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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems

Definitions

• the present invention relates to novel condensed imidazole derivatives useful as DPPIV inhibitors and uses thereof.
• Dipeptidyl peptidase-IV is a serine that specifically hydrolyzes one X-Pro (X may be any amino acid) dipeptide from the free N-terminus of a polypeptide chain.
• X may be any amino acid dipeptide from the free N-terminus of a polypeptide chain.
• a type of protease is a serine that specifically hydrolyzes one X-Pro (X may be any amino acid) dipeptide from the free N-terminus of a polypeptide chain.
• the DPP IV inhibitor can be a useful therapeutic or preventive agent for diseases involving GLP-1 and GIP such as obesity and diabetes. Furthermore, the relationship between dipeptidyl peptidase IV and various diseases described below has been reported, and from these facts, it can be expected that DPP IV inhibitors can be used as therapeutic agents for them.
• (1) Prevention and treatment of AIDS see Non-Patent Document 2
• Non-Patent Documents 5 and 6 Agent for preventing and treating diabetes, obesity and hyperlipidemia (see Non-Patent Documents 5 and 6) (5) Agent for preventing and treating angiogenesis (see Non-Patent Document 7)
• DPPP IV inhibitors Although several DPPP IV inhibitors are known (see Patent Documents 2 to 4), DPPP IV inhibitors having a hypoxanthine skeleton or an imidazopyridazinone skeleton have not been known.
• an object of the present invention is to provide a compound having a DPPIV inhibitory activity, which is useful as an agent for treating, preventing, or ameliorating a diabetic disease or the like. Disclosure of the invention
• the present inventors have conducted intensive studies in view of the above circumstances, and as a result, succeeded in synthesizing a novel condensed imidazole derivative such as a hypoxanthine derivative or an imidazopyridazinone derivative, and these compounds were excellent.
• the present inventors have found that they have a DPPIV inhibitory action, and completed the present invention. That is, the present invention includes the following.
• T 1 represents a 4- to 12-membered heterocyclic group containing 1 or 2 nitrogen atoms in the ring, which may have a substituent, and which is monocyclic or bicyclic. ;
• X which may have a substituent C ⁇ e alkyl group, which may have a substituent C 2 _ 6 alkenyl group which may have a substituent C 2 - 6 alkynyl group, a substituted Ce—i optionally having a group.
• Aryl group 5- to 10-membered optionally substituted teroaryl group, optionally substituted C 6 —i.
• R 1 and R 2 are each independently of the formula —A.
• a 1 -A 2 (where A is a single bond or a d-6 alkylene group which may have 1 to 3 groups selected from the following substituent group B;
• a 1 is a single bond, an oxygen atom, a sulfur atom, a sulfier group, a sulfonyl group, a carbonyl group, a formula —O—CO—, a formula CO—O—, a formula —NR A— , a formula CO—NRA—, Shiki NR a -CO-, wherein _S0 2 - NR a -, or Shiki NR a -S0 2 - means;
• a 2 and R A each independently represent a hydrogen atom, a halogen atom, Shiano group, - 6 alkyl groups, C 3 - 8 cycloalkyl group, C 2 one 6 alkenyl, C 2 - 6 alkyl groups, C 6 —.
• Ariru C - means 7 alkylcarbonyl two Le group - 6 alkyl or C 2.
• a 2 and R A are each independently selected from the group consisting of the following substituents B May have 1 to 3 groups. ) Means a group represented by.
• Substituent group B a hydroxyl group, a mercapto group, Shiano group, a nitro group, a halogen atom, triflate Ruo Russia methyl group, which may have a substituent - 6 alkyl groups, C 3 - 8 cyclo alkyl groups, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 6 - i.
• C — 6 alkylthio group Formula 1 SO 2 — NR B1 — R B2 , Formula 1 NR B1 — CO—R B2 , Formula 1
• NR B1_ R B2 (wherein, RB1 and RB 2 each independently hydrogen atom or C
• R 6 means an alkyl group.
• Arukiru group means a group consisting of groups represented by C 6 means one 10 Ariru C 6 Teroariru C i-6 alkyl Le group to an alkyl group or 5-10 membered).. Or a salt or hydrate thereof.
• n and m each independently represent 0 or 1); an azetidine-11-yl group which may have a substituent; and a group which has a substituent.
• T 1 is the formula
• a azetidine-11-yl group optionally having an amino group
• a pyrrolidine optionally having an amino group
• [1] which is a 1-yl group, a piperidine-11-yl group optionally having an amino group or a azepane-11-yl group optionally having an amino group, or a compound thereof; Salts or hydrates thereof.
• T 1 is a piperazine-11-yl group or a 3-aminopiperidine-11-yl group, or a salt thereof or a hydrate thereof.
• X is a group represented by the formula X 1 — X 2 (wherein X 1 represents a single bond or a methylene group which may have a substituent; X 2 may have a substituent C 2 _ 6 alkenyl group, a group represented by that.) means an optionally substituted C 2 _ 6 Arukyuru group or an optionally substituted phenylene Le group [1] Or the salt or a hydrate thereof according to any one of [5] to [5].
• X is a group represented by the formula X 11 — X 12 (wherein X 11 represents a single bond or a methylene group; 12 represents a ⁇ 2 _ 6 alkenyl group, a C 2 _ 6 alkynyl group or a substituent. Have Means a good phenyl group.
• the phenyl group which may have a substituent is a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a butyl group, a methoxy group, an ethoxy group, an acetyl group, a cyano group,
• a formyl group which is a phenyl group which may have a group selected from the group consisting of a C 2 _ 7 alkoxyl group in the 2-position, and a compound according to (6) or (7) or a compound thereof; Salts or hydrates thereof.
• X is a 3-methyl-2-butene-11-yl group, 2-butyn-11-yl group, benzinole group or 2-chloropheninole group; one of [1] to [5]. Or a salt or hydrate thereof.
• Z 1 is a nitrogen atom
• Z 2 is nitrogen atom
• R 1 is a hydrogen atom or a compound represented by the formula: A 10 — A 11 — A 12 (wherein A 10 may have 1 to 3 groups selected from the following substituent group C, alkylene Means base;
• a 11 represents a single bond, an oxygen atom, a sulfur atom or a hydroxyl group
• a 12 is a hydrogen atom, which may have 1 to 3 groups selected from the following substituent group C 6 to 10 7 reel groups, and 1 to 3 reel groups selected from the following substituent group C Even if it has a group Good 5 10-membered heteroaryl group, which may have 13 groups selected from the following substituent group C 5 13-membered heteroaryl C ⁇ 6 alkyl group or 13 substituents selected from the following substituent group C It has a group of 0 6 — 1 .
• Aryl 1 to 6 means an alkyl group.
• Substituent group C a hydroxyl group, a nitro group, Shiano group, a halogen atom, Ji alkyl group, an alkoxy group, Ji 6 alkylthio group, triflate Ruo Russia methyl, the formula - NR C1_ R C2 (wherein, RC1 and RC2, respectively .
• R 1 is a hydrogen atom, a Ci- 6 alkyl group optionally having 13 groups selected from the following substituent group C, 13 groups selected from the following substituent group C 5 or 10-membered heteroaryl C— 6 alkyl group or 13 groups selected from the following substituent C group. 6 — 10 reels.
• 1 - 6 Aruki Le is a group, [1] [1 3] The compound or a salt or hydrate thereof according to any one of.
• Substituent group C a hydroxyl group, a nitro group, Shiano group, a halogen atom, CI- 6 alkyl group, - 6 alkoxy group, - 6 alkylthio groups, trifluoperazine Ruo Russia methyl, the formula - NR C1_ R C2 (wherein, RC1 And RC2 are each independently a hydrogen atom or
• R 6 means an alkyl group.
• R C4 and R C5 each independently represent a hydrogen atom or a d-6 alkyl group. means.
• substituent group C Shiano group, alkoxy group, C 2 - 7 is a group consisting of alkoxy force Ruponiru group Contact Yopi halogen atoms [14] or compound or a salt thereof, or their according to [15] Hydrate.
• R 1 is a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyethyl group or a 4-methoxycarbonyldivinyl-1-yl group; [1] to [1] 3] The compound according to any one of the above, or a salt thereof or a hydrate thereof.
• R 2 is a hydrogen atom, a cyano group, or a compound represented by the formula: A 21 — A 22 (where A 21 is a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carboyl group, a formula — O— CO—, Formula I CO— O—, Formula I NR A2 —, Formula I CO— NR A2 — or Formula I NR A2 _CO—;
• a 22 and R A2 are each independently a hydrogen atom , Shiano group, C ⁇ 6 alkyl group, C 3 - 8 cycloalkyl group, C 2 - 6 alkenyl, C 2 one 6 alkynyl group, C 6 - 10 Ariru group, heteroaryl group 5-10 membered, 4-8 Membered heterocyclic group, 5- to 10-membered heteroaryl alkyl group or C 6 —i, which means an aryl Ci-e al
• Substituent group D includes a hydroxyl group, a cyano group, a nitro group, a halogen atom, an alkyl group, a Ci- 6 alkoxy group, a C- 6 alkylthio group, a trifluoromethyl group, a formula — NR D1 -R D2 (wherein R . D1 and R D2 is to mean independently hydrogen atom or C ⁇ 6 alkyl group) a group represented by the formula one CO-: R D3 (wherein, R D3 is 4 Means an 8-membered heterocyclic group.
• R D4 is a single bond, an oxygen atom or the formula one NR D6 - means, R D5 and R D6 are each independently a hydrogen atom means a group consisting of groups represented by means C 3 _ 8 cycloalkyl group, or C _ 6 alkyl group.).
• R 2 is a hydrogen atom, Shiano group, a carboxy group, C 2 - 7 alkoxycarbonyl - le group, CI- 6 alkyl group, wherein one CONR D7 R D8 (wherein, R D7 and R D8 it And independently represents a hydrogen atom or a 6 alkynole group.) Or a group represented by the formula —A 23 — A 24 (where A 23 represents an oxygen atom, a sulfur atom, or a NR A3 — A 24 and R A3 each independently represent a hydrogen atom, an alkyl group which may have one group selected from the following substituent D 1 group, and an alkyl group optionally selected from the following substituent D 1 group one may have a group C 3 _ 8 cycloalkyl group, substituent group D 1 group which may have one group selected from C 2 to - 6 alkenyl group, substituent D may have one group selected from a group C 2 - 6 Arukyuru group, have one group selected from
• R 2 is a hydrogen atom, a cyano group, a C- 6 alkoxy group or a formula —A 25 —A 26 (where A 25 represents an oxygen atom, a sulfur atom or a formula NR A4 —; A 26 and R A4 are each independently a hydrogen atom, and one substituent selected from the following group D1 One chosen of C ⁇ 6 alkyl group having a group, from one C 3 _ 8 that the have a cycloalkyl group or the following substituent D 1 group selected from Substituent group D 1 group.
