substituted with a 5- or 6-membered nitrogen-containing aromatic heterocyclic group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxy C 1-1 3 alkyl groups;
  • R 2a and R 2b are both hydrogen atoms;
  • R 3 is a hydrogen atom, a C 1-3 alkyl group or a C 1-3 alkyl
  • R 5 , R 6 and R 7 may be substituted together with the carbon atom to which they are attached, an optionally substituted dihydrofuranyl May form an imidazolyl group optionally substituted by a group, an optionally substituted pyrrolidinyl group or a C 1-6 alkyl group;
  • X 1 is C—R 8 ;
  • X 2 and X 3 are each independently a nitrogen atom or C—R 8 ;
  • R 8 is a hydrogen atom;
  • n is 0, 1 or 2;
  • Ring A is a group selected from the group consisting of a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thienyl group, and a thiazolyl group;
  • R 1a , R 1b and R 1c are each independently, and two of them may be bonded to the same carbon atom, and a hydrogen atom, a halogen atom, a hydroxy group, a C 1-3 alkoxy group, or a hydroxy group Or a C 1-3 alkyl group which may be substituted with a 5- or 6-membered nitrogen-containing aromatic heterocyclic group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxy C 1-1 3 alkyl groups;
  • R 2a and R 2b are both hydrogen atoms;
  • R 3 is a hydrogen atom, a C 1-3 alkyl group or a C 1-3
  • Ring A is a phenyl group or a pyridyl group;
  • R 1a , R 1b and R 1c are each independently a hydrogen atom, a hydroxy group or a hydroxymethyl group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxymethyl group ;
  • R 2a and R 2b are both hydrogen atoms;
  • R 3 is a hydrogen atom or a C 1-3 alkyl group;
  • R 4 is a hydrogen atom;
  • R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a C 3-10 cycloalkyl group, a C 1-6 alkoxy group, a C 3-10 cycloalkyloxy group, a C 1-6 alkylthio Group, di (C 1-6 alkyl) amino group, mono C 1-6 alkyl-carbonylamino group, phenyl group, phenoxy group, mono-
  • Ring A is a phenyl group or a pyridyl group;
  • R 1a , R 1b and R 1c are each independently a hydrogen atom, a hydroxy group or a hydroxymethyl group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxymethyl group ;
  • R 2a and R 2b are both hydrogen atoms;
  • R 3 is a hydrogen atom or a C 1-3 alkyl group;
  • R 4 is a hydrogen atom;
  • R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a C 3-10 cycloalkyl group, a C 1-6 alkoxy group optionally substituted by a C 3-10 cycloalkyl group, C 3-10 cycloalkyloxy group, C 1-6 alkylthio group, di (C 1-6 alkyl) amino group, mono C 1-6 alkyl-carbonylamino group,
  • Ring A is a phenyl group or a pyridyl group (more preferably, a phenyl group);
  • R 1a , R 1b and R 1c are each independently a hydrogen atom, a hydroxy group or a hydroxymethyl group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxymethyl group ;
  • R 2a and R 2b are both hydrogen atoms;
  • R 3 is a hydrogen atom or a methyl group;
  • R 4 is a hydrogen atom;
  • R 5 , R 6 and R 7 are each independently a hydrogen atom, a fluorine atom, a C 3-10 cycloalkyl group, a C 3-10 cycloalkyloxy group, a tert-butyl group, or a mono (tert-butyl) carbamoyl Group, methoxy group, isopropoxy group, isobutoxy group, tert-butyl
  • Ring A is a phenyl group or a pyridyl group (more preferably, a phenyl group);
  • R 1a , R 1b and R 1c are each independently a hydrogen atom, a hydroxy group or a hydroxymethyl group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxymethyl group ;
  • R 2a and R 2b are both hydrogen atoms;
  • R 3 is a hydrogen atom or a methyl group;
  • R 4 is a hydrogen atom;
  • R 5 , R 6 and R 7 are each independently a C 1-6 alkoxy group optionally substituted by a hydrogen atom, a fluorine atom, a C 3-10 cycloalkyl group or a C 3-10 cycloalkyl group ( examples, cyclopentylmethoxy, cyclopentylethoxy, etc.), C 2-6 alkenyl group (eg, 3,3-di
  • Ring A is a phenyl group, a pyridyl group or a pyrimidinyl group (more preferably, a phenyl group);
  • R 1a , R 1b and R 1c are each independently a hydrogen atom, a hydroxy group or a hydroxymethyl group, and at least one of R 1a , R 1b and R 1c is a hydroxy group or a hydroxymethyl group ;
  • R 2a and R 2b are both hydrogen atoms;
  • R 3 is a hydrogen atom or a methyl group;
  • R 4 is a hydrogen atom;
  • One of R 5 , R 6 and R 7 is a tert-butyl group, mono (tert-butyl) carbamoyl group, cyclobutyloxymethyl group, cyclopentyloxymethyl group, cyclopentylthiomethyl group, cyclohexen-1-yl group A cyclopenten-1-yl group or a 4,4-
  • Suitable compounds are the compounds of Examples 1 to 246, or salts thereof.
  • More preferred compounds are Examples 1 to 4, 6 to 17, 19, 21, 22, 28 to 31, 33, 36, 40 to 43, 49 to 51, 54 to 57, 60, 61, 63, 67 to 69, 73, 74, 76, 77, 79, 81, 83, 85 to 88, 90 to 93, 96, 99, 101 to 105, 108 to 110, 112 to 114, 117, 119, 121, 122, 124 to 129, 131, 132, 134 to 136, 140 to 168, 170, 173, 174, 178 to 180, 183, 185 to 211, 213 to 231, 233, 235 to 246, or salts thereof.
  • Further preferred compounds are Examples 1 to 3, 6 to 11, 13 to 15, 17, 21, 22, 28, 31, 33, 36, 40, 49 to 51, 54, 56, 61, 63, 67 to 69, 76, 77, 81, 83, 86-88, 90-93, 96, 105, 108, 109, 112, 113, 117, 119, 124, 125, 128, 129, 131, 132, 135, 136, 141, 142, 144-146, 148, 149, 151, 153, 155-161, 163-166, 168, 170, 174, 178-180, 183, 185-189, 191, 192, 195-198, 200, 204 to 206, 209 to 211, 213 to 217, 219, 221 to 223, 225 to 231, 233, 235 to 246, or salts thereof .
