Novel pyridone carboxylic acid derivatives or its salt

文档序号：1759896 发布日期：2019-11-29 浏览：31次中文

阅读说明：本技术 新型吡啶酮羧酸衍生物或其盐 (Novel pyridone carboxylic acid derivatives or its salt ) 是由山口朋则伊藤健治平野达也岛原留美子川久保阳平佐藤雅之山下准平矢崎明上于 2018-03-23 设计创作，主要内容包括：本发明提供一种抗肿瘤活性高、对正常细胞的毒性低的新型化合物。一种由下述式(1)表示的吡啶酮羧酸衍生物或其盐。〔式中,R1表示氢原子、卤素原子等；R2表示氢原子、卤素原子等,R3～R6表示氢原子等；R7表示氢原子等；R8表示氢原子、卤素原子、下述式(a)：(式中,Ra1和Ra2表示氢原子、羟基、可以具有取代基的低级烷基等)等,或者由R7和R8形成＝N－OR10(在此,R10表示氢原子、可以具有取代基的低级烷基、或芳烷基),或者R7和R8与邻接的碳原子一起形成可以具有取代基的4～6元的饱和杂环等；R9表示氢原子等,X表示氮原子等；Y表示氮原子等。〕<Image he="224" wi="700" file="DDA0002213058410000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides that a kind of anti-tumor activity is high, the new compound low to the toxicity of normal cell.The pyridone carboxylic acid derivatives or its salt that one kind is indicated by following formula (1).(in formula, R 1 Indicate hydrogen atom, halogen atom etc.；R 2 Indicate hydrogen atom, halogen atom etc., R 3 ~R 6 Indicate hydrogen atom etc.；R 7 Indicate hydrogen atom etc.；R 8 Indicate hydrogen atom, halogen atom, following formula (a): (in formula, R a1 And R a2 Indicate hydrogen atom, hydroxyl, the low alkyl group that can have substituent group etc.) etc., or by R 7 And R 8 Formation=N-OR 10 (here, R 10 The low alkyl group or aralkyl for indicating hydrogen atom, can have substituent group) or R 7 And R 8 4~6 yuan of the saturated heterocyclic etc. that can have substituent group is formed together with adjacent carbon atom；R 9 Indicate that hydrogen atom etc., X indicate nitrogen-atoms etc.；Y indicates nitrogen-atoms etc..〕)

1. a kind of pyridone carboxylic acid derivatives or its salt indicated by following formula (1),

In formula, R¹It indicates hydrogen atom, halogen atom, itrile group, the low alkyl group that can have substituent group, can have substituent group Lower alkoxy, ring low alkyl group, cyclic amino, can have substituent group at the low-grade alkyl amino that can have substituent group Aryl or the heteroaryl that can have substituent group,

R²Indicate hydrogen atom, halogen atom, nitro, hydroxyl, the low alkyl group that can have substituent group, lower alkoxy, amino, Can have the low-grade alkyl amino of substituent group, ring low alkyl group or can have substituent group 4~7 yuan of cyclic amino or C_1-17Alkanoylamino,

R³~R⁶Can be identical or different, indicate hydrogen atom, the low alkyl group that can have substituent group, carboxyl, lower alkoxy carbonyl Base or the carbamoyl that can have substituent group,

R⁷It indicates hydrogen atom, halogen atom, hydroxyl, the amino that can have substituent group, carboxyl, itrile group, can have substituent group Low alkyl group or lower alkoxy,

R⁸Indicate hydrogen atom, halogen atom, hydroxyl, the low alkyl group that can have substituent group, the rudimentary alkene that can have substituent group Base, the lower alkoxy that can have substituent group, can have the rudimentary of substituent group at the ring low alkyl group that can have substituent group Alkyl amino alkyl carbonyl, low-grade alkane acidyl oxygroup, low-grade alkane acidyl sulfenyl, aryl carbonyl sulfenyl, mercapto ,-SS-R^8a、 Or it is following 1)~7) shown in any group,

1) following formula (a)

In formula, R^a1And R^a2Can be identical or different, it indicates hydrogen atom, hydroxyl, the low alkyl group that can have substituent group, can have The low-grade alkenyl of substituted base, the lower alkoxy that can have substituent group, can have the low-grade alkynyl that can have substituent group Substituted base and the C with ehter bond_2-12Alkyl or alkoxy, can have substitution at the heteroaryl amino that can have substituent group Nitrogenous two rings the heteroaryl ,-R of base^a3- Cy¹, can have substituent group 5~6 yuan of heteroaryl, can have substituent group Heteroarylalkyl or group below,

Or indicate R^a1And R^a24~9 yuan of the cyclic amino that can have substituent group being formed together with adjacent nitrogen-atoms, * Indicate bonding the position ,-R^a3- Cy¹In, R^a3Indicate the alkyl or oxygroup of singly-bound, the divalent that can be substituted with halogen atoms, Cy¹Expression can have the ring low alkyl group of substituent group, 4~7 yuan of the cyclic ether group that can have substituent group, N- and replace Quinoline base,Piperazine alkyl is differentOxazoline base,

2) following formula (b)

In formula, Het indicates 4~6 yuan of heterocycle, R^b1For the substituent group on the heterocycle, and there are it is multiple when, can be identical Or it is different, it indicates halogen atom, hydroxyl, amino, nitro, amide groups, lower alkyl base, carboxyl, can have substituent group Low alkyl group, can have substituent group lower alkoxy, elementary alkoxy carbonyl, can have 4~7 yuan of substituent group Cyclic ether group, low-grade alkyl amino, lower alkanoylamino or oxygroup, m indicate that 0~2 integer, * indicate bonding position,

3) following formula (c)

R^c2-R^c1-* (c)

In formula, R^c1Indicate CO, SO or SO₂, R^c2It indicates to can have the low alkyl group of substituent group, can have the rudimentary of substituent group Alkoxy, 5~6 yuan of the heteroaryl that can have substituent group, can have substitution at the ring low alkyl group that can have substituent group The aralkyl of base or the heteroarylalkyl that can have substituent group, * indicate bonding position,

4) following formula (d)

In formula, R^d1It indicates hydrogen atom, can have the low alkyl group of substituent group or can have the C of substituent group_1-17Alkanoyl, R^d2 Expression hydrogen atom, can have the aralkyl of substituent group or can have substituent group the low alkyl group that can have substituent group Heteroarylalkyl, * indicate bonding position,

5) following formula (e)

In formula, R^e1And R^e2Can be identical or different, it indicates hydrogen atom, the low alkyl group that can have substituent group, can have and take The low-grade alkane acidyl of Dai Ji, the aralkyl that can have substituent group or 5~6 yuan of the heteroaryl that can have substituent group, * are indicated Position is bonded,

6) following formula (f)

In formula, R^f1And R^f2Can be identical or different, it indicates hydrogen atom, the low alkyl group that can have substituent group, can have and take The low-grade alkane acidyl of Dai Ji or 5~6 yuan of the heteroaryl that can have substituent group, n indicate that 0~2 integer, * indicate bonding part Position,

7) following formula (g)

In formula, R^g1It indicates hydrogen atom or can have the low alkyl group of substituent group, R^g2Indicate CO, CS, SO or SO₂, R^g3Indicate hydrogen Atom or the C that can have substituent group_1-17Alkyl, can have the low of substituent group at the lower alkoxy that can have substituent group Grade alkyl amino, can have substituent group 4~7 yuan of cyclic amino, can have substituent group 5~6 yuan of heteroaryl, can With 5~6 yuan of the heteroaryl amino with substituent group, * indicates bonding position,

Alternatively, by R⁷And R⁸Formation=N-OR¹⁰Or=O, or indicate R⁷And R⁸Being formed together with adjacent carbon atom can be with 4~6 yuan of the saturated heterocyclic with the substituent group ,-SS-R^8aIn, R^8aExpression can have the low alkyl group of substituent group, Described=N-OR¹⁰In, R¹⁰The low alkyl group or aralkyl for indicating hydrogen atom, can have substituent group,

R⁹Indicate hydrogen atom or ester residue,

X indicates nitrogen-atoms or C-R¹¹, the C-R¹¹In, R¹¹Indicate hydrogen atom, halogen atom, itrile group, nitro, low alkyl group, Lower alkoxy, the thienyl that can have substituent group, the phenyl that can have substituent group, or indicate R¹And R¹¹With it is adjacent Carbon atom is formed together phenyl ring or naphthalene nucleus,

Y indicates nitrogen-atoms or C-R¹², the C-R¹²In, R¹²It indicates hydrogen atom, halogen atom, itrile group or can have substitution The low alkyl group of base does not include still R⁷For amino and R⁸The case where for hydrogen atom and R⁷For hydrogen atom and R⁸For methylamino The case where.

2. pyridone carboxylic acid derivatives according to claim 1 or its salt, wherein R⁸For group shown in formula (a).

3. pyridone carboxylic acid derivatives according to claim 2 or its salt, wherein the R in formula (a)^a1And R^a2In any Person is hydrogen atom, and another one is that can have substituent group and the C with ehter bond_2-12Alkyl ,-R^a3- Cy¹Or it can have substitution 5~6 yuan of heteroaryl of base.

4. pyridone carboxylic acid derivatives according to claim 1 or its salt, wherein R⁸For group shown in formula (b).