• R 2 is a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group,
• a 27 represents an oxygen atom, a sulfur atom or 1 NH—
• a 28 and A 29 is that it means a hydrogen atom or d_ 6 alkyl group independently.
• the compound represented by the general formula (I) is 7- (2-butynyl) -1-2-cyano 1-methyl-8- (piperazine-1-yl)-1,7-dihydropurine-1-6-
• a medicament comprising the compound of [1] to [24].
• a dipeptidyl peptidase IV inhibitor comprising the compound according to [1] to [24].
• a pharmaceutical composition comprising the compound of any one of [1] to [: 24] and a formulation auxiliary [28] An agent for preventing or treating diabetes mellitus containing the compound of [1] to [24] o
• Diabetes obesity, hyperlipidemia, AIDS, osteoporosis, gastrointestinal disorder, angiogenesis, infertility, inflammatory disease, allergic disease or cancer containing the compound according to (1) to (24).
• Prophylactic or therapeutic agent Prophylactic or therapeutic agent.
• An immunomodulator, a hormonal modulator or an anti-rheumatic agent comprising the compound according to [1] to [24].
• (31) administering a pharmacologically effective amount of the compound according to (1) to (24) or a salt thereof or a hydrate thereof to a patient, for treating a disease in which dipeptidyl peptidase IV inhibition is effective or Prevention methods.
• T. I a group represented by T 1 in the above [1], a pyridyl group optionally having a substituent, a pyridinium group optionally having a substituent,
• n and m each independently represent 0 or 1), or a group which may have a substituent
• X 0 which may have a substituent C 3 one 8 cycloalkyl group which may have a substituent 6 alkyl group which may have a substituent c 2 _ 6 alkenyl group, a substituted which may have a group C 2 - 6 Arukyuru group may have a substituent Ce-i.
• RZ 1 and Z 2 are as defined respectively RZ 1 and Z 2 in the above [1]. ] The compound represented by these, its salt, or those hydrate.
• RR 2, T Zeta 1 and Zeta 2 the [1] RR 2, T 1 in the same meanings respectively Zeta 1 and Zeta 2.
• R 1 is as defined in the above [1];
• R p5 represents t-butoxycarboxy group, trityl group or formula —SO 2 NH 2 ;
• T 1Q represents a halogen atom or a hydrogen atom.
• R 1 is as defined in the above [1];
• T 11 is a halogen atom or a formula Means a group represented by T 13 represents a t-butoxycarbonyl group, a benzyloxycarbonyl group or a formyl group. Or a salt thereof, or a hydrate thereof.
• R 1 and X are as defined in the above [1].
• T 12 represents a halogen atom.
• X is the same as defined in the above [1]. However, when X is a benzyl group;
• T 21 and T 22 each independently represent a halogen atom
• T 11 is a halogen atom or a formula Means a group represented by T 13 is t-toxycarbonyl group, benzyloxy It means a carboel group or a formyl group. Or a salt thereof, or a hydrate thereof.
• T 22 represents a halogen atom
• T 13 represents a t-butoxycarbyl group, a benzyloxycarbinole group or a formyl group. ] The compound represented by these, its salt, or those hydrate.
• T 1 represents an optionally substituted monocyclic or bicyclic 6 to 12-membered heterocyclic ring containing two nitrogen atoms in the ring;
• X which may have a substituent C ⁇ e alkyl group, which may have a substituent C 2 - 6 alkenyl group which may have a substituent C 2 - 6 alkynyl group, a substituted good C 6 one 10 Ariru group which may have a group, Te to be or 5-10 membered substituted Roariru group which may have a substituent C 6 - 10 Ariru alkyl group or Represents a 5- to 10-membered heteroaryl C 6 alkyl group optionally having substituent (s);
• X may form a bond with the atoms constituting the ring in T 1.
• R 1 and R 2 each independently represent a hydrogen atom, a 4- to 8-membered heterocyclic group which may have a substituent or a formula A Q — A 1 — A 2 (where A Q is , A single bond, or 1 to 3 groups selected from the group consisting of the following replacement groups B — 6 alkylene groups;
• a 1 represents a single bond, an oxygen atom, a sulfur atom , Surufi group, scan Ruhoninore group, Karuponiru group, wherein one O-CO-, wherein one CO- O-formula one NR A -, wherein one CO- NRA-, wherein one NRA- CO-, wherein one S0 2 - NR a -, or wherein one NR a one SO 2 - means;
• a 2 and R A each independently represent a hydrogen atom, an alkyl group, C 3 - 8 consequent opening alkyl group, C 2 - 6 alkenyl - le group, C 2 - 6 alkyl groups, C 6 -.
• a 2 and R A may each independently have 1 to 3 groups selected from the group consisting of the following substituent B groups. ) Means a group represented by.
• Substituent group B a hydroxyl group, Shiano group, a halogen atom, an alkyl group, C 3 _ 8 cycloalkyl group, C 2 - 6 Arukeyuru groups, C 2 - 6 alkynyl group, C 6 ⁇ 0 Ariru group, 5- to 10-membered to Teroariru groups, heterocyclic groups 4-8 membered, 6 alkoxy group, C 1 _ 6 alkylthio groups
• the structural formula of a compound may represent a certain isomer for convenience, but the present invention includes all geometric isomers that occur in the structure of the compound and optical isomers based on asymmetric carbon. , Stereoisomers, tautomers and the like, and isomer mixtures, and are not limited to the description of formulas for convenience, and may be either one isomer or a mixture. Therefore, the compound of the present invention may have an asymmetric carbon atom in the molecule and may exist in an optically active form or a racemic form, but the present invention is not limited thereto, and any of them is included. It is.
• polymorphism may exist, but is not limited thereto, and any one of the crystal forms may be a single crystal or a mixture of crystal forms. And hydrates. Further, so-called metabolites generated by decomposing the compound according to the present invention in a living body are also included in the claims of the present invention.
• 0 ⁇ 6 alkyl group refers to a monovalent group derived from an aliphatic hydrocarbon having 1 to 6 carbon atoms by one arbitrary hydrogen atom. It means 6 linear or branched alkyl groups, specifically, for example, methyl group, ethyl group, 1-propyl group, 2-propyl group, 2-methyl-1-propyl group, 2-methyl- 2-propyl, 1-butyl, 2-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-2-butyl Group, 3-methyl-2-butyl group, 2,2-dimethyl-1-propyl group, 1-1hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-1-pentyl group, 3-— Methyl-1-pentyl, 4-methyl-11-pentyl, 2-methyl-2-pentyl, 3 Methyl-2-pentyl
• C 2 _ 6 alkenyl group in the present specification, also the number two to six straight meant branched alkenyl groups, specifically, for example, Bulle group, Ariru group, Examples thereof include 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butyl group, 3-butyl group, pentyl group, hexenyl group and the like.
• - - 6 alkyl C 2 Le group or the number two to six straight means branched alkynyl group, specifically, for example, Echuru group, 1 Examples include a monopropynyl group, a 2-propyl group, a petyl group, a pentyl group, and a hexyl group.
• C 3 8 cycloalkyl group means a cyclic aliphatic hydrocarbon group number 3-8 carbons, specifically, for example, cyclopropyl group, Shikuropuchi group, a cyclopentyl group And a cyclohexyl group, a cycloheptyl group, a cyclooctanol group and the like.
• the ⁇ rC ⁇ 6 alkylene group '' in the present specification means a divalent group derived by removing one arbitrary hydrogen atom from the above-mentioned definition ⁇ 0 ⁇ 6 alkyl group '', specifically, for example, Examples include methylene group, 1,2-ethylene group, 1,1-ethylene group, 1,3-propylene group, tetramethylene group, pentamethylene group, and hexamethylene group.
• C 3 8 cycloalkylene group means a divalent group derived the define further arbitrary hydrogen atom from the “C 3 _ 8 cycloalkyl group” 1 except for.
• Alkoxy group means an oxy group to which the above-defined 6 alkyl group is bonded, specifically, for example, a methoxy group, an ethoxy group Xy group, 1-propyloxy group, 2-propyloxy group, 2-methyl-1-propyloxy group, 2-methyl-2-propyloxy group, 1-butyloxy group, 2-butyloxy group, 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy, 2-methyl-1-butyloxy, 3-methyl-1-butyloxy, 2-methyl-2-butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl-1-propyloxy, 11 Hexyloxy group, 2-hexyloxy group, 3-hexyloxy group, 2-methynole-l-pentyloxy group, 3-methynolee-l-pentyloxy group, 4-methyl-l-pentyloxy group, 2-methyl-l-pentyno
• C i- 6 alkylthio group in the present specification means a thio group to which the above-mentioned “C i- 6 alkyl group” is bonded, and specifically, for example, a methylthio group, an ethylthio group, —Propylthio group, 2-propylthio group, butylthio group, pentylthio group and the like.
• C 2 _ 7 alkoxycarbonyl group in the present specification is a carbonyl group "6 alkoxy group.” Is bonded defined above, specifically, for example, main Tokishikarupo - group, Examples thereof include an ethoxycarbonyl group, a 1-propyloxycarbonyl group, and a 2-propyloxycarbonyl group.
• C 2 _ 7 alkylcarbonyl group means a carboxyl group to which the above-mentioned “alkyl group” is bonded, and specifically includes, for example, a methylcarbonyl group, an ethylcarbonyl group. Group, a 1-propylcarbonyl group, a 2-propylpropyl group and the like.
• Halogen atom in the present specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
• C 6 —i. Aryl group refers to an aromatic hydrocarbon cyclic group having 6 to 10 carbon atoms, and specifically includes, for example, a phenyl group and a 1-naphthyl group Group, 2-naphthyl group and the like.
• Hetero atom in the present specification means a sulfur atom, an oxygen atom or a nitrogen atom.