  • the most preferred compound is the compound of Example 1, 132, 157, 211, 227, or a salt thereof.
  • Particularly preferred compounds are specifically the following compounds or salts thereof.
  • the most preferred compounds are specifically the following compounds or salts thereof.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like.
  • examples include salts.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and barium salt; magnesium salt and aluminum salt.
  • the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), alkaline earth metal salt (eg, calcium salt, barium salt), magnesium salt, etc.
  • the compound has a basic functional group
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, trifluoroacetic acid
  • examples thereof include salts with organic acids such as phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • Compound (I) can also be produced by the methods shown in the following production methods 1 to 3, the examples described later, or methods analogous thereto.
  • Each raw material compound may form a salt as long as it does not inhibit the reaction.
  • Examples of such a salt include the same salts as the salt of compound (I).
  • a raw material compound can be easily obtained and used as a raw material compound, or can be produced according to a method known per se or a method analogous thereto.
  • a schematic diagram of the reaction formula is shown below, and each symbol of the compound in the schematic diagram has the same meaning as described above.
  • R 2a and R 2b are both hydrogen atoms and m is 1 (in this specification, sometimes abbreviated as compound (Ia)), the following production method 1 or 2 Or it can manufacture by the method according to this.
  • Step 1-1 This step is a step for producing the compound (3) by substituting the Y 1 group of the compound (1) with a ring A (aromatic ring).
  • This step is carried out with an aromatic boronic acid (2) or an aromatic boronic acid ester (eg, pinacol ester of an aromatic boronic acid, etc.) in a solvent that does not affect the reaction, for example, in the presence of a palladium catalyst and a base. It can be performed by a cross coupling reaction (Suzuki coupling reaction) or the like.
  • Compound (1) is commercially available, or can be produced by a method known per se or a method analogous thereto.
  • the leaving group represented by Y 1 of the compound (1) is not particularly limited as long as it does not cause a side reaction.
  • Examples thereof include a halogen atom (preferably a bromine atom), a trifluoromethanesulfonyloxy group, and the like.
  • the aromatic boronic acid (2) is commercially available, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (Richard C In the manner described by Larock) or a method analogous thereto.
  • the amount of the aromatic boronic acid to be used is generally 1 to 4 equivalents relative to 1 equivalent of compound (1).
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (hereinafter referred to as Pd (dppf) Cl 2 ), and triphenyl. Examples thereof include palladium acetate in the presence of phosphine. Among them, Pd (dppf) Cl 2 is preferably used.
  • the amount of the palladium catalyst to be used is generally 0.001 to 0.5 equivalent, preferably 0.02 to 0.2 equivalent, relative to 1 equivalent of compound (1).
  • Examples of the base include tripotassium phosphate, trisodium phosphate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like, and sodium carbonate is particularly preferable.
  • solvent examples include ethers such as THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, diglyme, 1,4-dioxane and DMF, and among these, 1,4-dioxane is particularly preferable.
  • ethers such as THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, diglyme, 1,4-dioxane and DMF, and among these, 1,4-dioxane is particularly preferable.
  • the reaction temperature is usually 50 ° C. to 150 ° C., preferably 60 ° C. to 130 ° C.
  • the reaction time is usually from 0.1 to 12 hours.
  • the compound (3) is obtained by converting the leaving group Y 1 of the compound (1) into the boronic acid ester (2 ′) and then the ring A (compound (1 ′′)) having the leaving group Y. It can also be produced by a cross-coupling reaction.
  • Step 1-1 ' This step is a step for producing the compound (2 ′) by substituting the Y 1 group of the compound (1) with a pinacol ester of boronic acid using bispinacolatodiboron and a palladium catalyst.
  • the same catalyst as in step 1-1 can be used, and the amount used is also the same.
  • the amount of bispinacolatodiboron used is usually 1 to 4 equivalents relative to compound (1).
  • solvent examples include ethers such as THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME and diglyme, 1,4-dioxane, etc. Among them, 1,4-dioxane and DMF are particularly preferable.
  • Step 1-2 ' This step is a step of producing the compound (3) by a cross-coupling reaction between the boronic ester (2 ′) of the compound (1) and the ring A having the leaving group Y (compound (1 ′′)). is there. This step can be performed under the same reaction conditions as in step 1-1.
  • Step 1-2 This step is a step for producing compound (Ia) by reacting compound (3) with compound (4) in the presence of a reducing agent.
  • the amount of compound (4) to be used is generally 1-10 equivalents, preferably 1-2 equivalents, relative to compound (3).
  • the reducing agent examples include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the amount of the reducing agent to be used is generally 1-10 equivalents, preferably 1-4 equivalents, relative to compound (3).
  • the generation of the Schiff base and the reduction reaction can be performed sequentially.
  • the reduction can be performed using hydrogen and a catalyst such as Raney nickel or platinum oxide.
  • an acid such as acetic acid can be added as a reaction accelerator.
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, methanol, ethanol, N, N-dimethylformamide, dimethyl sulfoxide, and the like.
  • Alcohol solvents such as methanol and halogen solvents such as dichloroethane are particularly preferred. These solvents may be used by mixing two or more kinds at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C., preferably under ice cooling to 50 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • R 9 represents an alkyl group or an aralkyl group, and other symbols have the same meanings as described above.
  • Step 2-1 This step is a step for producing compound (3 ′) by substituting Y 2 group of compound (1 ′) with ring A (aromatic ring).
  • This step can be performed under the same reaction conditions as in step 1-1 of production method 1.
  • Compound (1 ′) is commercially available, or a method known per se [eg, Noland, W. E., Baoude, F. J. Orgl Synth., Coll. Vol. 1973, 5, 567, Allenk Jr GR, Poletto, JF, Weiss, MJ J. Org. Chem. 1965, 30, 2897, etc.] or a method analogous thereto.
  • Step 2-2 This step is a step for producing the compound (5) by reducing the ester group of the compound (3 ′).