5. pyridone carboxylic acid derivatives according to claim 4 or its salt, wherein the m in formula (b) is that 0, Het is 6 π electricity Subsystem nitrogen heterocycle.

6. pyridone carboxylic acid derivatives according to claim 1 or its salt, wherein R⁸For group shown in formula (d).

7. pyridone carboxylic acid derivatives according to claim 6 or its salt, wherein the R in formula (d)^d1For hydrogen atom, R^d2For It can have the C of substituent group_1-7Alkyl.

8. pyridone carboxylic acid derivatives according to any one of claims 1 to 7 or its salt, wherein the R in formula (1)¹For Hydrogen atom or halogen atom, R²For hydrogen atom or it can have the C of substituent group_1-7Alkyl, R³~R⁶For hydrogen atom, R⁷For hydrogen original Son, R⁹For hydrogen atom, Y C-R¹²。

9. a kind of drug containing pyridone carboxylic acid derivatives according to any one of claims 1 to 8 or its salt and pharmaceutically may be used The carrier of permission.

10. a kind of antitumor agent, using pyridone carboxylic acid derivatives according to any one of claims 1 to 8 or its salt as having Imitate ingredient.

11. a kind of pyridone carboxylic acid derivatives according to any one of claims 1 to 8 or its salt in manufacture antitumor agent Application.

12. in order to prevent or treating cancer and the pyridone carboxylic acid derivatives according to any one of claims 1 to 8 that use or Its salt.

13. the prevention or treatment method of a kind of cancer, which is characterized in that by pyridone according to any one of claims 1 to 8 Carboxylic acid derivates or its salt are administered.

Technical field

The present invention relates to excellent cell inhibitory effect effect and the pyridone carboxylic acid derivatives useful as antitumor agent Or its salt.

Background technique

Known pyridone carboxylic acid derivatives have antibacterial activity, it is also known that certain pyridone carboxylic acid derivatives has antitumor work Property, anticancer activity (non-patent literature 1).Such as the pyridone carboxylic acid derivatives with 2- thiazolyl are reported with antitumor It acts on (patent document 1, patent document 2).Wherein, the Isosorbide-5-Nitrae recorded in patent document 1-dihydro-7- (3- methoxyl group-4- Methylamino -1- pyrrolidinyl) -4- oxo -1- (2- thiazolyl) -1,8- naphthyridines -3- carboxylic acid is thin to human carcinomas Born of the same parents confirm excellent antitumous effect (non-patent literature 2, non-patent literature 3) in vitro and in vivo, and in the Section III phase It is reported in clinical test when being combined with cytarabine, compared with placebo, to 60 years old or more recurrent/intractable acute Gu Marrow leukaemia shows significant therapeutic effect (non-patent literature 4).

However, for the compound, compared with placebo, as primary evaluation project using all patients as total life of object Depositing the phase does not show significant therapeutic effect (non-patent literature 5) yet, and cell inhibitory effect activity and antitumous effect are still insufficient.

Summary of the invention

The present invention relates to provide anti-tumor activity height, the new compound low to the toxicity of normal cell.

The inventors of the present invention have made intensive studies in order to solve the above problems, as a result, it has been found that having substituted nitrogen heterocyclic cyclobutyl at 7 Pyridone carboxylic acid compound there is excellent antitumor action, it is useful as antitumor agent so that complete the present invention.

That is, the present invention relates to (1) below~(6).

(1) a kind of pyridone carboxylic acid derivatives or its salt indicated by following formula (1).

(in formula, R¹It indicates hydrogen atom, halogen atom, itrile group, the low alkyl group that can have substituent group, can have substituent group Lower alkoxy, can have substituent group low-grade alkyl amino, ring low alkyl group, cyclic amino, can have substituent group Aryl or can have the heteroaryl of substituent group,

R²Indicate hydrogen atom, halogen atom, nitro, hydroxyl, the low alkyl group that can have substituent group, lower alkoxy, amino, Can have the low-grade alkyl amino of substituent group, ring low alkyl group, 4~7 yuan of the cyclic amino that can have substituent group or C_1-17Alkanoylamino,

R³~R⁶Can be identical or different, indicate hydrogen atom, the low alkyl group that can have substituent group, carboxyl, lower alkoxy Carbonyl or the carbamoyl that can have substituent group,

R⁷It indicates hydrogen atom, halogen atom, hydroxyl, the amino that can have substituent group, carboxyl, itrile group, can have substituent group Low alkyl group or lower alkoxy,

R⁸It indicates hydrogen atom, halogen atom, hydroxyl, the low alkyl group that can have substituent group, can have the rudimentary of substituent group Alkenyl, the lower alkoxy that can have substituent group, can have the low of substituent group at the ring low alkyl group that can have substituent group Grade alkyl amino alkyl carbonyl, low-grade alkane acidyl oxygroup, low-grade alkane acidyl sulfenyl, aryl carbonyl sulfenyl, mercapto ,-SS-R^8a (here, R^8aIndicate to can have the low alkyl group of substituent group) or it is following 1)~7) shown in any group,

1) following formula (a)

(in formula, R^a1And R^a2Can be identical or different, indicate hydrogen atom, hydroxyl, the low alkyl group that can have substituent group, can be with Low-grade alkenyl with substituent group, the low-grade alkynyl that can have substituent group, the lower alkoxy that can have substituent group, can be with With substituent group and with the C of ehter bond_2-12Alkyl or alkoxy, the heteroaryl amino that can have substituent group can have and take Nitrogenous two rings the heteroaryl ,-R of Dai Ji^a3- Cy¹(here, R^a3Indicate the hydrocarbon of singly-bound, the divalent that can be substituted with halogen atoms Base or oxygroup, Cy¹Indicate to can have the ring low alkyl group of substituent group, 4~7 yuan of the cyclic ether group that can have substituent group, N- substitution morpholinyl,Piperazine alkyl is differentOxazoline base), 5~6 yuan of heteroaryl can have substituent group, can have The heteroarylalkyl of substituent group or group below,

Or indicate R^a1And R^a24~9 yuan of the cyclic amino that can have substituent group being formed together with adjacent nitrogen-atoms, * Indicate bonding position.)

2) following formula (b)

(in formula, Het indicates 4~6 yuan of heterocycle, R^b1For the substituent group on above-mentioned heterocycle, and there are it is multiple when, Ke Yixiang It is same or different, it indicates halogen atom, hydroxyl, amino, nitro, amide groups, lower alkyl base, carboxyl, can have substitution The low alkyl group of base, the lower alkoxy that can have substituent group, elementary alkoxy carbonyl, can have substituent group 4~7 yuan Cyclic ether group, low-grade alkyl amino, lower alkanoylamino or oxygroup, m indicate 0~2 integer, * indicate bonding position.)

3) following formula (c)

R^c2-R^c1-* (c)

(in formula, R^c1Indicate CO, SO or SO₂, R^c2It indicates to can have the low alkyl group of substituent group, can have the low of substituent group Grade alkoxy, 5~6 yuan of the heteroaryl that can have substituent group, can have and take the ring low alkyl group that can have substituent group The aralkyl of Dai Ji or the heteroarylalkyl that can have substituent group, * indicate bonding position.)

4) following formula (d)

(in formula, R^d1It indicates hydrogen atom, can have the low alkyl group of substituent group or can have the C of substituent group_1-17Alkanoyl, R^d2Expression hydrogen atom, can have the aralkyl of substituent group or can have substituent group the low alkyl group that can have substituent group Heteroarylalkyl, * indicate bonding position.)

5) following formula (e)

(in formula, R^e1And R^e2Can be identical or different, expression hydrogen atom, can have the low alkyl group that can have substituent group The low-grade alkane acidyl of substituent group, the aralkyl that can have substituent group or 5~6 yuan of the heteroaryl that can have substituent group, * table Show bonding position.)

6) following formula (f)

(in formula, R^f1And R^f2Can be identical or different, expression hydrogen atom, can have the low alkyl group that can have substituent group The low-grade alkane acidyl of substituent group or 5~6 yuan of the heteroaryl that can have substituent group, n indicate that 0~2 integer, * indicate bonding Position.)

7) following formula (g)

(in formula, R^g1It indicates hydrogen atom or can have the low alkyl group of substituent group, R^g2Indicate CO, CS, SO or SO₂, R^g3It indicates Hydrogen atom or the C that can have substituent group_1-17Alkyl, can have substituent group at the lower alkoxy that can have substituent group Low-grade alkyl amino, 4~7 yuan of the cyclic amino that can have substituent group, 5~6 yuan of the heteroaryl that can have substituent group, It can have 5~6 yuan of heteroaryl amino of substituent group, * indicates bonding position.)

Alternatively, by R⁷And R⁸Formation=N-OR¹⁰(here, R¹⁰Indicate hydrogen atom, can have substituent group low alkyl group or Aralkyl) or=O, or indicate R⁷And R⁸It is formed together with adjacent carbon atom and can have 4~6 yuan of substituent group full And heterocycle,

R⁹Indicate hydrogen atom or ester residue,

X indicates nitrogen-atoms or C-R¹¹(here, R¹¹Indicate hydrogen atom, halogen atom, itrile group, nitro, low alkyl group, lower alkyl Oxygroup, the thienyl that can have substituent group, the phenyl that can have substituent group, or indicate R¹And R¹¹With adjacent carbon atom It is formed together phenyl ring or naphthalene nucleus),

Y indicates nitrogen-atoms or C-R¹²(here, R¹²It indicates hydrogen atom, halogen atom, itrile group or can have the rudimentary of substituent group Alkyl).But do not include R⁷For amino and R⁸The case where for hydrogen atom and R⁷For hydrogen atom and R⁸For the feelings of methylamino Condition.〕

(2) a kind of drug contains pyridone carboxylic acid derivatives or its salt described in (1) and pharmaceutically admissible carrier.