• the term "5- to 10-membered heteroaryl ring” refers to an aromatic ring having 5 to 10 ring-forming atoms and having one or more heteroatoms in the ring-forming atoms.
• L 0 -membered arylinole ring preferably, a pyridine ring, a thiophene ring, a furan ring, a pyrrol ring, an imidazole ring, a 1,2,4-triazole ring, a thiazole ring, a thiazole ring, A pyrazole ring, a furazane ring, a thiadiazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, an isoquinoline ring, a benzoxazonole ring, a benzthiazonole ring, and a benzimidazonole ring, and more preferably a pyridine ring.
• the term "5- to 10-membered heteroaryl group” refers to a mono- or di-valent group derived from the above-mentioned "5- to 10-membered heteroaryl ring” by removing one or two hydrogen atoms at any positions. Means the group
• the number of atoms constituting the ring is 4 to 8,
• the ring may contain 1-2 double bonds
• the ring may contain 1 to 3 carbonyl groups
• ⁇ means a non-aromatic ring that is monocyclic.
• the 4- to 8-membered hetero ring include, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepan ring, an azocan ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, Thiazolidine ring, dioxane ring, imidazoline ring, thiazoline ring,
• T 3 x represents a methylene group, an oxygen atom, or a formula ⁇ ⁇ 4 ⁇ — (wherein, ⁇ 4 ⁇ means a hydrogen atom or an alkyl group.) Means a group represented by.).
• a pyrrolidine ring, a piperidine ring, an azepane ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a dihydrofuran-2-one ring, and a thiazolidine ring are preferred.
• the term "4- to 8-membered heterocyclic group” refers to the above-mentioned “4- to 8-membered heterocyclic group”: a monovalent or divalent group derived by removing one or two hydrogen atoms at any position. Means a valence group.
• piperidine is preferably used.
• Aryl ⁇ alkyl group means any hydrogen atom in the above definition “. ⁇ Alkyl group” as defined above.
• Aryl group ", specifically, for example, benzyl group, phenethyl group, 3-phenyl-11-propyl group and the like.
• 510-membered heteroaryl C- 6 alkyl group refers to any hydrogen atom in the above-defined “C 6 alkyl group” as defined in the above-mentioned “510-membered heteroaryl group”. It means a substituted group, and specific examples include a 2-pyridylmethyl group and a 2-phenylmethyl group.
• the ⁇ 48-membered heterocyclic C 6 alkyl group '' is obtained by replacing any hydrogen atom in the above-defined ⁇ ⁇ - 6 alkyl group '' with the ⁇ 48-membered heterocyclic group '' defined above.
• the number of atoms constituting the ring of the cyclic group is 4 to 12,
• a non-aromatic cyclic group that is monocyclic or bicyclic.
• R 3 1 ⁇ :. 4 4 is A group represented by “may have a substituent” (substituent group S shown below) independently means a group selected or a hydrogen atom. Any two of R 31 to R 44 may be taken together to form a —6 alkylene group. ) Means a group represented by
• substituent may have a substituent
• the substitutable site may have one or more substituents in any combination.
• substituents include a group selected from the following substituent S group.
• R T is hydrogen, C 6 alkyl group, C 3 - means a group or C 2 one 6 alkynyl group - 8 cycloalkyl group, C 2 - 6 alkenyl.
• T 2x and 17 may each independently have 1 to 3 groups selected from the following substituent group T. ) A group consisting of a group represented by.
• Phenyl group (13) The group consisting of C ⁇ e alkoxy groups can be mentioned.
• n and m each independently represent 0 or 1).
• R 31 , R 32 , R 3 R 34 and R 35 are each independently a group selected from the group represented by “may have a substituent” (the above substituent S group) or (Meaning a hydrogen atom). (However, at least three of R 31 , R 32 , R 33 , R 34 and R 35 are hydrogen atoms.)
• n and m each independently represent 0 or 1).
• the “optionally substituted piperidine-11-yl group” refers to a group selected from the group represented by “optionally substituted” at a substitutable site
• substituent S group means a “piperidine-11-inole group” which may have one or more substituents.
• optionally substituted piperidine-11-inole group preferably a group represented by the formula
• R 31 , R 32 , R 33 , R 34 and R 35 are each independently a group selected from the group represented by “may have a substituent” (the above-mentioned substituent S group) Or a hydrogen atom.) (Wherein at least three of R 31 , R 32 , R 33 , R 34 and R 35 are hydrogen atoms), preferably a group represented by the formula:
• the “optionally substituted azetidine-11-yl group” refers to a group selected from the group represented by “optionally having a substituent” at a substitutable site by 1 or It means "azetidine-1-yl group” which may have a plurality.
• the ⁇ pyrrolidine-1-yl group which may have a substituent '' refers to a group selected from the group represented by ⁇ may have a substituent '' at a substitutable site by 1 or It means "pyrrolidine-1-yl group” which may have a plurality.
• the ⁇ piperidine-11-yl group which may have a substituent '' refers to a group selected from the group represented by ⁇ may have a substituent '' at a substitutable site by 1 or It means a "piperidine-1-yl group" which may have a plurality.
• the “optionally substituted azepan-1-yl group” refers to a group selected from the group represented by “optionally substituted” at a substitutable site by 1 or It means “azepan-1-yl group” which may have a plurality.
• piperidine-11-yl group optionally having an amino group means a “piperidine-11-yl group” which may have one amino group at a substitutable site. I do.
• the “piperidine-11-yl group optionally having an amino group” is specifically, for example,
• azetidine-11-yl group optionally having an amino group refers to an "azetidine-11-yl group” which may have one amino group at a substitutable site. means.
• pyrrolidine-1-yl group optionally having an amino group in the present specification means a “pyrrolidine-1-yl group” which may have one amino group at a substitutable site.
• piperidine-11-yl group optionally having an amino group means a “piperidine-11-yl group” which may have one amino group at a substitutable site. I do.
• azepan-1-yl group optionally having an amino group means an "azepan-11-yl group” which may have one amino group at a substitutable site. I do.
• the “optionally substituted C 6 alkyl group” in the above-mentioned Substituent group B refers to a group represented by “optionally substituted” at a substitutable site.
• a “. ⁇ 6 alkyl group” which may have one or more groups selected from the group consisting of: Preferably as the "optionally substituted alkyl group", Shiano group, forces Rupokishiru group, C 2 - 7 alkoxy force Rupoeru group, wherein one NR 3T COR 4T, wherein one CONR 3T R 4T (wherein , R 3T and R 4T each independently represent a hydrogen atom or a 6 alkyl group.) And a C alkyl optionally having 1 to 2 substituents selected from the group consisting of an alkoxy group Means a group.
• R 1 and R 2 are each independently a group represented by the formula: A 0 — A 1 — A 2 (where A 0 , ⁇ 1 and ⁇ 2 are Is the same as defined above).
• a 1 and A 1 are both a single bond, “1 A. 1 1 —” means one bond.
• a T1 is an oxygen atom, a sulfur atom, a sulfiel group, a sulfonyl group, a canolepol group, or a methylene group which may have a substituent. or have a substituent means a good nitrogen atom,;
• Alpha .tau.2 is which may have a substituent C 2 - containing 6 means an alkylene group
• a T1 is an oxygen atom good preferable.
• a T2 is preferably means C 2 _ 4 alkylene group.
• cyanobenzyl group refers to a benzyl group having one cyano group, and specifically refers to, for example, a 2-cyanobenzyl group, a 3-cyanobenzyl group, or a 4-cyanobenzyl group.
• fluorocyanobenzyl group refers to a benzyl group having one fluorine atom and one cyano group, and specifically, for example, a 2-cyano-14-fluorobenzyl group. , 2-cyano 6-fluorobenzyl group.
• captive rubamoylphenoxy group refers to a phenoxy group having one CO NH 2 of the formula, specifically, for example, a 2-captive rubamoylphenoxy group, Means rupamoylphenoxy group or 4 rupamoylphenoxy group.
• salt in the present specification is not particularly limited as long as it forms a salt with the compound of the present invention and is pharmacologically acceptable.
• examples thereof include inorganic acid salts, organic acid salts, and inorganic salts.
• Base salts, organic base salts, acidic or basic amino acid salts and the like can be mentioned.
• Preferred examples of the inorganic acid salt include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like.
• Preferred examples of the organic acid salt include, for example, acetate, succinate, Examples include fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, and monotoluenesulfonate.
• Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, and ammonium salt.
• Preferred examples of the organic base salt include getylamine salt, diethanolamine salt, meglumine salt, N, N, dibenzylethylenediamine salt and the like.
• the acid amino acid salt include, for example, aspartate and glutamate
• preferable examples of the basic amino acid salt include, for example, anoregginin salt, lysine salt, ordinine salt and the like.
• the present invention is a compound represented by the following general formula (I), a salt thereof, or a hydrate thereof.
• T 1 represents an optionally substituted monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring;
• X is Ji may have a substituent 6 alkyl group which may have a substituent C 2 - 6 Aruke - group, which may have a substituent C 2 _ 6 alkynyl group, C 6 — i which may have a substituent.
• Aryl group, optionally substituted 5- to 10-membered teloaryl group, optionally substituted C 640 aryl C ⁇ 6 alkyl group or optionally substituted 5 Means a 10-membered heteroaryl C ⁇ e alkyl group;
• R 1 and R 2 are each independently Formula 1A.
• a 1 —A 2 (where A is a single bond or a C 6 alkylene group optionally having 1 to 3 groups selected from the following substituent group B;
• a 1 is a single bond, an oxygen atom, a sulfur atom, a sulfier group, a sulfonyl group, a carbonyl group, a formula O—CO—, a formula CO—O—, a formula NR A— , and a formula CO—NR A— , wherein one NR a - CO-, wherein one S0 2 - NR a -, or wherein one NR a -S0 2 - means; a 2 and RA each independently represent a hydrogen atom, a halogen atom, Shiano group.
• Substituent group B includes a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, an alkyl group which may have a substituent, a C 3 _ 8 cycloalkyl group, and a C 2 — 6 Arukeniru group, C 2 - 6 Arukyuru group, C 6 _i.