  • This step is a step of producing the compound (5) from the compound (3 ′) in the presence of a reducing agent.
  • Examples of the reducing agent include lithium aluminum hydride and borane complex.
  • examples of the reducing agent include lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride and the like. It is done. Among these, lithium aluminum hydride is preferable.
  • the amount of the reducing agent to be used is generally 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound (3 ').
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, and the like, and ether solvents such as tetrahydrofuran and diethyl ether are particularly preferable. These solvents may be used by mixing two or more kinds at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 100 ° C., preferably under ice cooling to 50 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • Step 2-3 This step is a step of producing compound (3) from compound (5) in the presence of an oxidizing agent.
  • oxidizing agent examples include pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, desmartin periodinane, dimethyl sulfoxide-oxalyl chloride combination, dimethyl sulfoxide-trifluoroacetic anhydride combination, and the like. Dess Martin periodinane is preferred.
  • the amount of the oxidizing agent to be used is generally 1-10 equivalents, preferably 1-4 equivalents, relative to compound (5).
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, methylene chloride, chloroform, 1,2-dichloroethane, and methylene chloride is preferable. These solvents may be used by mixing two or more kinds at an appropriate ratio.
  • Step 2-4 This step is a step for producing compound (Ia) by reacting compound (3) with compound (4) in the presence of a reducing agent.
  • This step can be performed under the same reaction conditions as in Step 1-2 of Production Method 1.
  • Compound (I) can also be produced by the following production method 3 or a method analogous thereto.
  • Step 3-1 In this step, in the presence of a halogenating agent or an acylating agent (eg, sulfonylating agent), a leaving group Y 3 (eg, halogen atom, optionally substituted alkylsulfonyloxy group, substituted) is added to compound (5 ′).
  • a leaving group Y 3 eg, halogen atom, optionally substituted alkylsulfonyloxy group, substituted
  • a compound (3 ′′) is produced by introducing an arylsulfonyloxy group or the like which may be used.
  • a base can be added as necessary.
  • Compound (5 ′) is commercially available, or a method known per se [eg, Sripha, K., Zlotos, D. P., Buler, S., Mohr, K. Tetrahedron Lett. 2003, 44, 7183 , N. Amishiro et al. Bioorg. Med. Chem. 2000, 8, 1637, etc.] or a method analogous thereto.
  • halogenating agent When producing a compound (3 ′′) in which Y 3 is a halogen atom,
  • the halogenating agent include chlorinating agents such as acetyl chloride, thionyl chloride, oxalyl chloride, phosphorus trichloride, and sulfuryl chloride; brominating agents such as acetyl bromide, phosphorus tribromide, and diphenylphosphine / bromine. It is done.
  • the amount of the halogenating agent to be used is generally 1-2 equivalents, preferably 1-1.5 equivalents, relative to compound (5 ').
  • the solvent examples include halogenated hydrocarbons such as chloroform and methylene chloride; aromatic hydrocarbons such as toluene and xylene; ethers such as tetrahydrofuran and 1,4-dioxane; or a mixture thereof.
  • halogenated hydrocarbons such as chloroform and methylene chloride
  • aromatic hydrocarbons such as toluene and xylene
  • ethers such as tetrahydrofuran and 1,4-dioxane
  • Chloroform, methylene chloride, tetrahydrofuran, toluene and the like are preferable.
  • the reaction temperature is usually 10 to 150 ° C., preferably 30 to 80 ° C.
  • the reaction time is usually 0.5 to 30 hours, preferably 2 to 20 hours.
  • Y 3 is an acyloxy group such as an optionally substituted C 1-6 alkylsulfonyloxy group, an optionally substituted C 6-10 arylsulfonyloxy group
  • the sulfonylating agent include C 1-6 alkylsulfonylating agents (eg, trifluoromethanesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, etc.) that may be substituted with a halogen atom, And C 6-10 arylsulfonylating agents (eg, benzenesulfonyl chloride, p-toluenesulfonyl chloride, etc.) and the like.
  • C 1-6 alkylsulfonylating agents eg, trifluoromethanesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic an
  • the amount of the sulfonylating agent to be used is generally 1-2 equivalents, preferably 1-1.5 equivalents, relative to compound (5 ').
  • the solvent examples include halogenated hydrocarbons such as chloroform and methylene chloride; aromatic hydrocarbons such as toluene and xylene; ethers such as tetrahydrofuran and dioxane; and mixtures thereof, among which methylene chloride and chloroform , Tetrahydrofuran, toluene and the like are preferable.
  • halogenated hydrocarbons such as chloroform and methylene chloride
  • aromatic hydrocarbons such as toluene and xylene
  • ethers such as tetrahydrofuran and dioxane
  • mixtures thereof among which methylene chloride and chloroform , Tetrahydrofuran, toluene and the like are preferable.
  • the reaction temperature is usually 10 to 150 ° C., preferably 30 to 80 ° C.
  • the reaction time is usually 0.5 to 30 hours, preferably 2 to 20 hours.
  • Examples of the base include alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydride, potassium hydride, potassium tert-butoxide; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo
  • examples include organic bases such as [5.4.0] -7-undecene, and organic bases such as triethylamine, N, N-diisopropylethylamine, and pyridine are preferred.
  • the amount of the base to be used is generally 0.1-4 equivalents, preferably 1-2 equivalents, relative to compound (5 ').
  • Step 3-2 This step is a step for producing compound (I) by reacting compound (3 ′′) with compound (4) in the presence of a base.
  • the base examples include pyridine, tertiary amine (eg, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [ 2.2.2] octane) and other organic bases, and inorganic bases such as potassium fluoride, cesium fluoride, ammonium acetate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, among others pyridine Organic bases such as are preferred.
  • the leaving group represented by Y 3 of the compound (3 ′′) is not particularly limited as long as it does not cause a side reaction.
  • a halogen atom preferably a bromine atom
  • an optionally substituted C 1-6 alkylsulfonyloxy group preferably a trifluoromethanesulfonyloxy group
  • an optionally substituted C 6-10 arylsulfonyloxy group Group preferably, p-toluenesulfonyloxy group
  • the amount of base used is usually 0.1 to 4 equivalents, preferably 1 to 2 equivalents, relative to compound (4).