(3) a kind of antitumor agent, the pyridone carboxylic acid derivatives or its salt recorded using (1) are as effective component.

(4) application of pyridone carboxylic acid derivatives or its salt in manufacture antitumor agent described in a kind of (1).

(5) in order to prevent or treating cancer and use pyridone carboxylic acid derivatives described in (1) or its salt.

(6) prevention or treatment method of a kind of cancer, which is characterized in that by pyridone carboxylic acid derivatives described in (1) or its salt It is administered.

The effect of invention

Pyridone carboxylic acid derivatives of the invention or its salt there is excellent proliferation to press down the cancer cell line of entity and non-physical knurl Production is used, and low to the cytotoxicity of normal cell.Therefore, pyridone carboxylic acid derivatives of the invention or its salt are used as pre- Antitumor agent that is anti-or treating various cancers is useful.

Specific embodiment

Hereinafter, being described in detail to the present invention.

In this specification, term " rudimentary " unless otherwise specified, then for the term group hydrocarbon part carbon Atomicity refers to 1~12 in the case where hydrocarbon part is chain, in the case where hydrocarbon part is cricoid situation, refers to 3~12, Chain hydrocarbon part, which refers to, to be any one of linear chain or branched chain.

It should be noted that in this specification, carbon atom number (x~y) such as " C of hydrocarbon part_X-y" abridge like that.

In addition, " can have substituent group " refers to that the hydrogen atom of the group as object can be replaced by other groups, the substitution The quantity of base can be 1 or 1 or more, and when having 2 or more substituent groups, which can be identical or different.

Hereinafter, being illustrated to symbol used in formula (1).

As R¹Shown in " halogen atom ", fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine can be enumerated.

As R¹Shown in " low alkyl group ", preferably C_1-7Alkyl, can more preferably enumerate methyl, ethyl, propyl, isopropyl, The C such as butyl, isobutyl group, tert-butyl_1-4Alkyl, further preferably methyl, ethyl, isopropyl.

As the group that can replace on the low alkyl group, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7 Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), C_1-3Alkoxy C_1-7Alkoxy is (for example, methoxy ethoxy, second Oxygroup ethyoxyl etc.), amino, C_1-7Alkyl amino is (for example, methylamino, ethylamino, dimethylamino, diethylamino Deng), carboxyl, C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), C_1-7Alkanoyl (for example, acetyl group, Ethylcarbonyl group, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.) etc..

As R¹Shown in " lower alkoxy ", preferably C_1-7Alkoxy can more preferably enumerate methoxyl group, ethyoxyl, the third oxygen The C such as base, isopropoxy, butoxy_1-4Alkoxy, further preferably methoxyl group, ethyoxyl, propoxyl group.

As the group that can replace on the lower alkoxy, for example, can enumerate halogen atom (for example, fluorine atom), hydroxyl, C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), carboxyl, amino, C_1-7Alkyl amino (for example, methylamino, Ethylamino, dimethylamino, diethylamino etc.) etc..

As R¹Shown in " low-grade alkyl amino ", preferably single or two-C_1-7Alkyl amino can more preferably enumerate such as methyl The list such as amino, ethylamino, propylcarbamic, methylethylamine, dimethylamino, diethylamino or two-C_1-4Alkyl ammonia Base.As the group that can replace on the low-grade alkyl amino, such as hydroxyl, C can be enumerated_1-7Alkoxy is (for example, methoxyl group, second Oxygroup, propoxyl group etc.), carboxyl, amino, C_1-4Alkyl amino (such as methylamino, ethylamino etc.).

As R¹Shown in " ring low alkyl group ", preferably ring C_3-7Alkyl, more preferable cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.

As R¹Shown in " cyclic amino ", piperidyl, morpholino base, pyrrolidinyl, hexahydro azepine can be enumeratedBase, piperazinyl Deng 4~7 yuan of saturated cyclic amino.

As R¹Shown in " aryl ", such as the C such as phenyl, naphthalene, indenyl, anthryl can be enumerated_6-14Aryl, preferably C_6-10Virtue Base can more preferably enumerate phenyl.

As R¹Shown in " heteroaryl ", such as can enumerate pyrrole radicals, pyrazolyl, furyl, thienyl, pyridyl group, imidazole radicals, It is triazolyl, tetrazole radical, triazine radical, pyridazinyl, pyrimidine radicals, pyrazinyl, differentOxazolyl, thiazolyl, isothiazolyl, thiadiazolyl group,Oxazolyl,The heteroaryl that 5~6 yuan of di azoly etc., wherein preferred pyrrole radicals, pyrazolyl, imidazole radicals, triazolyl, pyridyl group, The nitrogenous heteroaryl containing 1~3 nitrogen-atoms such as pyrimidine radicals, pyridazinyl, pyrazinyl, triazine radical, more preferably (2-, 3- or 4-) pyridyl group, (4- or 5-) pyrimidine radicals.

As the group that can replace on the aryl or heteroaryl, for example, can enumerate halogen atom (for example, fluorine atom), hydroxyl, C_1-7Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl etc.), C_1-7Alkoxy is (for example, methoxy Base, ethyoxyl, propoxyl group etc.), amino, C_1-7Alkyl amino is (for example, methylamino, ethylamino, dimethylamino, diethyl Amino etc.), carboxyl etc..

R¹Preferably hydrogen atom, halogen atom, the low alkyl group that can have substituent group, the rudimentary alcoxyl that can have substituent group Base, the low-grade alkyl amino that can have substituent group, cyclic amino, more preferably hydrogen atom, halogen atom, C_1-4Alkyl, C_1-4 Alkoxy, C_1-4Alkyl amino, more preferably hydrogen atom or halogen atom.

As R²Shown in " halogen atom ", fluorine, chlorine, bromine, iodine, preferably fluorine atom or chlorine atom can be enumerated.

As R²Shown in " low alkyl group ", preferably C_1-7Alkyl can more preferably enumerate such as methyl, ethyl, propyl, isopropyl The C such as base, butyl, isobutyl group, tert-butyl_1-4Alkyl, further preferably methyl, ethyl.As can replace on the low alkyl group Group, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7Alkoxy is (for example, methoxyl group, ethyoxyl, the third oxygen Base etc.), amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.) etc..

As R²Shown in " lower alkoxy ", " low-grade alkyl amino ", " ring low alkyl group ", can enumerate and above-mentioned R¹In show The same group of group.

In addition, as the group that can replace on the low-grade alkyl amino, for example, can enumerate halogen atom (for example, fluorine atom), Hydroxyl, C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.) etc..

As R²Shown in " 4~7 yuan of cyclic aminos ", azelidinyl, pyrrolidinyl, morpholino base, different can be enumeratedAzoles Quinoline base etc..

As the group that can replace on the cyclic amino, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-4 Alkyl (such as methyl, ethyl, propyl, isopropyl etc.), halogenated C_1-4Alkyl (such as trifluoromethyl etc.), C_1-4Alkoxy (example Such as, methoxyl group, ethyoxyl, propoxyl group etc.), amino, C_1-4Alkyl amino is (for example, methylamino, ethylamino, dimethylamino Base, diethylamino etc.), carboxyl etc..

As R²Shown in " C_1-17Alkanoylamino " can preferably enumerate acetyl-amino, ethylcarbonylamino, propyl carbonyl The C such as amino, butyl carbonylamino, pentylcarbonylamino, hexyl carbonylamino_1-7Alkanoylamino and pentadecane acyl amino, The C such as Hexadecanoylamino, heptadecane acyl amino_15-17Alkanoylamino.

R²Preferably hydrogen atom, halogen atom, the low alkyl group that can have substituent group, hydroxyl, amino, more preferably hydrogen atom Or it can have the C of substituent group_1-7Alkyl.

As R³~R⁶Shown in " low alkyl group ", preferably C_1-7Alkyl can more preferably enumerate methyl, ethyl, propyl, isopropyl The C such as base, butyl, isobutyl group, tert-butyl_1-4Alkyl, further preferably methyl, ethyl.

As R³~R⁶Shown in " elementary alkoxy carbonyl ", preferably C_1-7Alkoxy carbonyl, more preferable methoxycarbonyl, ethoxy Base carbonyl.

As can be in R³~R⁶Shown in the group that replaces on carbamoyl, R⁸When being indicated by formula (a), it can enumerate by R^a1With R^a2"-the R indicated^a3- Cy¹(here, R^a3Indicate the alkyl of singly-bound or the divalent that can be substituted with halogen atoms, Cy¹Expression can With with substituent group ring low alkyl group, can have substituent group 4~7 yuan of cyclic ether group, N- replace morpholinyl,Piperazine Alkyl is differentOxazoline base) " group that shows, preferably R^a3Alkyl, Cy for divalent¹For 4~7 yuan for can have substituent group Cyclic ether group the case where.

R³~R⁶Preferably hydrogen atom, can have the C of substituent group_1-7Alkyl, more preferably hydrogen atom.