• R B3 is to mean heterocyclic groups 4-8 membered) group represented by the formula one CO- R B4 - R B5 and formula one CH 2 - CO- R B4 - R B5 ( formula among, R B4 is a single bond, an oxygen atom or formula one NR B 6 - means, each R B5 and R B6 independently hydrogen, alkyl group, C 3 - 8 cycloalkyl group, C 2 one 6 alkenyl group, C 2 - 6 alkynyl group, C 6 - 10 ⁇ aryl group, 5: Teroariru group to L 0-membered, hetero the 4-8 membered ring 0 1 - 6 Arukiru group, ⁇ 6-1 10 ⁇ Li Ichiru 6 alkyl groups or 5-10 Heteroaryl—means a 6-alkyl group.) Or a salt or hydrate thereof.
• preferred examples include the following compounds.
• Z 1 is a nitrogen atom
• (3) Z 2 is a nitrogen atom
• n and m each independently represent 0 or 1
• an azetidine-11-yl group which may have a substituent and a group which has a substituent.
• T 1 is the formula
• n and m each independently represent 0 or 1.
• azetidine-11-yl group optionally having an amino group
• pyrrolidine optionally having an amino group
• T 1 is a piperazine-111 group or a 3-aminopiperidine-11-yl group.
• X is a group represented by the formula — X 1 — X 2 (wherein X 1 represents a single bond or a methylene group which may have a substituent; X 2 may have a substituent C 2 _ 6 alkenyl group, an optionally off have a good C 2 alkynyl group or a substituted group may have a location substituent Means a ball group.
• X 1 represents a single bond or a methylene group which may have a substituent
• X 2 may have a substituent C 2 _ 6 alkenyl group, an optionally off have a good C 2 alkynyl group or a substituted group may have a location substituent Means a ball group.
• A a compound represented by the formula:
• X is a compound of the formula X 11 — X 12 , wherein X 11 represents a single bond or a methylene group;
• X 12 is C 2 - 6 alkenyl - le group, C 2 - 6 alkylene - means an group or but it may also be substituted phenylene Le group.
• an optionally substituted phenyl group is a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a vinyl group Group, methoxy group, ethoxy group, acetyl group, cyano group, formyl group, and a phenyl group optionally having a group selected from the group consisting of C 2 _ 7 alkoxycarbonyl group at the 2-position.
• R 1 is a hydrogen atom or a group represented by the formula: A 1 () — A 11 — A 12 .
• a 1G may have 1 to 3 groups selected from the following substituent group C—means a 6 alkylene group;
• a 11 represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group
• a 12 represents a hydrogen atom, and may have 1 to 3 groups selected from the following substituents C 6 _ 10
• Ariru group from 1 to 3 Teroariru groups have a group to be or 5-10 membered selected from the following substituent group C, a 1 to 3 groups selected from substituent group C group has Teroariru to be or 5-10 membered optionally - be 6 alkyl group or a group represented by the substituent C 1 to 3 groups selected from the group chromatic City Yoi Ji 6 - 1.
• Aryl 1 to 6 means an alkyl group.
• Substituent group C includes a hydroxyl group, a nitro group, a cyano group, a halogen atom, a 6 alkyl group, a 6 alkoxy group, a — 6 alkylthio group, a trifluoromethyl group,
• NR C1 _ R C2 (wherein, and RC 2 are each independently a hydrogen atom or C 6 means an alkyl group. )
• Groups represented by the formula one CO- R C3 - R C4 Oyopi Shiki CH 2 - CO- R C3 - in R c4 (wherein, R C3 is a single bond, an oxygen atom or a group represented by formula - NR C5 - means and means group consisting of the groups represented by R C4 and R C5 are each independently means a hydrogen atom or CI_ 6 alkyl group.).
• R 1 represents a hydrogen atom, an alkyl group which may have 1 to 3 groups selected from the following substituent group C, and 1 to 3 groups selected from the following substituent group C Teroariru to be or 5-10 membered optionally by C - 6 alkyl group or the following substituent C may have 1 to 3 substituents selected from group C 6 - J.
• Substituent group C includes a hydroxyl group, a nitro group, a cyano group, a halogen atom, a 6 alkyl group, a C- 6 alkoxy group, a Ci- 6 alkylthio group, a trifluoromethyl group,
• NR C1_ R C2 (wherein, RC1 and RC 2 are hydrogen atoms or each independently
• R 6 means an alkyl group.
• a group represented by formula one CO- R C3 - R C4 and Shikiichi CH 2 -CO-R C3 -R c4 (wherein, R C3 is a single bond, an oxygen atom or the formula one NR C5 - means, R C4 and R C5 each independently represent a hydrogen atom or an alkyl group.)
• the substituent C group may be a cyano group, a —6 alkoxy group, a C 2 _ 7 alkoxycarbyl group, or a halo group.
• R 1 is a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyl group, or a 4-methoxycarbylpyridine-12-yl group.
• R 2 is a hydrogen atom, a cyano group, or a group represented by Formula A 21 to A 22 .
• a 21 is a single bond, an oxygen atom, a sulfur atom, a sulfiel group, a sulfol group, a carbonyl group, a formula —O—CO—, a formula CO—O—, a formula NR A2 —, formula -CO one NR A2 - or the formula one NR A2 - means CO-;
• a 22 and R A2 are, their respective independently a hydrogen atom, Shiano group, C 6 alkyl group, C 3 _ 8 cycloalkyl group , C 2 - 6 Aruke - le group, C 2 - 6 alkyl - le group, C 6 -.
• a 22 and R A2 may each independently have 13 groups selected from the following substituent group D.
• Substituent group D includes a hydroxyl group, a cyano group, a nitro group, a halogen atom, a —6 alkyl group, a Ci- 6 alkoxy group, a 16- alkylthio group, a trifluoromethyl group,
• RD1 and RD2 are each independently a hydrogen atom or
• R D6 means an alkyl group.
• R 2 is a hydrogen atom, a cyano group, a carboxy group, a C 2 _ 7 alkoxycarbonyl group, a C- 6 alkyl group, a formula CONR D7 R D8 (wherein R D7 and R D8 are each And independently represents a hydrogen atom or an alkyl group.) Or a group represented by the formula: A 23 — A 24 (where A 23 represents an oxygen atom, a sulfur atom, or a formula NR A3 —) A 24 and R A3 each independently represent a hydrogen atom, an alkyl group which may have one group selected from the following substituent group D1, and one group selected from the following substituent group D1 it may have a group ⁇ 3 - 8 cycloalkyl group, one of which may have a group C 2 _ 6 alkenyl group selected from the following substituent group D 1 group, the following substituents D C 2 _ 6 alkyl group optionally having one group selected from group 1, the following substituent D phen
• R 2 is a hydrogen atom, Shiano group, an alkoxy group, or a group of the formula - in A 2 6 (wherein, A 25 is an oxygen atom, a sulfur atom or the formula one NR A4 - - A 25 means;
• R A4 each independently represent a hydrogen atom, a 16- alkyl group having one group selected from the following group of substituents D, and a group selected from the following group: to which C 3 - 8 cycloalkyl group or a group, compound represented by phenyl group) having one group selected from substituent group D 1 group.
• R 2 is a hydrogen atom, a cyano group, a methoxy group, a carpamoylphenyloxy group, a formula
• a 27 represents an oxygen atom, a sulfur atom or 1 NH—
• a 28 and A 29 each independently represent a hydrogen atom or a C 6 alkyl group.
• A) a compound represented by the formula:
• R 2 is a hydrogen atom, a cyano group, or a 2-lipamoylphenyloxy group.
• More specific combinations preferably include, for example, compounds of the following combinations.
• Z 1 and ⁇ 2 , ⁇ ⁇ X, and R ⁇ R 2 are the above-mentioned (1), (4), (8), and (13) , (18).
• Z 1 and Z 2 , TX, and R ⁇ R 2 force respectively, as described in (2), (6), (11), (16), and (19).
• Z 1 and ⁇ 2 , ⁇ ⁇ X, and R ⁇ R 2 force are respectively (2), (6), (11), and (16) , (20).
• Z 1 and Z 2 , T 1 , X, and R ⁇ R 2 are the above-mentioned (3), (6), (11), ( 16) and (21).
• (ii) to (ix) are more preferable in the order of (ii) to (ix). Further, (X) to (xvii) are more preferable in the order of (X) to (xvii).
• P1 piperazine-1-inole group
• P2 3-amino-biperidine-11-yl group
• 2Btyn 2-butyne-1-yl group
• 3Me2Bten 3-methyl-2-butene-11-yl Group
• Me methyl group
• Et ethyl group
• 2-CNBen 2-cyanobenzyl group
• 6P2CNBen 6-fluoro 2-cyanobenzyl group
• Phenethvl 2-phenyl Ethyl group
• 2Ph20xEt 2—Fujiru 2-oxoxethyl group
• —CR2 : -CR 2
• N CR2 PI 2Btyn -CH 3 -H
• N CR2 PI 2Btyn -CH 3
• N CR2 PI 2Btyn 2-CNBen -OMe
• N -CR2 PI 2Btyn 2-CNBen Kalha, 'Moylue :: Roxy group
• N -CR2 P2 2Btyn -CH 3 -0-CH 2 -C0 2 Et
• N -CR2 P2 2Btyn -CH 3 -0-l-cC 3 H4-l-C0 2 Et
• N -CR2 P2 2Btyn -CH 3 -S-CH 2 -C0 2 Me
• N -CR2 P2 2Btyn -CH3 Calcium, moylphenyl group
• RQ N — R2 po 2T3 ⁇ 4 vn
• N -CR2 P2 2Btyn Phenethyl Carmoy; Rephenyloxy group
• N-CR2 P2 2Btvn 2Ph20xEt -S-CH -C09Me
• the exemplified compound numbers 1, 2, 4, 6 7, 8, 10, 13, 16, 41, 42, 44, 50, 53, 81, 85, 86, 87, 111, 141, and 183, and more preferably, Exemplified Compound Nos. 2 and 4 , 8, 10, 81, 87, and 111.
• R 31 ⁇ R 42, n, m , RR 2, X, A D, AA 2, R A and T 1 is the same meaning as defined above.
• U 1 and U 3 each independently represent a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group.
• R pl and shaku shaku are each independently a NH-protecting group such as a piperyloxymethyl group or a trimethylsilylethoxymethyl group.
• R represents a hydroxyl-protecting group such as -butyldimethylsilyl group and -butyldiphenylsilyl group.
• R p5 represents an NH protecting group such as ⁇ , N-dimethylsulfamoyl, trityl, benzyl, and t-butoxycarbonyl.