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, Examples include dimethyl sulfoxide, methanol, ethanol, 2-propanol, acetonitrile and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio. Of these, methylene chloride is preferred.
  • the reaction temperature is usually 0 to 100 ° C., preferably room temperature to 60 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • the target compound In each reaction of the target compound and raw material synthesis, when the raw material compound has an amino group, a carboxy group, or a hydroxy group as a substituent, these groups are protected with a protecting group generally used in peptide chemistry and the like. It may be. In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Examples of such protecting groups e.g., Wiley-Interscience, Inc. 1999 annual “Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter G. M. Wuts Author) include those described in.
  • amino-protecting groups include acyl groups (formyl group, acetyl group, propionyl group, benzoyl group, methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, methanesulfonyl group, benzenesulfonyl group).
  • Group a benzyl group, a benzhydryl group, a trityl group, a phthaloyl group and the like, and these protecting groups may have a substituent.
  • substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms, etc.), C 1-6 alkyl groups, nitro groups and the like, and the number of substituents is about 1 to 3.
  • Examples of the protecting group for carboxy group include C 1-6 alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, etc.), phenyl group, trityl group, silyl group Groups and the like, and these protecting groups may have a substituent.
  • Examples of these substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms, etc.), acyl groups (formyl group, acetyl group, propionyl group, pivaloyl group, etc.), nitro groups, etc. The number is about 1 to 3.
  • Examples of the protective group for hydroxy group include C 1-6 alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl group, etc.), phenyl group, C 7-10 aralkyl group (benzyl group).
  • acyl group (formyl group, acetyl group, propionyl group, pivaloyl group, benzoyl group etc.), aryloxycarbonyl group (phenoxycarbonyl group etc.), C 7-10 aralkyloxy-carbonyl group (benzyloxycarbonyl group etc.)
  • substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms, etc.), C 1-6 alkyl groups, phenyl groups, C 7-10 aralkyl groups, nitro groups, etc. The number is about 1 to 4.
  • inorganic acid hydrogen chloric acid, sulfuric acid, hydrobromic acid, etc.
  • organic acid methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid
  • Oxalic acid fumaric acid, maleic acid, tartaric acid, etc.
  • inorganic bases alkali metals such as sodium and potassium, alkaline earth metals such as calcium and barium, magnesium, aluminum or ammonium
  • organic bases trimethylamine, triethylamine, A salt with pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N′-dibenzylethylenediamine, etc.
  • the compound when the raw material compound can form a salt, the compound may be used as a salt.
  • a salt for example, those exemplified as the salt of compound (I) are used.
  • the compound (I) (including, for example, the compound (Ia) obtained by the above production methods 1 and 2) is further subjected to per se known means for further introduction of substituents and conversion of functional groups, and the scope of the present invention. Can also be produced.
  • substituent conversion a known general method is used, for example, conversion to a carboxy group by hydrolysis of an ester, conversion to a carbamoyl group by amidation of a carboxy group, conversion to a hydroxymethyl group by reduction of the carboxy group, Conversion to alcohol form by reduction or alkylation of carbonyl group, reductive amination of carbonyl group, oximation of carbonyl group, acylation of amino group (including urea, sulfonylation, etc.), alkylation, activity by amine Examples include amination of halogen, conversion to an amino group by reduction of a nitro group, acylation of a hydroxy group (including carbamate formation, sulfonylation, etc.), and alkylation
  • a protective group is introduced into the reactive substituent in advance by a publicly known means as necessary.
  • the protecting group can be removed by means known per se to produce compounds within the scope of the present invention.
  • the compound (I) produced by the method as described above can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), as well as synthetic methods and separation methods known per se (concentration). , Solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product.
  • compound (I) has an optical isomer
  • the optical isomer resolved from the compound is also encompassed in compound (I).
  • optical isomer can be produced by a method known per se. Specifically, optical isomers are obtained by using optically active synthetic intermediates or by optically resolving the final racemate in accordance with a conventional method.
  • the compound (I) may be a crystal, and it is included in the compound (I) regardless of whether the crystal form is single or a crystal form mixture.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
  • Compound (I) labeled with an isotope eg, 2 H, 3 H, 13 C, 14 C, 15 N, 35 S
  • an isotope eg, 2 H, 3 H, 13 C, 14 C, 15 N, 35 S
  • the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • Examples of the dosage form of the pharmaceutical composition include oral forms such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, and powders.
  • Agents; and injections eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops), external preparations (eg, transdermal preparations, ointments), suppositories (eg, rectum) Parenterals such as suppositories and vaginal suppositories).
  • the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is usually about 0.1 to 100% by weight, preferably about 1 to 70% by weight. It is.
  • an oral preparation When manufacturing an oral preparation, it may be coated for the purpose of taste masking, enteric solubility or sustainability, if necessary.
  • Examples of the coating base used for coating include various known coating bases.
  • the compound of the present invention can be used as a preventive or therapeutic agent for various diseases or a diagnostic agent for mammals (eg, humans, cows, horses, dogs, cats, monkeys, mice, rats).
  • mammals eg, humans, cows, horses, dogs, cats, monkeys, mice, rats.
  • the compound of the present invention can also be used as a preparation for children in addition to adults.
  • the compound of the present invention has an excellent sphingosine kinase inhibitory action, and is useful as a preventive or therapeutic agent for inflammatory diseases, hyperproliferative diseases, and autoimmune diseases.
  • inflammatory diseases include prevention of inflammatory bowel diseases (Crohn's disease, ulcerative colitis), arthritis, rheumatism, asthma, allergy, inflammatory kidney disease, chronic obstructive pulmonary disease, periodontal disease, dermatitis, etc. Or it is useful as a therapeutic agent.