As R⁷Shown in " halogen atom ", fluorine, chlorine, bromine, iodine, preferably fluorine atom or chlorine atom can be enumerated.

As R⁷Shown in " low alkyl group ", preferably C_1-7Alkyl can more preferably enumerate methyl, ethyl, propyl, isopropyl, fourth The C such as base, isobutyl group, tert-butyl_1-4Alkyl.

As the group that can replace on the low alkyl group, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7 Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), C_1-3Alkoxy C_1-7Alkoxy is (for example, methoxy ethoxy, second Oxygroup ethyoxyl etc.), amino, C_1-7Alkyl amino is (for example, methylamino, ethylamino, dimethylamino, diethylamino Deng) etc..

As R⁷Shown in " lower alkoxy ", preferably C_1-7Alkoxy can more preferably enumerate such as methoxyl group, ethyoxyl, third The C such as oxygroup, isopropyl, butoxy_1-4Alkoxy, further preferably methoxyl group.

As R⁷Shown in amino substituent group, C can be enumerated_1-4Alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, Tert-butyl etc.) and the C that is replaced by hydroxyl or halogen atom_1-4Alkyl etc..

R⁷Preferably hydrogen atom, halogen atom, the low alkyl group that can have substituent group, more preferably hydrogen atom.

As R⁸Shown in " halogen atom ", can preferably enumerate fluorine atom or chlorine atom.

As R⁸Shown in " low alkyl group ", preferably C_1-7Alkyl can more preferably enumerate methyl, ethyl, propyl, isopropyl, fourth The C such as base, isobutyl group, tert-butyl_1-4Alkyl can further preferably enumerate methyl, ethyl, propyl, butyl.

As the group that can replace on the low alkyl group, such as halogen atom (for example, fluorine atom, chlorine atom), hydroxyl can be enumerated Base, C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), C_1-3Alkoxy C_1-7Alkoxy is (for example, methoxyl group ethoxy Base, ethoxy ethoxy, methoxy propoxy etc.), halogenated C_1-7Alkoxy is (for example, fluorine methoxyl group, difluoro-methoxy, fluoroform Oxygroup, 2,2,2- trifluoro ethoxy etc.), hydroxyl C_1-7Alkoxy is (for example, hydroxyl-oxethyl, 2- hydroxy propyloxy group, 3- hydroxyl Propoxyl group etc.) amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.), 4~ 7 yuan of cyclic ether C_1-3Alkoxy is (for example, tetrahydrofuran ylmethoxy, oxinane ylmethoxy, oxinane base oxethyl Deng), 4~7 yuan of cyclic ether C_1-3Alkyl amino is (for example, tetrahydrofuran vlmethyl, oxinane vlmethyl, tetrahydro Pyranose ethylamino etc.), carboxyl, the group (for example, t-butyldimethylsilyl etc.) that can be exchanged into hydroxyl etc..

As R⁸Shown in " low-grade alkenyl ", preferably C_2-7Alkenyl can more preferably enumerate such as vinyl, acrylic, 2- first Base -1- acrylic, 1- methyl-1-propylene base etc..

As the group that can replace on the low-grade alkenyl, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7 Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), carboxyl etc..

As R⁸Shown in " ring low alkyl group ", preferably ring C_3-7Alkyl, more preferable cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.

As the group that can replace on the ring low alkyl group, halogen atom (for example, fluorine atom), hydroxyl, carboxyl, oxygen can be enumerated For base etc..

As R⁸Shown in " lower alkoxy ", preferably C_1-7Alkoxy can more preferably enumerate such as methoxyl group, ethyoxyl, third The C such as oxygroup, isopropyl, butoxy_1-4Alkoxy, further preferably methoxyl group, ethyoxyl, propoxyl group.

As the group that can replace on the lower alkoxy, such as halogen atom, hydroxyl, C can be enumerated_1-3Alkoxy (for example, Methoxyl group, ethyoxyl, propoxyl group), C_1-3Alkoxy C_1-7Alkoxy (for example, methoxy ethoxy, ethoxy ethoxy etc.), Amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.), carboxyl, 4~6 yuan Cyclic ether group (for example, oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl, twoAlkyl etc.) etc..

As R⁸Shown in " low-grade alkyl amino carbonylic alkyl ", preferably single or two-C_1-4Alkyl amino-carbonyl C_1-4Alkyl, example Ethylaminocarbonylmethyl, isopropylaminocarbonyl methyl can such as be enumerated.

As the group that can replace on the low-grade alkyl amino carbonylic alkyl, hydroxyl, C can be preferably enumerated_1-3Alkoxy (example Such as, methoxyl group, ethyoxyl, propoxyl group), carboxyl etc..

As R⁸Shown in " low-grade alkane acidyl oxygroup ", preferably C_1-4Alkanoyl oxygroup can more preferably enumerate such as acetyl group oxygen Base, propiono oxygroup, iso-propionyl oxygroup.

As R⁸Shown in " low-grade alkane acidyl sulfenyl ", C can be enumerated_1-4Alkanoyl sulfenyl can more preferably enumerate such as acetyl group Sulfenyl, propiono sulfenyl, iso-propionyl sulfenyl.

As R⁸Shown in " elementary alkoxy carbonyl ", preferably C_1-7Alkoxy carbonyl, more preferable methoxycarbonyl, ethyoxyl carbonyl Base.

As R^8aShown in " low alkyl group ", preferably C_1-7Alkyl can more preferably enumerate the C such as methyl, ethyl, propyl_1-4Alkane Base.

As the group that can replace on the low alkyl group, such as hydroxyl, C can be enumerated_1-4Alkoxy is (for example, methoxyl group, ethoxy Base etc.), amino, C_1-4Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.), carboxyl Deng.

In formula (a), as R^a1Or R^a2Shown in " low alkyl group ", preferably C_1-7Alkyl, can more preferably enumerate methyl, ethyl, The C such as propyl, isopropyl, butyl, isobutyl group, tert-butyl, amyl, isopentyl, neopentyl_1-5Alkyl.

As the group that can replace on the low alkyl group, for example, can enumerate halogen atom (for example, fluorine atom), itrile group, hydroxyl, Amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.), carboxyl, C_1-7Alkane Epoxide carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), C_1-7Alkanoyl is (for example, acetyl group, ethylcarbonyl group, carbonyl propyl Base, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.), sulfydryl, C_1-7Alkyl sulfenyl is (for example, methyl sulfenyl, ethyl Sulfenyl, propyl sulfenyl, butyl sulfenyl etc.), C_1-7Alkyl sulphinyl is (for example, methylsulfinyl, ethyl Sulfinyl, propylsulfenyl, butylsulfinyl etc.), C₁- 7 alkyl sulphonyls are (for example, methyl sulphonyl, ethyl sulphur Acyl group, sulfonyl propyl base, butyl sulfonyl etc.), aralkyl oxy (such as benzyl oxygroup, 1- phenylethyl oxygroup, 2- phenyl Ethyl oxygroup etc.) etc., preferably halogen atom, hydroxyl, C_1-4Alkoxy, C_1-4Alkyl sulphonyl, carboxyl, C_1-7Alkanoyl.

As R^a1Or R^a2Shown in " low-grade alkenyl ", preferably C_2-7Alkenyl can more preferably enumerate vinyl, allyl, 1- third The C such as alkenyl_2-4Alkenyl.

As R^a1Or R^a2Shown in " low-grade alkynyl ", preferably C_2-7Alkynyl can more preferably enumerate such as acetenyl, 1- propine The C such as base, 1- butynyl_2-4Alkynyl.

As the group that can replace on the low-grade alkynyl, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7 Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.) etc..

As R^a1Or R^a2Shown in " lower alkoxy ", preferably C_1-7Alkoxy can more preferably enumerate such as methoxyl group, ethoxy The C such as base, propoxyl group, isopropoxy, butoxy_1-4Alkoxy, further preferably methoxyl group, ethyoxyl, propoxyl group.

As the group that can replace on the lower alkoxy, halogen atom, hydroxyl can be preferably enumerated.

As R^a1Or R^a2Shown in " with ehter bond C_2-12Alkyl or alkoxy " can be enumerated and contain 1 or more in the substituent group The C of ehter bond (- C-O-C-)_2-12Alkyl or C_2-12Alkoxy.Wherein, the C of 1~3 ehter bond is preferably comprised_2-7Alkyl or C_2-7Alkoxy.It should be noted that the C_2-7Alkyl or C_2-7The alkyl chain of alkoxy can be any one of linear chain or branched chain.

As the C with ehter bond_2-12Alkyl, such as group as shown below can be enumerated.

As the C with ehter bond_2-12Alkoxy, such as group as shown below can be enumerated.

As can be in the C with ehter bond_2-12The group replaced on alkyl or alkoxy can enumerate hydroxyl, halogen atom.Below It shows with substituent group and with the C of ehter bond_2-12An example for alkyl (in formula, Hal indicates halogen atom).

As " the C with ehter bond_2-12Alkyl or alkoxy ", the preferably C containing 1~3 ehter bond_2-7Alkyl, more preferably Group as shown below.

As R^a1Or R^a2Shown in heteroaryl in " heteroaryl amino ", can preferably enumerate pyrrole radicals, pyrazolyl, imidazole radicals, 5~6 yuan of the nitrogenous heteroaryl containing 1~3 nitrogen-atoms such as triazolyl, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, triazine radical Base, preferably (2-, 3- or 4-) pyridyl group, more preferable 2- pyridyl group.