• U 2 and U 4 are each independently a chlorine atom, a bromine atom, an iodine atom, a methanesulfoninoleoxy group, a ⁇ -toluenesulfoeroxy group, a formula B (OH) 2 , 4,4,5 , 5-Tetramethyl-1,3,2-dioxaborane-12-yl group, a group represented by the formula -S n (R 2 ) 3 (where R z represents a 6- alkyl group).
• R x 2 may have a group represented by the formula 1 O—A 2 , a group represented by the formula 1 S—A 2 , a group represented by the formula 1 N (RA) A 2 , or a substituent 4
• a substituent 4 to 8 heterocyclic groups (for example, 1 pyrrolidinyl group, 1 1 morpholinyl group, 1 1 piperazyl group or 1-piperidyl group) and the like.
• R x3 may have a cyano group or a substituent Alkyl group, which may have have a substituent C 3 _ 8 cycloalkyl group which may have a substituent C 2 _ 6 an alkenyl group, which may have a substituent C 2 - 6 wherein one such alkynyl groups, which may have a substituent C 6 0 Ariru group A.
• A means a group represented by A 1 -A 2 .
• a 2COOR contain ester groups, C 6 alkyl group, C 3- 8 cycloalkyl group, C 2 _ 6 alkenyl, C 2 - 6 alkyl groups, C 6 -.
• Aryl groups 5 to 10 membered heteroaryl groups, 4 to 8 membered heterocyclic groups, 5 to 10 membered heteroaryl — 6 alkyl groups or C 6 — i.
• Aryl refers to a C i _ 6 alkyl group.
• a 2 COOH contains a carboxylic acid, C - 6 alkyl group, C 3 - 8 cycloalkyl group, C 2 one 6 alkenyl, C 2 - 6 alkynyl group, C 6 - 10 Ariru group, the 5-10 membered Teroaryl groups, 4- to 8-membered heterocyclic groups, 5- to 10-membered heteroaryls. Means 10 Ariru C -6 alkyl group - 6 alkyl group or C 6.
• a 2N02 contains a nitro group, Ji 6 alkyl group, C 3 - 8 cycloalkyl group, C 2 - 6 alkenyl - le group, C 2 - 6 alkyl groups, C 6 one 10 Ariru group, 5-10 Te Roariru group to-membered, heterocyclic groups 4-8 membered, heteroaryl 5-10 membered 6 alkyl group or C 6 _ i.
• Aryl C — means a 6- alkyl group.
• a 2 NH2 contains an amino group, alkyl group, C 3 _ 8 cycloalkyl group, C 2 - 6 alkenyl group, C 2 - 6 alkynyl group, C 6 -.
• Ariru group, Te to 5-10 membered Roariru groups, heterocyclic groups 4-8 membered, heteroaryl CI- 6 alkyl group or C 6 _ i to 5-10 membered.
• a 2CN contains nitrile groups, CI- 6 alkyl group, C 3 _ 8 cycloalkyl group, C 2 - 6 Arukeyuru groups, C 2 - 6 alkynyl group, C 6 -.
• Aryl C — means a 6- alkyl group.
• a CONH2 contains carboxylic acid amide group, alkyl group, C 3 - 8 Shikuroa alkyl group, C 2 - 6 alkenyl group, C 2 - 6 alkynyl group, C 6 - i.
• Aryl group, 5 to 10 membered heteroaryl group, 4 to 8 membered heterocyclic group, 5 to 10 membered heteroaryl C! A 6- alkyl group or C 6 —i.
• Aryl C — means a 6- alkyl group.
• M represents one MgCl, one MgBr, -S n (R z ) 3 (wherein, R z has the same meaning as defined above) and the like.
• Room temperature means a temperature of about 20-30 ° C.
• T la has the same meaning as the group represented by T 1 or a formula
• R 31 to R 4 ° has the same meaning as the above definition, but one of R 31 to R 4 ° means a group represented by the formula: NH—R p3 ) I do.
• the amounts of reagents, catalysts, etc. used indicate the ratio to the main compound in the reaction schemes, unless otherwise specified.
• the main compound is a compound having the basic skeleton of the compound of the present invention in the chemical structural formula in the reaction scheme.
• the reaction can be carried out under the reaction conditions for introducing a protecting group, which are generally used for the reagent, according to the mono-NH-protecting reagent to be used.
• protecting reagent for —NH— it is generally used to introduce a protecting group for 1 NH—
• a reagent can be used, and specifically, for example, chloromethyl pivalate or the like can be used. It is preferable to use 1-2 equivalents of the protective reagent.
• the reaction can be carried out using acetonitrile, N, N-dimethylformamide, N-methylvinylidone, 1,4-dioxane, tetrahydrofuran, dimethoxetane, etc., and preferably N, N- Dimethylformamide can be used.
• the reaction can be carried out in the presence of a base, but when the reaction is carried out in the presence of a base, cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, etc. can be used as the base.
• cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, etc. can be used as the base.
• sodium hydride can be used. In this case, it is preferable to use 1 to 5 equivalents of the base.
• the reaction can be carried out at a temperature of 0 ° C. to 150 ° C., preferably at room temperature.
• the compound (2a) is reacted with the compound (2a-2) to obtain the compound (3a).
• the compound (2a-2) may be any electrophilic reagent such as an alkyl halide, but specific examples thereof are preferably alkyl halides such as eodomethane, odoethane, eodopropane, and benzylbutamide; And alkyl halides such as 1-bromo-3-methyl-2-butene and the like, or alkyl halides such as propargylpromide and 1-promo-2-butyne. It is preferable to use 1 to 2 equivalents of the electrophile.
• reaction solvent examples include dimethylsulfoxide, N, N-dimethylhonolemamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, toluene and the like.
• the reaction can be carried out in the presence of a base or in the absence of a base, but when the reaction is carried out in the presence of a base, the base may be lithium hydroxide, sodium hydroxide, Use lithium, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyl lithium, methyllithium, lithium pistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, etc. be able to. In this case, it is preferable to use 1-2 equivalents of the base.
• the reaction can be performed at a reaction degree of 0 ° C to 150 ° C.
• reaction conditions are not particularly limited. Specifically, for example, a compound (3a) is obtained by a catalytic reduction reaction in a hydrogen atmosphere in the presence of a metal catalyst to obtain a compound (4a). be able to.
• reaction solvent examples include methanol, ethanol, propanol, acetic acid, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, toluene and the like.
• metal catalyst examples include palladium carbon, platinum oxide, Raney nickel and the like. It is preferable to use 0.5 to 50% by mass of the metal catalyst.
• the hydrogen pressure is preferably 1 to 5 atm, and the reaction can be carried out at a reaction temperature of 0 to 150 ° C.
• the compound (4a-2) include alkyl halides such as lode methane, lode ethane, lode propane, and benzyl bromide, aryl bromide, alkenyl halides such as 1-bromo-3-methyl-2-butene, and propargyl bromide.
• alkyl halides such as lode methane, lode ethane, lode propane, and benzyl bromide, aryl bromide, alkenyl halides such as 1-bromo-3-methyl-2-butene, and propargyl bromide.
• 1-Promom Alkynyl halides such as 2-butyne can be used Wear. Such a halide is preferably used in an amount of 1 to 2 equivalents.
• reaction solvent dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, toluene and the like can be used.
• the reaction can be carried out in the presence of a base or in the absence of a base.
• the base may be lithium hydroxide, sodium hydroxide, hydroxide hydroxide, lithium carbonate, sodium carbonate, Potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, lithium hydride, butyllithium, methyllithium, lithium pistrimethylsilylamide, sodium pistrimethylsilylamide, potassium pistrimethylsilylamide and the like can be used. In this case, it is preferable to use 1 to 4 equivalents of the base.
• the reaction can be carried out at a temperature of 0 ° C to 150 ° C.
• Compound (4a) can be reacted with compound (4a-2) in the presence of a copper catalyst and a base to give compound (5a).
• a copper catalyst and a base
• X may have a substituent.
• a 5- to 10-membered heteroaryl group which may have an aryl group or a substituent, and wherein U 2 is 1 B (OH) 2 or the like, and is reacted with an arylboronic acid or a heteroarylboronic acid. It can be performed. In this case, it is preferable to use 1 to 3 equivalents of the compound (4a-2).
• reaction solvent dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, pyridine, ⁇ , ⁇ -dimethylformamide, ⁇ methylpyrrolidone and the like can be used.
• triethylamine, diisopropylethylamine, pyridine, ⁇ , ⁇ -dimethylaminopyridine and the like can be used as the base.
• Copper catalysts include copper acetate (II), copper trifluoroacetate (11), copper chloride (II), copper iodide (II), etc. Can be used. The reaction can be carried out at a temperature of 0 ° C to 150 ° C.
• compound (5a) is reacted with a halogenating agent to obtain compound (6a).
• a halogenating agent include N-chloro succinimide, N-promo succinimide, N-ode succinimide and the like. It is preferable to use 1 to 4 equivalents of such a halogenating agent.
• reaction solvent acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane and the like can be used.
• the reaction can be performed at a temperature of 0 ° C to 150 ° C.
• the reaction can be carried out in a solvent such as tetrahydrofuran, acetonitrile, N, N-dimethinolehonolemamide, N-methylpyrrolidone, methanol, ethanol, 1,4-dioxane, toluene, xylene, or without a solvent.
• the reaction can be carried out at a temperature of 0 ° C to 200 ° C in the presence or absence of a base.
• a base triethylamine, potassium carbonate, 1,8-diazabicyclo [5,4,0] indene and the like can be used. In this case, it is preferable to use 1 to 4 equivalents of the base.
• the reaction can be carried out under the deprotection conditions generally used for the protecting group according to the protecting group of 1 NH— to be eliminated.
• R p 2 is a bivalyloxymethyl group
• methanol or methanol Of sodium methoxide sodium hydride, 1,8-diazabicyclo [5,4,0] —7-pandene at a temperature of 0 ° C to 150 ° C in a mixed solution of toluene and tetrahydrofuran Then, the reaction can be performed. In this case, it is preferable to use 0.1 to 2 equivalents of the base.
• R p 2 is a trimethylsilylethoxymethyl group
• tetrabutylammonium fluoride in a solvent such as acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, etc.