  • hyperproliferative diseases include cancer (eg, pancreatic cancer, colorectal cancer, thyroid cancer, seminoma, myelodysplastic syndrome, lung cancer (non-small cell cancer), acute myeloid leukemia, ovarian cancer, liver Cancer, malignant melanoma, skin cancer, bladder cancer, breast cancer, stomach cancer, adrenal tumor, gallbladder cancer, bile duct cancer, bone tumor, central nervous system tumor, uterine cancer (cervical cancer / uterine body cancer), prostate cancer, salivary gland cancer (Tumor), malignant lymphoma, pituitary tumor, peritoneal tumor, esophageal cancer, small intestine tumor, head and neck tumor, kidney cancer, thymic tumor), atherosclerosis, restenosis, mesangial cell proliferative disorder, psoriasis, etc. It is useful as a preventive or therapeutic agent.
  • cancer eg, pancreatic cancer, colorectal cancer, thyroid cancer, seminoma, mye
  • autoimmune diseases include amyotrophic lateral sclerosis, multiple sclerosis, Sjogren's syndrome, systemic lupus erythematosus, rejection after organ transplantation, arthritis, systemic inflammatory response syndrome, sepsis, hemophagocytic syndrome, macrophages It is useful as a preventive or therapeutic agent for activation syndrome, Still disease, Kawasaki disease, multiple organ failure and the like.
  • the compound of the present invention effectively inhibits sphingosine kinase 1 and exhibits a suppressive action on enteritis via a suppressive action on cytokine production, it is particularly useful as a prophylactic or therapeutic agent for inflammatory bowel disease (Crohn's disease, ulcerative colitis). Useful.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when administered orally to an adult bone disease patient, it is usually about 0.01 to 100 mg / kg as a single dose.
  • the body weight is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.
  • Step 1 Synthesis of 5- (3-tert-butylphenyl) -1H-indole-2-carbaldehyde
  • Step 3 Synthesis of ((2R) -1- ⁇ [5- (3,3-dimethyl-2H-benzofuran-7-yl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of ethyl 5- (2-tert-butylpyrimidin-4-yl) -1H-indole-2-carboxylate
  • Step 2 Synthesis of 5- (2-tert-butylpyrimidin-4-yl) -1H-indole-2-carbaldehyde
  • Step 3 Synthesis of ((2R) -1- ⁇ [5- (2-tert-butylpyrimidin-4-yl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • the obtained residue was dissolved in THF (5 mL), lithium aluminum hydride (56.5 mg, 1.49 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hr.
  • the reaction solution is diluted with water (50 ⁇ L), 10% aqueous sodium hydroxide solution (50 ⁇ L) and water (150 ⁇ L) are added in that order, and the mixture is stirred at room temperature for 30 minutes. Washed with saturated saline.
  • the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the obtained residue was dissolved in methylene chloride (10 mL), manganese dioxide (1.0 g) was added, and the mixture was stirred at room temperature for 1 hr.
  • Step 2 Synthesis of 5- (3-tert-butylphenyl) -1-methyl-indole-2-carbaldehyde
  • Step 1 of Example 1 was used. To give the title compound.
  • Step 3 Synthesis of ((2R) -1- ⁇ [5- (3-tert-butylphenyl) -1-methyl-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (3,3-dimethyl-2H-benzofuran-7-yl) -1-methyl-indole-2-carbaldehyde
  • Step 2 ((2R) -1- ⁇ [5- (3,3-Dimethyl-2H-benzofuran-7-yl) -1-methyl-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol Composition
  • the reaction mixture was diluted with water, 10 wt% aqueous sodium hydroxide solution and water were added successively, and the mixture was stirred at room temperature for 1 hr.
  • the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to give the TFA salt (102 mg) of the title compound.
  • Step 1 Synthesis of [5- (3,3-Dimethyl-2H-benzofuran-7-yl) -1H-pyrrolo [2,3-c] pyridin-2-yl] methanol
  • 3,3-Dimethylbenzofuran-7-ylboronic acid (277 mg, 1.44 mmol) and Pd (dppf) Cl 2 (40.6 mg, 0.0555 mmol) were added to this reaction solution, and microwave irradiation was performed at 150 ° C. for 20 minutes. Stir. Further, 3,3-dimethylbenzofuran-7-ylboronic acid (277 mg, 1.44 mmol) and Pd (dppf) Cl 2 (40.6 mg, 0.0555 mmol) were added, and the mixture was stirred at 150 ° C. for 20 minutes under microwave irradiation. The reaction mixture was diluted with saturated brine and extracted with ethyl acetate.
  • the obtained residue was suspended in methanol, D-cis-hydroxyproline (112 mg, 0.856 mmol) and sodium cyanoborohydride (53.8 mg, 0.856 mmol) were added, and the mixture was stirred overnight at room temperature.
  • the reaction mixture was concentrated under reduced pressure, the resulting residue was suspended in THF, lithium aluminum hydride (16.9 mg, 0.446 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hr. Stir for hours.
  • the reaction mixture was diluted with water, 10 wt% aqueous sodium hydroxide solution and water were added successively, and the mixture was stirred at room temperature for 1 hr.
  • the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • Step 1 Synthesis of 5- (3-trimethylsilylphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-trimethylsilylphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 2- [3- (2-formyl-1H-indol-5-yl) phenyl] -2-methyl-propanenitrile
  • Step 2 of 2- [3- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) phenyl] -2-methyl-propanenitrile Composition
  • Step 1 Synthesis of 5- (3-tert-butylphenyl) -1H-pyrrolo [3,2-b] pyridine-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-tert-butylphenyl) -1H-pyrrolo [3,2-b] pyridin-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (3,3-dimethyl-2H-benzofuran-7-yl) -1H-pyrrolo [3,2-b] pyridine-2-carbaldehyde
  • Step 2 ((2R) -1- ⁇ [5- (3,3-Dimethyl-2H-benzofuran-7-yl) -1H-pyrrolo [3,2-b] pyridin-2-yl] methyl ⁇ pyrrolidine- Synthesis of 2-yl) methanol
  • Step 1 Synthesis of 5- (4-tert-butylphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (4-tert-butylphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (3-tert-butylsulfanylphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-tert-butylsulfanylphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (3-isopropoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-isopropoxyphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- [3- (trifluoromethyl) phenyl] -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of [(2R) -1-( ⁇ 5- [3- (trifluoromethyl) phenyl] -1H-indol-2-yl ⁇ methyl) pyrrolidin-2-yl] methanol
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (m-tolyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 2 Synthesis of ⁇ (2R) -1-[(5-phenyl-1H-indol-2-yl) methyl] pyrrolidin-2-yl ⁇ methanol
  • Step 1 Synthesis of methyl (2R, 4R) -4-fluoropyrrolidine-2-carboxylate
  • the obtained compound was dissolved in methanol (10 mL), 10% palladium carbon (20 mg) was added, and the mixture was replaced with hydrogen gas and stirred overnight.