As the group that can replace on the heteroaryl amino, refer to can in the miscellaneous nuclear substituted group, as the substituent, C can be enumerated_1-7Alkyl (for example, methyl, ethyl etc.), halogen atom, hydroxyl, C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, Propoxyl group etc.), C_1-3Alkoxy C_1-7Alkoxy (for example, methoxy ethoxy, ethoxy ethoxy etc.) etc..

R^a1Or R^a2Shown in " nitrogenous two rings heteroaryl ", as the specific example for the heterocycle for constituting heteroaryl, can enumerate Benzimidazole, purine, isoquinolin, quinoline, quinoxaline etc..

As the group that can replace on the nitrogenous two rings heteroaryl, C can be enumerated_1-7Alkyl (for example, methyl, ethyl etc.), Halogen atom, hydroxyl, C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), carboxyl etc..

R^a1Or R^a2Shown in "-R^a3- Cy¹" in, as R^a3Shown in divalent alkyl, C can be enumerated_1-6Alkylidene (for example, Methylene, 1,1- ethylidene, 1,2- ethylidene, 1,2- propylidene, 1,3- propylidene, 1,4- butylidene, 1,2- Aden Base, 1,2- pentylidene, 1,2- hexylidene, 2,3- butylidene, 2,4- pentylidene etc.), C_2-6Alkenylene is (for example, 1,1- is sub- Vinyl, 1,2- ethenylidene, 1,2- ethenylidene methylene, 1- methyl-1,2- ethenylidene, the Asia 1,2- ethylene Base -1,1- ethylidene, 1,2- ethenylidene -1,2- ethylidene, 1,2- ethenylidene -1,2- propylidene, 1,2- are sub- Vinyl -1,3- propylidene, 1,2- ethenylidene -1,4- butylidene, 1,2- ethenylidene -1,2- butylidene etc.), C_2-4Alkynylene is (for example, ethynylene, ethynylene methylene, ethynylene -1,1- ethylidene, ethynylene -1,2- Ethylidene, ethynylene -1,2- propylidene, ethynylene -1,3- propylidene, ethynylene -1,4- butylidene, sub- second Alkynyl -1,2- butylidene etc.).

The alkyl of the divalent can be replaced by halogen atom (for example, fluorine atom, chlorine atom).As two be substituted with halogen atoms The alkyl of valence, such as fluorine methylene, chlorine methylene, difluoro methylene, chlorine fluorine methylene, difluoro ethylidene, fluoro- 1 can be enumerated, 1- ethenylidene, fluoro- 1,4- butylidene, 1,2- ethenylidene-fluoro- 1,2- ethylidene, ethenylidene -3 1,2-, The fluoro- 1,2- propylidene of 3,3- tri-, the fluoro- 1,2- propylidene of ethynylene -3,3,3- three, ethynylene -4- fluoro- 1, 4- butylidene, the fluoro- 1,2- butylidene of ethynylene -4,4,4- three etc..

As Cy¹Shown in " ring low alkyl group ", can preferably enumerate ring C_3-6Alkyl, more preferably cyclopropyl, cyclobutyl, ring Amyl, cyclohexyl.

As the group that can replace on the ring low alkyl group, halogen atom, hydroxyl, C can be preferably enumerated_1-7Alkyl (for example, Methyl, ethyl etc.), C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group, isopropoxy etc.), C_1-4Alkoxy C_1-4Alkane Base is (for example, methoxy, ethoxyl methyl, methoxy ethyl, methoxyisopfopyl, i-propoxymethyl, isopropoxy second Base), amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.) etc..

As Cy¹Shown in " 4~7 yuan of cyclic ether groups ", oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl, two can be enumerated Hydrogen pyranose, dioxolane base, twoAlkyl, oxepane alkyl, Dioxepane base etc., preferably 3- oxa- ring fourth Base, (2- or 3-) tetrahydrofuran base, (2-, 3- or 4-) THP trtrahydropyranyl, 2- (1,4- bis-Alkyl) group.

As the group that can replace in the cyclic ether group, C can be enumerated_1-7Alkyl (for example, methyl, ethyl etc.), halogen atom, Hydroxyl, C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), C_1-4Alkoxy C_1-4Alkyl is (for example, methoxy methyl Base, ethoxyl methyl), halogenated C_1-7Alkyl (methyl fluoride, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl etc.), amino, Oxygroup etc..

As Cy¹Shown in " N- replace morpholinyl ", refer to the nitrogen-atoms of morpholine ring by C_1-4The aralkyl such as alkyl, benzyl, can With the C with substituent group (halogen atom, hydroxyl etc.)_1-4The morpholinyl that the aroyls such as alkanoyl, benzoyl replace, preferably It can enumerate such as N-methylmorpholine base, N- Benzvlmorpholin base, N- acetylmorpholine base, N- benzoyl morpholinyl.

As "-R^a3- Cy¹", R^a3Preferably C_1-6Alkylidene, Cy¹Preferably 4~7 yuan of cyclic ether group (preferably tetrahydro pyrrole It mutters base, tetrahydrofuran base etc.).

As R^a1Or R^a2Shown in " 5~6 yuan of the heteroaryl that can have substituent group ", preferably comprise 1~4 it is former selected from nitrogen Heteroatomic 5~6 yuan of heteroaryl in son, oxygen atom and sulphur atom, can enumerate such as pyrrole radicals, furyl, thienyl, miaow Oxazolyl, pyrazolyl,It is oxazolyl, differentOxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazole radical,Di azoly, thiadiazolyl group Deng 5 yuan of heteroaryl；The heteroaryl of 6 yuan of pyridyl group, pyrazinyl, pyrimidine radicals, pyridazinyl, triazine radical, tetrazine base etc., wherein excellent Select pyrrole radicals, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical,It is oxazolyl, differentOxazolyl, thiazolyl, isothiazolyl, pyridyl group, The nitrogenous heteroaryl containing 1~4 nitrogen-atoms such as pyrimidine radicals, pyridazinyl, pyrazinyl, triazine radical, tetrazine base, more preferably (2-, 3- or 4-) pyridyl group, 2-Oxazolyl, 2- thiazolyl, 3- pyrazolyl, 3- are differentOxazolyl.

As the group that can replace on the heteroaryl, such as halogen atom (for example, fluorine atom) can be enumerated；Hydroxyl；C_1-7Alkane Base (for example, methyl, ethyl etc.)；It is selected from halogen atom (such as fluorine atom), hydroxyl, amino, C_1-4In alkyl amino and carboxyl 1 kind or more of group replace C_1-7Alkyl is (for example, methyl fluoride, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyls, hydroxyl Ylmethyl, hydroxyethyl, hydroxypropyl, dimethylaminomethyl, dimethyl aminoethyl, methoxyl group -1,1- bis-fluoro ethyls, Ethyoxyl -1,1- bis-fluoro ethyls, two fluoropropyl of methoxyl group -1,1-, hydroxyl -1,1- bis-fluoro ethyls, hydroxyl -1,1- two Fluoropropyl, methylamino -1,1- bis-fluoro ethyls etc.)；C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.)；It is selected From halogen atom (such as fluorine atom), hydroxyl, amino, C_1-4The C that the group of one or more of alkyl amino and carboxyl replaces_1-7 Alkoxy is (for example, the fluoro- 2- hydroxy propyloxy group of trifluoromethoxy, hydroxyl-oxethyl, dimethylamino ethoxy, 3-, 2- ammonia Base -3- fluorine propoxyl group, the fluoro- 2- hydroxybutoxy of 4,4,4- tri-, the fluoro- 2- methoxybutoxy of 4,4,4- tri- etc.)；It can With the C replaced by the group selected from one or more of halogen atom (such as fluorine atom) and hydroxyl_1-4Alkyl amino is (for example, hydroxyl Base ethylamino, hydroxypropylamino, trifluoroethyl amino, (the fluoro- 2- hydroxypropyl of 3-) amino, (4,4,4- tri- is fluoro- 2- hydroxybutyl) amino etc.)；Ring C_3-7Alkyl；C with ehter bond_3-7Alkyl or alkoxy (such as-O (CH₂)₂OCH₃,-O (CH₂)₂O(CH₂)₂OCH₃,-O (CH₂)₂O(CH₂)₂O(CH₂)₂OCH₃,-O (CH₂)₃OCH₃,-O (CH₂)₃O(CH₂)₃OCH₃,- (CH₂)₂OCH₃,-OCH₂OCH₃Deng)；Amino；By C_1-7Alkyl (such as methyl, ethyl etc.) and/or the C with ehter bond_2-7Alkyl (such as-(CH₂)₃O(CH₂)₂CH₃,-(CH₂)₂O(CH₂)₂OCH₃,-(CH₂)₂OCH₃,-(CH₂)₃OCH₃Deng) replace ammonia Base；Sulfydryl；C_1-7Alkyl sulfenyl is (for example, methyl sulfenyl, ethyl sulfenyl, propyl sulfenyl, butyl time sulphur Acyl group etc.)；C_1-7Alkyl sulphinyl is (for example, methylsulfinyl, ethylsulfinyl, propylsulfenyl, butyl Asia sulphur Acyl group etc.)；C_1-7Alkyl sulphonyl (for example, methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, butyl sulfonyl etc.)；Carboxylic Base, C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.)；C_1-7Alkanoyl is (for example, acetyl group, ethyl carbonyl Base, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.) etc..