• the reaction can be carried out by allowing a fluoride reagent such as sulfide or cesium fluoride to act at a temperature of 0 ° C to 150 ° C. In this case, it is preferable to use 1 to 5 equivalents of the fluoride reagent.
• reaction conditions are not particularly limited, the reaction can be carried out under the reaction conditions generally used for chlorination, for example, in a solvent such as phosphorus oxychloride at 0 ° C. to 150 ° C.
• the reaction can be performed at a temperature of ° C.
• the halogenating agent is preferably used in an amount of 10 to 200 times by weight.
• R p 3 is deprotected under the above reaction conditions using phosphorus oxychloride or the like such as t-butoxycarbonyl group, the protecting group is introduced again.
• the conditions for protection are not particularly limited, but in the case of t-butoxycanolepodinole, acetutrile, N, N-dimethylhonolemamide, N-methinolepyrrolidone, 1,4-dioxane, tetrahydrofuran Bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium bicarbonate, triethylamine, etc. In the presence, it is obtained by allowing a mono-NH-protecting reagent, such as di-t-butyl dicarbonate, to act at a temperature of 0 to 150 ° C.
• a mono-NH-protecting reagent such as di-t-butyl dicarbonate
• a 2 - alcohol I arsenide compound or the phenol compound represented by OH, Amin compound represented by A 2 (R A) NH, etc., A 2 - is represented by SH Thiol compounds can be mentioned.
• the compound (11a-2) is preferably used 1 to 10 times equivalent or 5 to 100 times by weight.
• the reaction solvent acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxetane, methanol, ethanol and the like can be used.
• the reaction can be carried out in the presence or absence of a base, but when the reaction is carried out in the presence of a base, the base may be lithium hydroxide, sodium hydroxide, lithium hydroxide, lithium carbonate, or carbonate.
• the base may be lithium hydroxide, sodium hydroxide, lithium hydroxide, lithium carbonate, or carbonate.
• the reaction can be carried out at a temperature of 0 ° C to 150 ° C.
• compound (10a) and compound (13a) are reacted in the presence of a metal catalyst to obtain compound (12a).
• a metal catalyst In this case, it is preferable to use 1 to 50 equivalents of the compound (13a).
• reaction solvent acetonitrile, N, N-dimethylformamide, N-methinolepyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxetane, methanol, ethanol and the like can be used.
• the metal catalyst examples include a palladium catalyst and a copper catalyst.
• a palladium catalyst tetrakistriphenylphosphine palladium, palladium acetate Dim, dibenzylideneacetone palladium and the like can be used, and as the copper catalyst, copper iodide and the like can be used. It is preferable to use 0.01 to 2 equivalents of the metal catalyst.
• the reaction can be carried out in the presence of an organophosphorus ligand, but when the reaction is carried out in the presence of an organophosphorus ligand, as the organophosphorus ligand, ortho tolyl phosphine, diphenyl phosphinophene phenol, etc. Can be used. In this case, it is preferable to use 1 to 5 equivalents of the organic ligand based on the metal catalyst.
• the reaction can be carried out in the presence of a base or in the absence of a base, but when the reaction is carried out in the presence of a base, the base may be lithium hydroxide, sodium hydroxide, lithium hydroxide, lithium carbonate, lithium carbonate, or the like.
• the base may be lithium hydroxide, sodium hydroxide, lithium hydroxide, lithium carbonate, lithium carbonate, or the like.
• the reaction can be performed at a reaction temperature of 0 ° C to 150 ° C.
• the compound (10a) is reacted with a cyanation reagent to give a compound (14a).
• cyanating reagent specifically, for example, sodium cyanide, cyanide rim, or the like can be used. It is preferable to use 1 to 20 equivalents of the cyanating reagent compound.
• reaction solvent for example, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, ethanol and the like can be used.
• the reaction can be carried out at a temperature of 0 to 150 ° C.
• reaction conditions are not particularly limited, but the reaction can be carried out under conditions generally used for a reaction of hydrolyzing a cyano group to convert it to a carpamoyl group.
• reaction solvent N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxetane, methanol, ethanol, a mixed solvent of tetrahydrofuran and methanol can be used.
• the reaction can be performed in the presence of a base or in the absence of a base. Can be used.
• the reaction can be carried out by adding aqueous hydrogen peroxide (preferably 30% aqueous hydrogen peroxide).
• the reaction can be carried out at a reaction temperature of 0 ° C to 150 ° C.
• the reaction for elimination of the protecting group of 1 NH— can be carried out under reaction conditions generally used for elimination of the protecting group.
• RP 3 when RP 3 is a t-butoxycarbol group, perform the reaction in the presence of an acid such as anhydrous hydrogen chloride methanol solution, anhydrous hydrogen chloride ethanol solution, anhydrous hydrogen chloride dioxane solution, trifluoroacetic acid, or formic acid.
• an acid such as anhydrous hydrogen chloride methanol solution, anhydrous hydrogen chloride ethanol solution, anhydrous hydrogen chloride dioxane solution, trifluoroacetic acid, or formic acid.
• an acid such as anhydrous hydrogen chloride methanol solution, anhydrous hydrogen chloride ethanol solution, anhydrous hydrogen chloride dioxane solution, trifluoroacetic acid, or formic acid.
• an acid such as anhydrous hydrogen chloride methanol solution, anhydrous hydrogen chloride ethanol solution, anhydrous hydrogen chloride dioxane solution, trifluoroacetic acid, or formic acid.
• compound (18a) is chlorinated to obtain compound (19a).
• the reaction conditions are not particularly limited, but a force that can be performed under the reaction conditions generally used for chloridani, for example, in a solvent such as oxychloride phosphorus, from 0 ° C to 150 ° C
• the reaction can be carried out at a temperature of
• the chlorinating agent is preferably used in a weight ratio of 10 to 200 times.
• the conditions for protection are not particularly limited, but in the case of t-butoxycanolevonyl group, acetate, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxy
• a solvent such as tan
• a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, triethylamine, etc. It is obtained by applying a protective reagent for mono-NH— such as di-tert-carbonate at a temperature of 0 to 150 ° C.
• compound (19a) is partially hydrolyzed to obtain compound (20a).
• the reaction is carried out in the presence of a base such as sodium acetate, carbonated carbonate, sodium hydroxide and the like.
• the base is preferably used in an amount of 1 to 10 equivalents.
• a reaction solvent a solvent such as dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran or water, or a mixed solvent thereof can be used.
• the reaction can be carried out at a reaction temperature of 0 ° C to 10 ° C.
• the reaction can be carried out under the same conditions as in [Step A 2] of production method A.
• An alternative method for the preparation of compound (19a). OO
• compound (24a) is obtained by subjecting compound (23a) [CAS No. 1076-22-8] to a substitution reaction with compound (4a-2).
• the reaction can be carried out under the same conditions as in [Step A4] of production method A.
• the reaction can be carried out under the same conditions as in [Step A5] of production method A.
• compound (25a) is chlorinated to obtain compound (26a).
• the reaction conditions are not particularly limited, but the compound (25a) and phosphorus oxychloride, phosphorus pentachloride or a mixture thereof in a solvent or without solvent at a temperature of 0 ° C to 150 ° C.
• the solvent for example, toluene, acetotrile, dichloroethane and the like can be used.
• the reaction can be carried out under the same reaction conditions as in [Step A 6] of production method A.
• Manufacturing method B [Step B3]
• the compound (Ib) is benzylated, and then the sugar chain is cleaved to obtain the compound (2b).
• the reaction conditions are not particularly limited, but include acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, tetrahydrofuran, dimethoxetane, methanol, ethanol, and the like.
• Benzyl bromide is allowed to act at a temperature of 0 ° C to 150 ° C in the above solvent, and then 3 to 10 equivalents of hydrochloric acid are added, and the mixture is allowed to act at a temperature of 0 ° C to 150 ° C, and the sugar chain moiety Obtained by cutting the minute. It is preferable to use 1-3 equivalents of benzylpromide.
• the reaction can be carried out under the same halogenation reaction conditions as in [Step A5] of production method A.
• the reaction can be carried out under the same conditions as in [Step A2] of production method A.
• R p3 of compound ( 6b ) is deprotected to obtain compound (7b).
• the reaction can be carried out under the same conditions as in [Step A13] of production method A.
• Compound (10b) represented by 10b can be obtained.
• Preferred examples of the compound (8b) include piperidine-13-ylcarbamic acid t-butyl ester and the like. be able to.
• the reaction can be carried out under the same conditions as in [Step A4] of production method A.
• the reaction conditions are not particularly limited, but the reaction is carried out in a solution of compound (2c) in ethanol in the presence of an acid such as sulfuric acid, hydrochloric acid, and the like, while heating and refluxing. c) can be obtained. In this case, it is preferable to use 1-2 equivalents of the acid.
• the compound (3c) is reacted with the compound (3c-2), and the compounds (4c) and (5 This is the step of obtaining c).
• the reaction can be carried out under the same conditions as in [Step A4] of production method A.
• the reaction can be carried out under the same conditions as in [Step A 6] of production method A.
• a reaction solvent methanol, ethanol, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane and the like can be used.
• the thioamidation reagent for performing the thioamidation reaction ammonium sulfide, sodium sulfide, hydrogen sulfide and the like can be used. It is preferable to use 2 to 10 equivalents of the thioamidating reagent.
• the reaction is performed in the presence of a base such as triethylamine or N, N-diisopropylethylamine.
• a base such as triethylamine or N, N-diisopropylethylamine.
• the reaction can be performed at a reaction temperature of 0 to 150 ° C.
• the compound (8c) is reacted with a methylation reagent to obtain a compound (9c).
• a methylation reagent examples include trimethyloxodimethyl tetrafluoroborate, methyl sulfate, methyl iodide, and trimethyl phosphite. It is preferable to use 1.0 to 1.5 equivalents of the methylating reagent.
• the compound (9c) can be obtained by performing the reaction in a halogen-based solvent such as dichloromethane at a temperature of 0 ° C to 50 ° C.
• methyl sulfate, methyl iodide, or trimethyl phosphite is used as the methyl reagent
• the reaction is carried out in the presence of a base group such as potassium carbonate, triethylamine, N, N-diisopropylethylamine to obtain compound (9c). be able to.
• the base It is preferable to use 1.0 to 1.5 equivalents.
• the reaction solvent acetone, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxetane, etc. can be used, and the reaction is carried out at a reaction temperature of 0 to 100 ° C. Can be.