  • the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • Step 2 Synthesis of ((2R, 4S) -1- ⁇ [5- (3-tert-butylphenyl) -1H-indol-2-yl] methyl ⁇ -4-fluoropyrrolidin-2-yl) methanol
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-isopropyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- [3- (dimethylamino) phenyl] -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of [(2R) -1-( ⁇ 5- [3- (dimethylamino) phenyl] -1H-indol-2-yl ⁇ methyl) pyrrolidin-2-yl] methanol
  • Step 1 Synthesis of 3- (2-formyl-1H-indol-5-yl) -N, N-dimethyl-benzenesulfonamide
  • Step 2 Synthesis of 3- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) -N, N-dimethyl-benzenesulfonamide
  • Step 1 Synthesis of 5- [3- (cyclopentoxy) -2,4-difluorophenyl] -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of [(2R) -1-( ⁇ 5- [3- (cyclopentoxy) -2,4-difluorophenyl] -1H-indol-2-yl ⁇ methyl) pyrrolidin-2-yl] methanol
  • Step 1 Synthesis of 5- (3-chlorophenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-chlorophenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (5-tert-butyl-2-methoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (5-tert-butyl-2-methoxyphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (2-ethoxy-4-pyridyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (2-ethoxy-4-pyridyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (5-methoxy-3-pyridyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (5-methoxy-3-pyridyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- [3-Isopropoxy-5- (trifluoromethyl) phenyl] -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of [(2R) -1-( ⁇ 5- [3-Isopropoxy-5- (trifluoromethyl) phenyl] -1H-indol-2-yl ⁇ methyl) pyrrolidin-2-yl] methanol
  • Step 1 Synthesis of 5- (3-isopropylphenyl) -1H-pyrrolo [3,2-b] pyridine-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-isopropylphenyl) -1H-pyrrolo [3,2-b] pyridin-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (2-fluoro-5-isopropylphenyl) -1H-pyrrolo [3,2-b] pyridine-2-carbaldehyde
  • Step 2 Synthesis of 2-chloro-4- (3,3-diethoxypropynyl) pyrimidin-5-amine
  • Step 4 Synthesis of ((2R) -1- ⁇ [2- (3-tert-butylphenyl) -5H-pyrrolo [3,2-d] pyrimidin-6-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • the obtained residue was dissolved in methanol (2 mL), D-prolinol (5.8 ⁇ L, 0.060 mmol) and sodium cyanoborohydride (3.8 mg, 0.060 mmol) were added, and the mixture was stirred overnight at room temperature.
  • the reaction was quenched with water, diluted with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to give the TFA salt (14.4 mg) of the title compound.
  • Step 1 Synthesis of 5- (3-phenylphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-phenylphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (5-isopropyl-2-methoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (5-isopropyl-2-methoxyphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • the obtained residue was dissolved in THF (3 mL), lithium aluminum hydride (26.0 mg, 0.686 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hr.
  • the reaction solution was quenched with water, 10 wt% aqueous sodium hydroxide solution and water were sequentially added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to obtain the TFA salt (54.3 mg) of the title compound.
  • Step 1 Synthesis of (2R, 4S) -2- ⁇ [tert-butyl (diphenyl) silyl] oxymethyl ⁇ piperidin-4-ol
  • the obtained residue was dissolved in methylene chloride (40 mL), tert-butylchlorodiphenylsilane (6.10 g, 22.2 mmol) and triethylamine (1.41 mL, 25.5 mmol) were added, and the mixture was stirred at room temperature for 3 days.
  • the reaction was diluted with water and extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Synthesis of (2R, 4S) -1- ⁇ [5- (3-tert-butylphenyl) -1H-indol-2-yl] methyl ⁇ -2- (hydroxymethyl) piperidin-4-ol
  • Step 1 Synthesis of 5- (3-isopropylphenyl) -1H-pyrrolo [2,3-c] pyridine-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-isopropylphenyl) -1H-pyrrolo [2,3-c] pyridin-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (2-fluoro-5-isopropoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (2-Fluoro-5-isopropoxyphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (3-isopropoxy-4-methoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-Isopropoxy-4-methoxy-phenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of N-tert-butyl-3- (2-formyl-1H-indol-5-yl) benzenesulfonamide
  • Step 2 Synthesis of N-tert-butyl-3- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) benzenesulfonamide
  • N-tert-butyl-3- (2-formyl-1H-indole-5 obtained in Step 1 of this example was used.
  • -Yl The TFA salt of the title compound was obtained in the same manner as in Step 2 of Example 1 using benzenesulfonamide.
  • Step 1 Synthesis of 5- (1-tert-butylpyrazol-4-yl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (1-tert-butylpyrazol-4-yl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • the obtained residue was dissolved in methanol (2 mL), D-prolinol (55.2 ⁇ L, 0.568 mmol) and sodium triacetoxyborohydride (120 mg, 0.568 mmol) were added, and the mixture was stirred at room temperature for 3 hr.
  • the reaction solution was diluted with water, diluted with a saturated aqueous sodium bicarbonate solution, and extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the resulting residue was purified by thin layer chromatography, then purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to obtain the TFA salt (22.1 mg) of the title compound.
  • the obtained residue was purified by silica gel column chromatography.
  • the obtained compound was dissolved in methanol (2 mL), D-prolinol (62.1 ⁇ L, 0.638 mmol) and sodium triacetoxyborohydride (135 mg, 0.638 mmol) were added, and the mixture was stirred overnight at room temperature.
  • the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to obtain the TFA salt (79.2 mg) of the title compound.