As R^a1Or R^a2Shown in " heteroarylalkyl ", can enumerate heteroaryl moiety be divided into 5~6 yuan, the carbon atom numbers of moieties be 1~2 heteroarylalkyl (5~6 yuan of heteroaryl C_1-2Alkyl), as 5~6 yuan of heteroaryl, can enumerate with it is foregoing illustrative miscellaneous The same heteroaryl of aryl, wherein preferred furyl, pyridyl group, pyrazolyl, thiazolyl,Oxazolyl etc..

As the group that can replace on the heteroarylalkyl, can enumerate as the above-mentioned group illustration that can replace on heteroaryl Group can preferably enumerate halogen atom (for example, fluorine atom), hydroxyl, C_1-7It is alkyl (for example, methyl, ethyl etc.), halogenated C_1-7Alkyl (methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group etc.), C_1-7Halogenated alkoxy C_1-7Alkyl is (for example, ethoxy Base bis-fluoro ethyls, methoxy ethoxy bis-fluoro ethyls etc.), hydroxyl C_1-7Alkyl (hydroxymethyl, hydroxyethyl, hydroxypropyl etc.), C_1-4Alkoxy C_1-4Alkyl (for example, methoxy, ethoxyl methyl), C_1-7Alkoxy is (for example, methoxyl group, ethyoxyl, third Oxygroup, isopropoxy etc.), C_1-3Alkoxy C_1-7Alkoxy (for example, methoxy ethoxy, ethoxy ethoxy etc.), carboxyl C_1-7Alkyl, amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.), C_1-4 Alkoxy C_1-4Alkyl amino (for example, methoxymethylamino group, ethoxyl methyl amino), C_1-7Alkyl sulphonyl is (for example, first Base sulfonyl, ethylsulfonyl, sulfonyl propyl base, butyl sulfonyl etc.), carboxyl, C_1-7Alkanoyl is (for example, acetyl group, ethyl Carbonyl, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.) etc..

As " heteroarylalkyl ", 2- pyridylmethyl, 2- furyl methyl can be preferably enumerated.

As R^a1And R^a24~9 yuan of cyclic amino being formed together with adjacent nitrogen-atoms, can enumerate azelidinyl, pyrroles Alkyl, piperidyl, piperazinyl, morpholino base,It is oxazoline base, differentOxazoline base and loop coil azelidinyl as shown below.

As the group that can replace on the cyclic amino, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7 Alkyl (for example, methyl, ethyl etc.), C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group, isopropoxy etc.), 4~6 yuan Cyclic amino (for example, piperidyl, morpholino base etc.), carboxyl, acyl group, oxygroup etc..

As group shown in formula (a), preferably R^a1Or R^a2Any one of be hydrogen atom, another one be can have substituent group C_1-7Alkyl can have substituent group and the C with ehter bond_2-12Alkyl or alkoxy ,-R^a3- Cy¹, can have substituent group 5~6 yuan of heteroaryl, can have the heteroarylalkyl of substituent group, more preferably can have substituent group and with ehter bond C_2-12Alkyl ,-R^a3- Cy¹, can have 5~6 yuan of heteroaryl of substituent group.

In formula (b), as the heterocycle for constituting " 4~6 yuan of heterocycles " shown in Het, it can enumerate containing former selected from nitrogen-atoms, oxygen The heterocycle of son and one or more of sulphur atom, such as azetidine, oxetanes, pyrrolidines, pyrazolidine, miaow can be enumerated Oxazolidine, pyrrolin, pyrazoline, imidazoline, piperidines, piperazine cry (ピペリデイ Application), piperidines, triazine alkane, oxinane, 1,3- bis-Alkane, 1,4- bis-Alkane, morpholine,It is oxazolidine, differentThe aliphatic heterocycles such as oxazolidine；

Pyrroles, pyrazoles, imidazoles, triazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine,It is azoles, differentAzoles,Two The 6 pi-electron system heterocycle such as azoles, thiazole, isothiazole, thiadiazoles.

Wherein, the nitrogen-containing heterocycle preferably containing the above nitrogen-atoms of at least one, more preferably 6 pi-electron system nitrogen-containing heterocycles, into one Step be preferably pyrazoles,Azoles, thiazole, pyridine.

A preferred example of Het is shown in following.

As R^b1Shown in " halogen atom ", fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine can be enumerated.

As R^b1Shown in " low alkyl group ", preferably C_1-7Alkyl, can more preferably enumerate methyl, ethyl, propyl, isopropyl, The C such as butyl, isobutyl group, tert-butyl_1-4Alkyl, further preferably methyl, ethyl, isopropyl.

As the group that can replace on the low alkyl group, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7 Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, Dimethylamino, diethylamino etc.), carboxyl, C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), C_1-7Alkanoyl (for example, acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.), 4~7 yuan Cyclic ether group (oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl) etc..

As R^b1Shown in " lower alkoxy ", preferably C_1-7Alkoxy can more preferably enumerate methoxyl group, ethyoxyl, the third oxygen The C such as base, isopropoxy, butoxy_1-4Alkoxy, further preferably methoxyl group, ethyoxyl, propoxyl group.

As the group that can replace on the lower alkoxy, hydroxyl, C can be enumerated_1-7Alkoxy is (for example, methoxyl group, ethoxy Base, propoxyl group etc.), carboxyl, amino, C_1-7Alkyl amino is (for example, methylamino, ethylamino, dimethylamino, diethyl amino Base etc.) etc..

As R^b1Shown in " lower alkyl base ", preferably C_1-7Alkylamidoalkyl, more preferably methyl acylamino, ethyl acyl Amido, dimethyl acylamino.

As R^b1Shown in " elementary alkoxy carbonyl ", preferably C_1-7Alkoxy carbonyl, more preferably methoxycarbonyl, ethyoxyl Carbonyl.

As R^b1Shown in " low-grade alkyl amino ", preferably single or two-C_1-7Alkyl amino can more preferably enumerate such as first The list such as base amino, ethylamino, propylcarbamic, methylethylamine, dimethylamino, diethylamino or two-C_1-4Alkyl Amino.

As R^b1Shown in " lower alkanoylamino ", preferably C_1-7Alkanoylamino can enumerate such as acetyl-amino, ethyl Carbonylamino, propylcarbonylamino, butyl carbonylamino, pentylcarbonylamino, hexyl carbonylamino etc..

As R^b1Shown in " 4~7 yuan of cyclic ether groups ", oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl, two can be enumerated Hydrogen pyranose, dioxolane base, twoAlkyl etc. can preferably enumerate 3- oxetanylmethoxy, (2- or 3-) tetrahydrofuran Base, (2-, 3- or 4-) THP trtrahydropyranyl, 2- (1,4- bis-Alkyl) base.In addition, as that can be taken in the cyclic ether group The group in generation can enumerate C_1-7Alkyl (for example, methyl, ethyl etc.), halogen atom, hydroxyl, C_1-7Alkoxy is (for example, methoxy Base, ethyoxyl, propoxyl group etc.) etc..

R^b1It preferably can have the C of substituent group_1-7Alkyl, the C that can have substituent group_1-7Alkoxy, bis--C of Dan Huo_1-4Alkane Base amino.

In addition, m is preferably 0 or 1.

In formula (c), R^c1Shown in CO, SO or SO₂Respectively indicate carbonyl, sulfinyl, sulfonyl, wherein preferred carbonyl.

As R^c2Shown in can have the low alkyl group of substituent group, preferably C_1-7Alkyl can more preferably enumerate methyl, second The C such as base, propyl, isopropyl, butyl, isobutyl group, tert-butyl_1-4Alkyl, further preferably methyl, ethyl, isopropyl.

As the group that can replace on the low alkyl group, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7 Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, Dimethylamino, diethylamino etc.), carboxyl, C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), C_1-7Alkanoyl (for example, acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.),Piperazine alkane Base etc.

As R^c2Shown in " lower alkoxy ", preferably C_1-7Alkoxy can more preferably enumerate methoxyl group, ethyoxyl, the third oxygen The C such as base, isopropoxy, butoxy_1-4Alkoxy, further preferably methoxyl group, ethyoxyl, propoxyl group.

As the group that can replace on the lower alkoxy, such as halogen atom (for example, fluorine atom), hydroxyl, carboxylic can be enumerated Base, amino etc..

As R^c2Shown in " ring low alkyl group ", preferably ring C_3-7Alkyl, more preferable cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base.

As the group that can replace on the ring low alkyl group, halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7Alkane Base (for example, methyl, ethyl etc.), oxygroup etc..

As R^c2Shown in " 5~6 yuan of heteroaryls ", such as pyrrole radicals, pyrazinyl, pyrazolyl, tetrazole radical, furans can be enumerated It is base, thienyl, pyridyl group, imidazole radicals, triazolyl, triazine radical, pyridazinyl, pyrimidine radicals, differentOxazolyl, thiazolyl, isothiazolyl, Thiadiazolyl group,Oxazolyl,Di azoly etc., wherein the nitrogenous heteroaryl of 6 yuan of preferred pyridyl group etc..

As the group that can replace on the heteroaryl, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7Alkane Base (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl etc.), C_1-7Alkoxy is (for example, methoxyl group, ethoxy Base, propoxyl group etc.) etc..