• compound (10c) is obtained by hydrolyzing compound (9c).
• the conditions of the hydrolysis reaction are not particularly limited, but the temperature is from 0 ° C to 80 ° C in a mixed solvent of ethanol and water in the presence of an acid such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and the like. At temperatures, the reaction can be carried out. In this case, it is preferable to use 5 to 50 equivalents of the acid.
• the conditions for the protective group introduction reaction are not particularly limited, but in the case of t-butoxycarbonyl group, pyridine, 4-aminopyridine in a solvent such as dichloromethane, chloroform, N, N-dimethylformamide, and tetrahydrofuran.
• the reaction can be carried out in the presence of a base such as triethylamine, N, N-diisopropylethylamine and the like at a temperature of 0 ° C. to 80 ° C. using a reagent such as mono-butyl dicarbonate. In this case, it is preferable to use 2-3 equivalents of the base.
• compound (10c) is reacted with a reducing agent to obtain compound (11c).
• the reaction conditions for the reduction reaction are not particularly limited, but in a solvent such as benzene, ethanol, 2-propanol, or acetone, in the presence of Raney-Keckel, at a temperature of 0 ° C to 50 ° C.
• the compound (11c) is subjected to an oxidation reaction to obtain the compound (12c).
• the oxidation reaction uses an oxidizing agent such as manganese dioxide, pyridinium chromate, or pyridinium dichromate, use dichloromethane, chloroform, etc. as the reaction solvent at a temperature of 20 ° C to 80 ° C.
• an oxidizing agent such as manganese dioxide, pyridinium chromate, or pyridinium dichromate
• dichloromethane, chloroform, etc. By carrying out the reaction, compound (12c) can be obtained.
• the compound (12c) can be obtained by carrying out the reaction generally used for oxidation reaction of primary alcohol to aldehyde such as Swan reaction.
• the oxidizing agent is preferably used in an amount of 5 to 20 equivalents.
• compound (13c) it is preferable to use 2 to 10 equivalents of the compound (13c).
• the reaction conditions are not particularly limited, but may be in a solvent such as methanol, ethanol, 1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxetane or in the absence of a solvent (12c).
• (13c) are mixed and reacted at a temperature of 20 ° C to 150 ° C to obtain compound (17c).
• the reaction can be carried out under the same conditions as in [Step C11] of production method C. It is preferable to use 2 to 10 equivalents of hydrazine.
• Step C 13 the compound (17c) is obtained by subjecting the compound (15c) to a substitution reaction with the compound (16c).
• the reaction can be carried out under the same conditions as in [Step A2] of production method A. It is preferable to use 1 to 3 equivalents of the compound (16c).
• the reaction conditions for the hydrolysis reaction are not particularly limited.
• the compound (18c) is reacted at a temperature of 0 ° C. to 100 ° C. in the presence of a base to give the compound (19 c) can be obtained.
• reaction solvent methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof or the like can be used.
• base lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like can be used. It is preferable to use 1 to 2 equivalents of the base.
• a compound (20c) is obtained by reacting the compound (19c) with a reducing agent.
• the reaction conditions for the reduction reaction can be the same as those generally used for the reduction reaction of carboxylic acid to methyl alcohol.
• a borane derivative such as a porane-tetrahydrofuran complex or a borane methylsulfide complex, sodium borohydride, or the like can be used. It is preferable to use 5 to 30 equivalents of the reducing agent.
• the compound (20c) can be obtained by carrying out the reaction using tetrahydrofuran, dimethoxyethane or the like at a temperature of 178 ° C to 35 ° C.
• the compound (19c) is first reacted with an activator such as isoptyl chloroformate at a temperature of 178 ° C to 20 ° C. Then, a reducing agent such as sodium borohydride is allowed to act at a temperature of 1 to 78 ° C to obtain a compound (20c).
• an activator such as isoptyl chloroformate
• a reducing agent such as sodium borohydride is allowed to act at a temperature of 1 to 78 ° C to obtain a compound (20c).
• 1,4-dioxane, tetrahydrofuran, dimethoxyethane and the like can be used.
• a compound (21c) is obtained by a thioamidation reaction of the compound (20c).
• the reaction can be carried out under the same conditions as in [Step C 6] of production method C.
• compound (21c) is reacted with a silylating agent in the presence of a base to obtain compound (22c).
• reaction solvent dichloromethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, dimethoxetane and the like can be used.
• base imidazole, pyridine, 4-dimethylaminopyridine, triethylamine, N, N-diisopropylethylamine and the like can be used.
• silylating agent include p-butyl dimethyl silane, dibutyl dimethyl silane, and the like. It is preferable to use 1.0 to 1.5 equivalents of the base and 1.0 to 1.5 equivalents of the silylating agent.
• the reaction can be performed at a reaction temperature of 0 ° C to 80 ° C.
• compound (23c) is obtained by methylating compound (22c).
• the reaction can be carried out under the same conditions as in [Step C 7] of production method C.
• the conditions for the hydrolysis reaction are not particularly limited, but in a mixed solvent of ethanol and water, in the presence of an acid such as sulfuric acid, hydrochloric acid, and -toluenesulfonic acid, at a temperature of 50 ° C to 100 ° C.
• an acid such as sulfuric acid, hydrochloric acid, and -toluenesulfonic acid
• reaction conditions one ' be accompanied by deprotection of the P 3, re protected by a protective reaction of an NH-.
• the R P3 is t- Butokishikarupo two group, dichloromethane, black hole Holm, N, N-di Mechiruhoruami de, in a solvent such as tetrahydrofuran, pyridine
• the reaction is carried out in the presence of a base such as 4-aminoviridine, triethylamine, N, N-diisopropylpropylethylamine, at a temperature of 0 ° C to 80 ° C, using a reagent such as mono-butyl dicarbonate. It can be carried out.
• the compound (2d) is obtained by reacting the compound (Id) with the compound (1d-2).
• alkyl halides such as eodomethane, eodoethane, 3-propane, benzylbutamate, 2-bromoacetophenone, chloromethinole benzyl ether, and bromoacettotrile; It is possible to use ⁇ / kenyl halides such as 1-promo 3-methyl-2-butene or alkynyl halides such as propargyl bromide or 1-promo 2-butyne.
• the compound (1d-2) is preferably used in an amount of 1 to 1.5 equivalents.
• Reaction solvents include N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxetane, 1,4-dioxane, dichloromethane
• dichloromethane can be used.
• the reaction can be carried out in the presence or absence of a base, but when the reaction is carried out in the presence of a base, the base may be 1,8-diazabicyclo [5,4,0] indene, triethylamine, N, N-diisopropyl pyrethylamine, sodium hydride and the like can be used. In this case, it is preferable to use 1 to 1.5 equivalents of the base.
• the reaction can be performed at a reaction temperature of 0 ° C to 150 ° C.
• reaction solvent a mixed solvent of water with a solvent such as N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like can be used.
• nitrite sodium nitrite, nitrous acid lime, or the like can be used. It is preferable to use 3 to 5 equivalents of nitrite.
• the reaction can be performed at a reaction temperature of 20 ° C to 120 ° C.
• compound (4d) is obtained by reacting compound (3d) with ammonia. It is preferable to use 10 to 20 equivalents of ammonia.
• the reaction can be carried out in a solvent such as methanol, ethanol, 1,4-dioxane or the like at a temperature of 20 ° C to 200 ° C.
• a solvent such as methanol, ethanol, 1,4-dioxane or the like at a temperature of 20 ° C to 200 ° C.
• the compound (4d) is subjected to catalytic reduction using a metal catalyst in a hydrogen atmosphere or in the presence of 2 to 3 equivalents of hydrazine to obtain a compound (5d).
• a reaction solvent methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,2-dimethyloxetane, 1,4-dioxane, water, or a mixed solvent thereof can be used.
• the metal catalyst palladium carbon, platinum oxide, Raney nickel or the like can be used.
• the metal catalyst has a mass ratio of 0. It is preferred to use an amount of 5-10%.
• the reaction can be carried out at a temperature of 0 ° C to 150 ° C.
• the reaction is performed in the presence of a carboxylic anhydride such as acetic anhydride.
• a carboxylic anhydride such as acetic anhydride.
• the orthoformate methyl orthoformate, ethyl ethylformate and the like can be used. It is preferable that the orthoformate is used in an amount of 1 to 20 times by mass and the carboxylic anhydride is used in an amount of 3 to 10 equivalents.
• the reaction temperature can be from 20 ° C to 200 ° C [Step D6]
• the 1-position H group of compound (6d) is protected to obtain compound (7d).
• a protective agent N, N-dimethylsulfamoyl chloride, trityl chloride, di-t-butyl dibenzyl carbonate or the like can be used. It is preferable to use 1 to 1.5 equivalents of the protective agent.
• dichloromethane, chloroform, carbon tetrachloride, toluene, ⁇ , ⁇ -dimethylformamide, tetrahydrofuran and the like can be used.
• pyridine 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] indene, triethynoleamine, ⁇ , ⁇ -diisopropylethylamine and the like can be used.
• the protecting agent is di-t-butyl dicarbonate, it is preferable to use 0.005 to 0.1 equivalent of 4-dimethylaminopyridine.
• the reaction can be carried out at a reaction temperature of 20 ° C to 200 ° C.
• the reaction conditions are not particularly limited.
• the reaction is performed as follows.
• the compound (7d) can be reacted with a base at a temperature of 100 ° C to 20 ° C, and then reacted with a chlorinating reagent to obtain a compound (8d).
• the presence of chlorinating reagents Compound (8d) can be obtained by reacting a base in the presence.
• the reaction solvent for example, getinoleatenole, tetrahydrofuran, 1,2-dimethoxetane, 1,4-dioxane and the like can be used.
• the base monobutyllithium, t-butyllithium, lithium diisopropylamide, lithium bis (trimethinolesilyl) amide, magnesium diisopropylamide and the like can be used.
• the base is preferably used in an amount of 1 to 1.5 equivalents.
• Hexachloroethane, N-chloro succinimide and the like can be used as the chlorinating reagent. It is preferable to use 1 to 3 equivalents of the chlorinating reagent.
• the reaction can be carried out under the same conditions as in [Step A6] of production method A.
• the reaction can be carried out under the same conditions as in [Step A4] of production method A.