  • Step 1 Synthesis of 5- (3-fluoro-5-isobutoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-Fluoro-5-isobutoxyphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- [3- (1-adamantyl) -4-methoxyphenyl] -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of [(2R) -1-( ⁇ 5- [3- (1-adamantyl) -4-methoxyphenyl] -1H-indol-2-yl ⁇ methyl) pyrrolidin-2-yl] methanol
  • the obtained compound was dissolved in methanol (2 mL), D-prolinol (49.4 ⁇ L, 0.508 mmol) and sodium triacetoxyborohydride (108 mg, 0.508 mmol) were added, and the mixture was stirred overnight at room temperature.
  • the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to obtain the TFA salt (27.5 mg) of the title compound.
  • Step 1 Synthesis of 5- (3-tert-butylphenyl) -1H-pyrrolo [2,3-c] pyridine-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-tert-butylphenyl) -1H-pyrrolo [2,3-c] pyridin-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (3-isopropoxyphenyl) -1H-pyrrolo [2,3-c] pyridine-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-isopropoxyphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • the obtained residue was purified by silica gel chromatography.
  • the obtained compound was suspended in methanol, D-prolinol (86.8 ⁇ L, 0.892 mmol) and sodium triacetoxyborohydride (189 mg, 0.892 mmol) were added, and the mixture was stirred overnight at room temperature.
  • the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to obtain the TFA salt (95.1 mg) of the title compound.
  • Step 1 Synthesis of 5- [3- (morpholinomethyl) phenyl] -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of [(2R) -1-( ⁇ 5- [3- (morpholinomethyl) phenyl] -1H-indol-2-yl ⁇ methyl) pyrrolidin-2-yl] methanol
  • Step 1 Synthesis of 5- (2-isopropyl-4-methylthiazol-5-yl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (2-isopropyl-4-methylthiazol-5-yl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- ⁇ 3-[(4-methoxyphenyl) methoxy] phenyl ⁇ -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ⁇ (2R) -1-[(5- ⁇ 3-[(4-methoxyphenyl) methoxy] phenyl ⁇ -1H-indol-2-yl) methyl] pyrrolidin-2-yl ⁇ methanol
  • Step 1 Synthesis of ethyl (E) -3- [5- (3-tert-butylphenyl) -1H-indol-2-yl] -2-propenoate
  • Step 2 Synthesis of 3- [5- (3-tert-butylphenyl) -1H-indol-2-yl] propyl-4-methylbenzenesulfonate
  • Step 1 of this example The crude product obtained in Step 1 of this example was suspended in tetrahydrofuran (8.0 mL) and lithium aluminum hydride (32 mg, 0.56 mmol) was added at 0 ° C. under an argon atmosphere. After stirring at 0 ° C. for 30 minutes, the reaction solution was diluted with water (2.0 mL) and filtered through celite. Thereafter, the residual solvent was distilled off. The residue was suspended in methylene chloride (5.0 ml), pyridine (57 ⁇ L, 0.7 mmol) and p-toluenesulfonyl chloride (80 mg, 0.42 mmol) were added, and the mixture was stirred at 50 ° C. for 2 hours.
  • methylene chloride 5.0 ml
  • pyridine 57 ⁇ L, 0.7 mmol
  • p-toluenesulfonyl chloride 80 mg, 0.42 mmol
  • Step 3 Synthesis of ((2R) -1- ⁇ 3- [5- (3-tert-butylphenyl) -1H-indol-2-yl] propyl ⁇ pyrrolidin-2-yl) methanol
  • Step 3 Synthesis of ((2R) -1- ⁇ [5- (3,3-dimethyl-2H-benzofuran-5-yl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- [3- (methoxymethyl) phenyl] -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of [(2R) -1-( ⁇ 5- [3- (methoxymethyl) phenyl] -1H-indol-2-yl ⁇ methyl) pyrrolidin-2-yl] methanol
  • Step 1 Synthesis of 2- [3- (2-formyl-1H-indol-5-yl) phenyl] acetonitrile
  • Step 2 Synthesis of 2- [3- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) phenyl] acetonitrile
  • Step 1 Synthesis of 5- [3- (1-piperidylmethyl) phenyl] -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ 5- [3- (1-piperidylmethyl) phenyl-1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of N-tert-butyl-3- (2-formyl-1H-pyrrolo [2,3-c] pyridin-5-yl) benzamide
  • Step 2 N-tert-butyl-3- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-pyrrolo [2,3-c] pyridin-5-yl Synthesis of benzamide
  • Step 1 Synthesis of 5- (3-fluoro-5-isobutoxyphenyl) -1H-pyrrolo [2,3-c] pyridine-2-carbaldehyde
  • Step 2 ((2R) -1- ⁇ [5- (3-Fluoro-5-isobutoxyphenyl) -1H-pyrrolo [2,3-c] pyridin-2-yl] methyl ⁇ pyrrolidin-2-yl) Synthesis of methanol
  • the obtained residue was purified by silica gel column chromatography.
  • the obtained compound was dissolved in methanol (2 mL), D-prolinol (69.1 ⁇ L, 0.710 mmol) and sodium triacetoxyborohydride (150 mg, 0.710 mmol) were added, and the mixture was stirred overnight at room temperature.
  • the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to obtain the TFA salt (120 mg) of the title compound.
  • Step 1 Synthesis of 5- (3-isobutoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-isobutoxyphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (2-fluoro-5-isobutoxyphenyl) -1H indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (2-Fluoro-5-isobutoxy-phenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of ((2R) -1- ⁇ [5- (3-aminophenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 2 N- [3- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) phenyl] -2,2-dimethyl-propane Synthesis of amide
  • the obtained residue was dissolved in a mixed solvent of methanol (3.0 mL) and methylene chloride (2.0 mL), D-prolinol (21 ⁇ L, 0.22 mmol) was added and stirred for 5 minutes, and then sodium triacetoxyborohydride ( 45 mg, 0.22 mmol) was added and stirred for 12 hours.
  • the solvent was distilled off from this reaction mixture, and the resulting residue was purified by reverse phase HPLC (0.1% TFA acetonitrile / 0.1% TFA water) and lyophilized to obtain the TFA salt (1.1 mg) of the title compound. It was.