As R^c2Shown in " aralkyl ", the carbon atom number of preferred aryl groups part is 6~12, the carbon atom number of moieties is 1 ~7 aralkyl (C_6-12Aryl C_1-7Alkyl), for example, can enumerate benzyl, 2- phenyl-propane -2- base, 1- phenylethyl, 2- phenylethyl, 1- propyloxy phenyl base, 2- propyloxy phenyl base, phenyl-tert-butyl, Alpha-Naphthyl methyl, 1- Alpha-Naphthyl second Base, 2- Alpha-Naphthyl ethyl, 1- Alpha-Naphthyl isopropyl, 2- Alpha-Naphthyl isopropyl, betanaphthyl methyl, 1- betanaphthyl second Base, 2- betanaphthyl ethyl, 1- betanaphthyl isopropyl, 2- betanaphthyl isopropyl etc., preferably benzyl.

As R^c2Shown in " heteroarylalkyl ", preferably heteroaryl moiety be divided into 5~6 yuan, the carbon atom numbers of moieties be 1~2 Heteroarylalkyl (5~6 yuan of heteroaryl C_1-2Alkyl), as 5~6 yuan of heteroaryl, can enumerate with it is above-mentioned shown in heteroaryl it is same The heteroaryl of sample.

As the group that can replace on above-mentioned aralkyl or heteroarylalkyl, can enumerate can replace as above-mentioned on heteroaryl The group that group illustrates, can preferably enumerate halogen atom (for example, fluorine atom), hydroxyl, C_1-7Alkyl is (for example, methyl, ethyl Deng), halogenated C_1-7Alkyl (methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group etc.), C_1-7Alkoxy (for example, methoxyl group, Ethyoxyl, propoxyl group etc.), C_1-7Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.), C_1-7Alkanoyl (such as acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.) etc..

R^c2It preferably can have the C of substituent group_1-7Alkyl, the ring C that can have substituent group_3-7Alkyl can have substituent group Heteroarylalkyl.

In formula (d), as R^d1Shown in " low alkyl group ", preferably C_1-7Alkyl, can more preferably enumerate methyl, ethyl, propyl, The C such as isopropyl, butyl, isobutyl group, tert-butyl_1-4Alkyl, further preferably methyl, ethyl.

As the group that can replace on the low alkyl group, such as hydroxyl, C can be enumerated_1-7Alkoxy is (for example, methoxyl group, ethoxy Base, propoxyl group etc.), amino, carboxyl, C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), C_1-7Alkanoyl (for example, acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.) etc..

As R^d1Shown in " C_1-17Alkanoyl ", can preferably enumerate acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl, The C such as pentylcarbonyl, hexyl carbonyl_1-7The C such as alkanoyl and pentadecane acyl group, hexadecanoyl, heptadecane acyl group_15-17Alkane acyl Base.

As can be in the C_1-17The group replaced on alkanoyl, such as amino, aryl (for example, phenyl etc.) can be enumerated etc..

As R^d2Shown in " low alkyl group ", can enumerate and R^d1Shown in the same low alkyl group of low alkyl group, preferably C_1-7 Alkyl.

As the group that can replace on the low alkyl group, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7 Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group, isopropoxy etc.), amino, carboxyl, C_1-7Alkoxy carbonyl is (for example, first Epoxide carbonyl, ethoxy carbonyl etc.), C_1-7Alkanoyl is (for example, acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl, amyl Carbonyl, hexyl carbonyl etc.), halogenated C_1-7Alkoxy (fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy Base, five fluorine ethyoxyls etc.), hydroxyl C_1-7Alkoxy (hydroxyl-oxethyl, 2- hydroxy propyloxy group, 3- hydroxy propyloxy group etc.), 5~6 The heterocycle containing 1 or more nitrogen-atoms of member (can be enumerated in formula (b) as the heterocycle shown in Het, for example, pyrroles, pyrrole Azoles,It is azoles, differentAzoles, thiazole, isothiazole, pyridine, pyrimidine etc.), 4~7 yuan of cyclic ether group (oxetanylmethoxy, tetrahydrofuran Base, THP trtrahydropyranyl) etc..

As R^d2Shown in " aralkyl that can have substituent group ", can enumerate and R^c2Shown in the same aralkyl of aralkyl.

As R^d2Shown in " heteroarylalkyl that can have substituent group ", can enumerate and R^c2Shown in heteroarylalkyl it is similarly miscellaneous Aralkyl.

As formula (d), preferably R^d1For hydrogen atom, R^d2For the low alkyl group that can have substituent group, more preferable R^d1For hydrogen atom, R^d2For C_1-7Alkyl.

In formula (e), as R^e1Or R^e2Shown in " low alkyl group ", preferably C_1-7Alkyl, can more preferably enumerate methyl, ethyl, The C such as propyl, isopropyl, butyl, isobutyl group, tert-butyl_1-4Alkyl can further preferably enumerate methyl, ethyl, propyl.

As the group that can replace on the low alkyl group, such as hydroxyl, C can be enumerated_1-7Alkoxy is (for example, methoxyl group, ethoxy Base, propoxyl group etc.), carboxyl, C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), 5~6 yuan contain 1 The heterocycle of the above nitrogen-atoms (can be enumerated in formula (b) as the heterocycle shown in Het, for example, pyrrolidinyl, morpholinyl, pyrroles Base, pyrazolyl, pyridyl group, pyrimidine radicals,It is oxazolyl, differentOxazolyl, thiazolyl, isothiazolyl, thiadiazolyl group,Di azoly Deng), 4~7 yuan of cyclic ether group (oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl) etc..

As R^e1Or R^e2Shown in " low-grade alkane acidyl ", can preferably enumerate acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl The C such as base, pentylcarbonyl, hexyl carbonyl_1-7Alkanoyl.

As the group that can replace on the low-grade alkane acidyl, such as hydroxyl, C can be enumerated_1-7Alkoxy is (for example, methoxyl group, second Oxygroup, propoxyl group etc.), halogenated C_1-7Alkoxy (fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, five fluorine ethyoxyls etc.), virtue Alkyl-carbonyl-amino (for example, b enzylcarb onylamino, 1- phenylethyl carbonylamino etc.), C_1-7Alkoxycarbonyl amino (for example, Methyloxycarbonylamino, ethoxycarbonylamino group, propoxy carbonylamino etc.), amino, carboxyl etc..

As R^e1Or R^e2Shown in " aralkyl that can have substituent group ", can enumerate and R^c2Shown in aralkyl it is similarly fragrant Alkyl.

As R^e1Or R^e2Shown in " 5~6 yuan of heteroaryls ", can enumerate and R^c2Shown in the same heteroaryl of heteroaryl, In, the preferred nitrogenous heteroaryl such as pyrazolyl, thiazolyl, pyridyl group.

In addition, as the group that can replace on the heteroaryl, for example, can enumerate halogen atom (for example, fluorine atom), hydroxyl, C_1-7Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl etc.), C_1-7Alkoxy is (for example, methoxy Base, ethyoxyl, propoxyl group etc.) etc..

As formula (e), preferably R^e1For hydrogen atom or it can have the low alkyl group of substituent group, R^e2To can have substituent group Low alkyl group, more preferable R^e1For hydrogen atom, R^e2For C_1-7Alkyl.

In formula (f), as R^f1Or R^f2Shown in " low alkyl group ", preferably C_1-7Alkyl, can more preferably enumerate methyl, ethyl, The C such as propyl, isopropyl, butyl, isobutyl group, tert-butyl_1-4Alkyl, further preferably methyl, ethyl, propyl.

As the group that can replace on the low alkyl group, such as hydroxyl, C can be enumerated_1-7Alkoxy is (for example, methoxyl group, ethoxy Base, propoxyl group etc.), halogenated C_1-7Alkoxy (fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, five fluorine ethyoxyls etc.), amino, Carboxyl, C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), C_1-7Alkanoyl is (for example, acetyl group, ethyl Carbonyl, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.) etc..

As R^f1Or R^f2Shown in " low-grade alkane acidyl ", can preferably enumerate acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl The C such as base, pentylcarbonyl, hexyl carbonyl_1-7Alkanoyl.

As the group that can replace on the low-grade alkane acidyl, can enumerate with as can be in above-mentioned R^f1Or R^f2Shown in lower alkyl The same group of the group shown in group replaced on base.

As R^f1Or R^f2Shown in " 5~6 yuan of heteroaryls ", can enumerate and R^c2Shown in the same heteroaryl of heteroaryl, In, the preferred nitrogenous heteroaryl such as pyrazolyl, thiazolyl, pyridyl group, pyrimidine radicals.

As formula (f), preferably R^f1For hydrogen atom, R^f2For the C that can have substituent group_1-7Alkyl can have the 5 of substituent group ~6 yuan of heteroaryl, more preferable R^f1For hydrogen atom, R^f2For 6 yuan of the heteroaryl that can have substituent group.

In addition, n is preferably 0 or 1.

In formula (g), R^g2Shown in CO, CS, SO or SO₂Respectively indicate carbonyl, thiocarbonyl, sulfinyl, sulfonyl, wherein It is preferred that carbonyl.

As R^g1Shown in " low alkyl group ", preferably C_1-7Alkyl, can more preferably enumerate methyl, ethyl, propyl, isopropyl, The C such as butyl, isobutyl group, tert-butyl_1-4Alkyl, further preferably methyl.