• R p3 of compound ( 11d ) is deprotected to obtain compound (12d).
• the reaction can be carried out under the same conditions as in [Step A13] of production method A.
• the reaction conditions for the dealkylation reaction are not particularly limited, for example, the reaction can be performed as follows.
• R 1 is benzyloxymethyl, 3 to 10 equivalents of boron tribromide or boron trichloride, etc. in a solution of the compound (lid) in dichloromethane or the like at a temperature of 100 to 20 ° C. By reacting, compound (13d) can be obtained.
• reaction conditions involve deprotection of R p3, re coercive by protection reaction of an NH- Protect.
• R p3 represents a t-methoxycarbonyl group
• pyridine in a solvent such as dichloromethane, chloroform, N, N-dimethylformamide, tetrahydrofuran, etc.
• bases such as, 4-aminoviridine, triethylamine, N, N-diisopropylethylamine at a temperature of 0 ° C to 80 ° C using a reagent such as dibutyl dimethyl carbonate. It can be performed.
• the reaction can be carried out under the same conditions as in [Step D1] of production method D.
• the reaction can be carried out under the same conditions as in [Step A13] of production method A.
• the reaction can be performed under generally used conditions in accordance with the protecting group.
• a base such as sodium hydroxide, potassium carbonate, ammonia or the like can be used in tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol, water or a mixed solvent thereof.
• ° C Can be deprotected by operating at 100 ° C.
• the compound (8d) can also be deprotected without isolation by adding these solvents and bases in the post-treatment of the chloridani reaction in the previous step.
• Alcohol (X-OH) can also be introduced by the Mitsunobu reaction. That is, compound (16d) can be obtained by reacting anolecol (X-OH) with dialkyl azodicanoleponate and triphenylphosphine in a solvent such as tetrahydrofuran at 170 to 50 degrees.
• the ester group of the compound (1f) is hydrolyzed to obtain the compound (2f).
• the reaction can be carried out under the same conditions as in [Step C16] of production method C.
• R p3 of compound ( 2f ) is deprotected to obtain compound (3f).
• the reaction can be carried out under the same conditions as in [Step A13] of production method A.
• the nitro group of the compound (1 g) is reduced to obtain the compound (2 g).
• a reaction solvent methanol, ethanol, tetrahydrofuran, water and the like, or a mixed solvent thereof can be used.
• the reducing agent iron, tin, zinc and the like can be used.
• hydrochloric acid or an ammonium salt such as ammonium chloride can be used. The reaction can be performed at a reaction temperature of 20 ° C to 120 ° C.
• the reaction conditions are not particularly limited.
• the reaction is performed as follows.
• Compound (2) can be obtained by reacting compound (1 h) with hydrogen peroxide at a temperature of from 20 ° C. to 50 ° C. in the presence of a base.
• a base As the solvent, methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof or the like can be used.
• ammonia or an alkylamine such as triethylamine can be used.
• reaction conditions are not particularly limited.
• the reaction is performed as follows.
• Compound (1i) can be reacted with alkyl lithium, aryl lithium, alkyl Grignard, aryl Grignard, etc. in a solvent such as getyl ether, tetrahydrofuran, etc. at a temperature of 100 ° C to 100 ° C. it can.
• aryl zinc and aryl zinc can be reacted in a solvent such as N, N-dimethylformamide or 1-methyl-2-pyrrolidone at a temperature of 0 ° C to 50 ° C.
• a reagent generally used for oxidizing alcohol can be used.
• manganese dioxide can be used in a solvent such as dichloromethane or black form at a temperature of 20 ° C to 100 ° C.
• sulfur trioxide pyridine can be used in a solvent such as dimethyl sulfoxide at a temperature of 20 ° C to 100 ° C.
• a solvent such as dichloromethane or black form At temperatures from C to 50 ° C., Dess-Martin perodin (Dess-Martinpinperiodinane) can be used.
• the reaction can be carried out under the same conditions as in [Step C12] of the production method.
• compound (6i) is obtained by subjecting compound (4i) to a substitution reaction with compound (5i).
• the reaction can be carried out under the same conditions as in the production method [Step A2].
• cyanating agent sodium cyanide, potassium cyanide and the like can be used.
• Acetic acid or the like can be used as a catalyst.
• solvent for example, acetonitrile and the like can be used. The reaction can be performed at a reaction temperature of 0 to 10 ° C.
• the reaction can be carried out under the same conditions as in [Step HI] of production method H.
• the hydroxyl group of the compound (3j) is oxidized to obtain the compound (4j).
• the reaction can be carried out under the same conditions as in [Step I 2] of production method I.
• the reaction can be carried out under the same conditions as in [Step C 11] of production method C.
• the reaction can be carried out under the same conditions as in [Step A13] of production method A.
• the dehydrating agent for example, phosphorus oxychloride can be used.
• An alkylamine such as triethylamine can be used as the base.
• dichloromethane and chloroform can be used.
• the reaction can be performed without a solvent. The reaction can be carried out at a reaction temperature of 0 ° C to 1 oo ° C.
• Step 1 compound (3k) is obtained by subjecting compound (1k) to a substitution reaction with compound (2k).
• the reaction can be carried out under the same conditions as in [Step A2] of production method A.
• a compound (5k) is obtained by subjecting the compound (3k) to a substitution reaction with the compound (4k).
• reaction conditions are not particularly limited, but in a solvent such as methanol, ethanol, 1-methyl ⁇ -1-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxetane, or in the absence of a solvent, ( Compounds (5k) can be obtained by mixing 3k) and (4k) and reacting at a temperature of 20 ° C to 200 ° C.
• a solvent such as methanol, ethanol, 1-methyl ⁇ -1-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxetane
• compound (6k) is obtained by chloridizing compound (5k).
• the reaction can be carried out under the same conditions as in [Step D7] of production method D.
• compound (7k) is reacted with compound (6k) to obtain compound (8k).
• the reaction can be carried out under the same conditions as in [Step A 6] of production method A.
• Rp5 of compound ( 8k ) is deprotected to obtain compound (9k).
• the conditions for the deprotection reaction of R p 5, can be carried out under the conditions as elimination reaction of NH-protecting group, which is generally used.
• the reaction in the case of R p 5 Gabe Njiru group, liquefied ammonia - in ⁇ , at a reaction temperature in the first 30 ° C from a 78 ° C, the reaction can be carried out using lithium, a metal such Natoriumu.
• the compound (9k) is subjected to a substitution reaction with the compound (10k) to obtain a compound (Ilk).
• the reaction can be carried out under the same conditions as in [Step A4] of production method A. [Process K7]
• the compound (11) is reacted with the compound (21) in the presence of an oxidizing agent to obtain a compound (31).
• Salts such as iron chloride (III) can be used as the oxidizing agent.
• the solvent methanol, ethanol, water and the like can be used.
• the reaction can be performed at a reaction temperature of 20 to 10 ° C.
• reaction conditions involve deprotection of the N-RP 3, re protected by a protective reactive amino groups.
• a protective reactive amino groups for example, as a specific example, when Pro 3 represents a propyloxycarbonyl group, in a solvent such as dichloromethane, chloroform, ⁇ , ⁇ -dimethylformamide, and tetrahydrofuran, pyridine, 4 Amino
• the reaction can be carried out in the presence of a base such as pyridine, triethylamine or N, N-diisopropylethylamine at a temperature of 0 ° to 80 ° using a reagent such as di-butyl dicarbonate.
• the reaction can be carried out under the same conditions as in [Step A4] of production method II.
• R p3 of compound (51) is deprotected to obtain compound (61).
• the reaction can be carried out under the same conditions as in [Step A13] of production method A.
• the compound (3 m) is reacted with the compound (4 m) to obtain a compound (5 m).
• the reaction can be carried out under the same conditions as in [Step A4] of production method A.
• a step of reacting the compound (In) with an arylamine to obtain a compound ( 2n ) ( The reaction can be performed at a reaction temperature of 20 ° C to 150 ° C.
• a reaction solvent methanol, ethanol, water, a mixed solvent thereof or the like can be used.
• Tin salts such as tin chloride can be used as the reducing agent.
• Concentrated hydrochloric acid can be used as a solvent.
• the reaction can be performed at a reaction temperature of 20 ° C to 150 ° C.
• compound (4 ⁇ ) is obtained by reacting compound (3 n) with ⁇ , —disuccinimidyl carbonate.
• a solvent such as acetonitrile and tetrahydrofuran can be used.
• the reaction can be carried out at a temperature of 20 ° C to 100 ° C.
• the compound (4n) is reacted with the compound (5n) to obtain a compound (6n).
• the reaction can be carried out under the same conditions as in [Step A4] of production method A.
• the aryl group of compound (6n) is eliminated to obtain compound (7n).
• the reaction conditions are not particularly limited.
• osmium in a solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and water at 20 ° C to 100 ° C
• the compound (7n) can be obtained by the action of an acid and sodium periodate.
• the reaction conditions are not particularly limited, but the reaction can be carried out under the reaction conditions generally used for Kronoreich.
• a solvent such as oxysalt
• the compound (8n) can be obtained by reacting the reagent of Goshidani Rin at a temperature of 0 ° C to 150 ° C.
• the compound (10n) is obtained by reacting the compound (8n) with the compound (9n).
• the reaction can be carried out under the same conditions as in [Step A6] of production method A.
• the compound (2 ⁇ ) is reacted with ethyl phosphonoacetate in the presence of a base to obtain a compound (3 ⁇ ).
• the base use sodium hydride, lithium diisopropylamide, etc. be able to.
• the solvent for example, tetrahydrofuran, N, N-diformamide and the like can be used. The reaction can be performed at a reaction temperature of 0 ° C to 100 ° C.
• the ester of compound (3o) is hydrolyzed to obtain compound (4o).
• the reaction can be carried out under the same conditions as in [Step C16] of the production method.
• reaction solvent toluene, t-ptanol, tetrahydrofuran, dichloromethane or the like can be used.
• base tertiary amines such as triethynoleamine and diisopyrupyrethylamine can be used.
• reaction temperature As the reaction temperature,
• the reaction can be performed at 50 ° C to 50 ° C.
• the reaction can be performed in t-butanol at 50 to 100 ° C.
• the compound (7 ⁇ ) is obtained by hydrolyzing the etryl group of the compound (6o).
• the reaction can be carried out under the same conditions as in [Step HI] of Production method II.

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