  • Step 1 Synthesis of 5- (3-isobutoxy-4-methoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 Synthesis of ((2R) -1- ⁇ [5- (3-isobutoxy-4-methoxyphenyl) -1H-indol-2-yl] methyl ⁇ pyrrolidin-2-yl) methanol
  • Step 1 Synthesis of 5- (2-fluoro-3-isobutoxyphenyl) -1H-indole-2-carbaldehyde
  • Step 2 [(2R) -1-[[5- (2-Fluoro-3-isobutoxyphenyl) -1H-indol-2-yl] methyl] pyrrolidin-2-yl] methanol
  • 6-Bromonicotinic acid 200 mg, 0.990 mmol was dissolved in acetonitrile (2 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (228 mg, 1.19 mmol), 1-hydroxybenzo Triazole (162 mg, 1.19 mmol), tert-butylamine (126 ⁇ L, 1.19 mmol) and pyridine (96.9 ⁇ L, 1.19 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Synthesis of N-tert-butyl-6- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) pyridine-2-carboxamide
  • Step 2 Synthesis of N-tert-butyl-2- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) pyridine-4-carboxamide
  • Example 61 using 2-bromo-N-tert-butyl-pyridine-4-carboxamide obtained in Step 1 of this example instead of methyl 2- (3-bromophenyl) -2-methylpropanoate In the same manner as above, the TFA salt of the title compound was obtained.
  • Step 2 Synthesis of N-tert-butyl-4- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) pyridine-2-carboxamide
  • Example 61 was conducted using 4-bromo-N-tert-butyl-pyridine-2-carboxamide obtained in Step 1 of this example instead of methyl 2- (3-bromophenyl) -2-methylpropanoate. In the same manner as above, the TFA salt of the title compound was obtained.
  • Step 2 Synthesis of N-tert-butyl-2-fluoro-5- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) benzamide
  • Example 61 was conducted using 5-bromo-N-tert-butyl-2-fluoro-benzamide obtained in Step 1 of this example instead of methyl 2- (3-bromophenyl) -2-methylpropanoate. In the same manner as above, the TFA salt of the title compound was obtained.
  • Step 1 Synthesis of 6- (2- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl ⁇ -1H-indol-5-yl) pyridine-2-carboxylic acid

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  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un inhibiteur de sphingosine kinase comprenant un composé représenté par la formule (I) [où chaque symbole est tel que défini dans la description] ou un sel de celui-ci, et fournit un composé utile pour la prévention et/ou le traitement d'une maladie intestinale inflammatoire et similaire.
PCT/JP2014/058631 2013-03-29 2014-03-26 Inhibiteur de sphingosine kinase WO2014157382A1 (fr)

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JP2013-075300 2013-03-29

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016085933A1 (fr) 2014-11-24 2016-06-02 The Board Of Trustees Of The University Of Illinois Méthode de prévention ou de traitement d'une maladie ou d'une affection pulmonaire
WO2017129769A1 (fr) 2016-01-28 2017-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes permettant d'améliorer la puissance d'inhibiteurs de points de contrôle immunitaires
WO2019162325A1 (fr) 2018-02-21 2019-08-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de sk1 en tant que biomarqueur pour prédire la réponse à des inhibiteurs de point de contrôle immunitaire
US10696666B2 (en) 2016-10-18 2020-06-30 CellCentric Limited Pharmaceutical compounds
US11453662B2 (en) 2018-04-18 2022-09-27 Cellcentric Ltd Process for preparing modulators of p300 and/or CBP

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US20040248899A1 (en) * 2003-05-07 2004-12-09 Cowart Marlon D. Fused bicyclic-substituted amines as histamine-3 receptor ligands
JP2007501858A (ja) * 2003-05-07 2007-02-01 アボット・ラボラトリーズ ヒスタミン−３受容体リガンドとしての縮合二環式置換アミン
WO2007129473A1 (fr) * 2006-05-09 2007-11-15 Daiichi Sankyo Company, Limited Dérivé arylique bicyclique
JP2009114108A (ja) * 2007-11-06 2009-05-28 Daiichi Sankyo Co Ltd 二環性アリール誘導体を含有する医薬組成物
JP2011525502A (ja) * 2008-06-23 2011-09-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング チアゾリルピペリジン誘導体
WO2013033258A1 (fr) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Composés antibactériens et leurs méthodes d'utilisation

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US20040248899A1 (en) * 2003-05-07 2004-12-09 Cowart Marlon D. Fused bicyclic-substituted amines as histamine-3 receptor ligands
JP2007501858A (ja) * 2003-05-07 2007-02-01 アボット・ラボラトリーズ ヒスタミン−３受容体リガンドとしての縮合二環式置換アミン
WO2007129473A1 (fr) * 2006-05-09 2007-11-15 Daiichi Sankyo Company, Limited Dérivé arylique bicyclique
JP2009114108A (ja) * 2007-11-06 2009-05-28 Daiichi Sankyo Co Ltd 二環性アリール誘導体を含有する医薬組成物
JP2011525502A (ja) * 2008-06-23 2011-09-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング チアゾリルピペリジン誘導体
WO2013033258A1 (fr) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Composés antibactériens et leurs méthodes d'utilisation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016085933A1 (fr) 2014-11-24 2016-06-02 The Board Of Trustees Of The University Of Illinois Méthode de prévention ou de traitement d'une maladie ou d'une affection pulmonaire
US11026918B2 (en) 2014-11-24 2021-06-08 The Board Of Trustees Of The University Of Illinois Method of preventing or treating a pulmonary disease or condition
WO2017129769A1 (fr) 2016-01-28 2017-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes permettant d'améliorer la puissance d'inhibiteurs de points de contrôle immunitaires
US10696666B2 (en) 2016-10-18 2020-06-30 CellCentric Limited Pharmaceutical compounds
US11377443B2 (en) 2016-10-18 2022-07-05 CellCentric Limited Pharmaceutical compounds
WO2019162325A1 (fr) 2018-02-21 2019-08-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de sk1 en tant que biomarqueur pour prédire la réponse à des inhibiteurs de point de contrôle immunitaire
US11453662B2 (en) 2018-04-18 2022-09-27 Cellcentric Ltd Process for preparing modulators of p300 and/or CBP

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