As R^g3Shown in " C_1-17Alkyl " can preferably enumerate methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, uncle The C such as butyl_1-4The C such as alkyl and pentadecyl, cetyl, heptadecyl_15-17Alkyl.

As can be in the C_1-17The group replaced on alkyl, for example, can enumerate halogen atom (for example, fluorine atom), hydroxyl, amino, C_1-4Alkyl amino (for example, methylamino, ethylamino, dimethylamino etc.), C_1-7Alkoxy is (for example, methoxyl group, ethoxy Base, propoxyl group etc.), C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), C_1-7Alkoxycarbonyl amino (for example, methyloxycarbonylamino, ethoxycarbonylamino group, tertbutyloxycarbonylamino etc.), C_1-7Alkanoyl is (for example, acetyl Base, ethylcarbonyl group, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl etc.), aryl, 4~7 yuan of cyclic ether group (example Such as, tetrahydrofuran base, THP trtrahydropyranyl etc.) etc..

As R^g3Shown in " lower alkoxy ", preferably C_1-7Alkoxy can more preferably enumerate methoxyl group, ethyoxyl, the third oxygen The C such as base, isopropoxy, butoxy_1-4Alkoxy, further preferably methoxyl group, ethyoxyl, propoxyl group.

As R^g3Shown in " low-grade alkyl amino ", preferably single or two-C_1-7Alkyl amino can more preferably enumerate such as first The list such as base amino, ethylamino, propylcarbamic, methylethylamine, dimethylamino, diethylamino or two-C_1-4Alkyl Amino.

As the group that can replace on the low-grade alkyl amino, such as hydroxyl, C can be enumerated_1-7Alkoxy (for example, methoxyl group, Ethyoxyl, propoxyl group etc.), carboxyl, amino, C_1-4Alkyl amino (such as methylamino, ethylamino etc.).

As R^g3Shown in " 5~6 yuan of heteroaryls ", can enumerate and R^c2Shown in the same heteroaryl of heteroaryl, wherein it is excellent Select 6 yuan of pyridyl group, pyrimidine radicals etc. of nitrogenous heteroaryl.

As R^g3Shown in " 5~6 yuan of heteroaryl aminos ", can enumerate with above-mentioned heteroaryl carry out 1 or 2 replace obtained by Amino.

As the group that can replace on the heteroaryl, for example, can enumerate halogen atom (for example, fluorine atom, chlorine atom), hydroxyl, C_1-7Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl etc.), C_1-7Alkoxy is (for example, methoxy Base, ethyoxyl, propoxyl group etc.), C_1-7Alkoxy carbonyl (for example, methoxycarbonyl, ethoxy carbonyl etc.), C_1-7Alkanoyl (example Such as, acetyl group, ethylcarbonyl group, propyl carbonyl, butyl carbonyl, pentylcarbonyl, hexyl carbonyl), amino, C_1-7Alkyl amino (example Such as, methylamino, ethylamino, dimethylamino, diethylamino etc.), halogenated C_1-7Alkyl (methyl fluoride, difluoromethyl, three Methyl fluoride, 2,2,2- trifluoroethyl etc.), hydroxyl C_1-7Alkyl (hydroxymethyl, hydroxyethyl, hydroxypropyl etc.), halogenated C_1-7 Alkoxy (fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 2,2,2- trifluoro ethoxy etc.), hydroxyl C_1-7Alkoxy (hydroxyl Ethyoxyl, 2- hydroxy propyloxy group, 3- hydroxy propyloxy group etc.) etc..

As R^g3Shown in " 4~7 yuan of cyclic aminos ", such as azelidinyl, pyrrolidinyl, morpholino base, different can be enumeratedOxazoline base, piperidyl,Piperazine alkyl etc..

As the group that can replace on the cyclic amino, such as halogen atom (such as fluorine atom), hydroxyl, C can be enumerated_1-4 Alkyl (such as methyl, ethyl, propyl, isopropyl etc.), halogenated C_1-4Alkyl (such as trifluoromethyl etc.), C_1-4Alkoxy (example Such as, methoxyl group, ethyoxyl, propoxyl group etc.), amino, C_1-4Alkyl amino is (for example, methylamino, ethylamino, dimethylamino Base, diethylamino etc.), carboxyl etc..

As formula (g), preferably R^g1For hydrogen atom, R^g2For carbonyl, R^g3For 5~6 yuan of the heteroaryl that can have substituent group.

As by R⁷And R⁸Form oxime (=N-OR¹⁰) when R¹⁰Shown in low alkyl group, can preferably enumerate C_1-4Alkyl, more Preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl.As the base that can replace on the low alkyl group Group, can enumerate hydroxyl, 4~6 yuan of cyclic ether group (for example, oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl, twoAlkyl Deng) etc..In addition, as R¹⁰Shown in aralkyl, the carbon atom number of preferred aryl groups part is the carbon atom of 6~12, moieties Aralkyl (the C that number is 1~2_6-12Aryl C_1-2Alkyl), such as benzyl, 1- phenylethyl, 2- phenylethyl can be enumerated etc..

As R⁷And R⁸Heterocycle when 4~6 yuan of the saturated heterocyclic that can have substituent group is formed together with adjacent carbon atom, The saturated heterocyclic containing oxygen atom and/or nitrogen-atoms, such as oxetanes, pyrrolidines, pyrazolidine, imidazolidine, pyrrole can be enumerated Cough up quinoline, pyrazoline, imidazoline, piperidines, piperazine cry, piperidines, triazine alkane, morpholine,It is oxazolidine, differentOxazolidine, tetrahydrofuran, tetrahydro Pyrans etc..

The heterocycle can be formed together azaspiro with azetidine ring.

As can be in the miscellaneous nuclear substituted group, such as halogen atom (for example, fluorine atom), hydroxyl, C can be enumerated_1-7Alkyl (for example, methyl, ethyl etc.), C_1-7Alkoxy (for example, methoxyl group, ethyoxyl, propoxyl group etc.), amino, C_1-7Alkyl amino (for example, methylamino, ethylamino, dimethylamino, diethylamino etc.), oxo base etc..

As R⁹Shown in " ester residue ", can enumerate and be easier to be broken and generate any group of corresponding free carboxy.Such as The C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, amyl, hexyl, heptyl can be enumerated_1-7Alkyl；Ethylene The C such as base, allyl, 1- acrylic, cyclobutenyl, pentenyl, hexenyl, heptenyl_2-7Alkenyl；The aralkyl such as benzyl；Phenyl, naphthalene The group or acetoxyl group that aryl such as base etc. are detached from and being handled under conditions of hydrolysis or catalysis reduction etc. are mild The C such as methyl, oxy acid methyl neopentyl_1-7Alkanoyloxy C_1-4Low alkyl group；Methoxycarbonyloxymethyl, 1- ethoxy carbonyl The C such as oxygroup ethyl_1-4Alkoxy-carbonyl oxy C_1-4Alkyl；The C such as methoxy_1-4Alkoxy methyl；The lactone groups such as phthalein ketone group； Two C such as 1- dimethyl aminoethyl_1-4Alkyl amino C_1-4Alkyl；The R such as methoxyethoxyethoxyethyl¹⁸O- (CH₂CH₂O)_p- R¹⁹(here, R¹⁸Indicate C_1-4Alkyl, R¹⁹Indicate C_1-4Alkylidene, p indicate 0~4 integer)；(5- first Base -2- oxo -1,3- dioxole -4- base) group etc. that is detached from vivo such as methyl.R⁹For in life The compound of the present invention for the ester residue being detached from object plays a role as so-called pro-drug.

It should be noted that R⁹Preferably hydrogen atom.

It is C-R as X¹¹When R¹¹Shown in " halogen atom ", refer to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, more preferably Fluorine.

As R¹¹Shown in " low alkyl group ", " lower alkoxy ", can enumerate and R¹Shown in low alkyl group, lower alkoxy it is same The group of sample.

As can be in R¹¹Shown in the group that replaces on " thienyl " or " phenyl ", can enumerate halogen atom (for example, fluorine atom, Bromine atom), hydroxyl, nitro etc..

It is C-R as Y¹²When R¹²Shown in " halogen atom ", preferably fluorine atom or chlorine atom, more preferable fluorine atom.

It is C-R as Y¹²When R¹²Shown in " low alkyl group that can have substituent group ", can enumerate and R¹Shown in it is rudimentary The same low alkyl group of alkyl, can preferably enumerate the C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl_1-4 Alkyl and the C being substituted with halogen atoms_1-4Alkyl is (for example, methyl fluoride, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyls Deng) etc..

In pyridone carboxylic acid derivatives illustrated above, particularly preferred R¹For hydrogen atom or halogen atom (preferably fluorine atom or chlorine Atom), R²For hydrogen atom or it can have the C of substituent group_1-7Alkyl (preferably methyl or ethyl), R³~R⁶For hydrogen atom, R⁷For Hydrogen atom, R⁹It is nitrogen-atoms or C-R for hydrogen atom, X¹¹(R¹¹It is preferred that hydrogen atom or halogen atom), Y C-R¹²(R¹²It is preferred that hydrogen Atom or halogen atom) and R⁸For the pyridone carboxylic acid derivatives of following any group.

1)R⁸For group shown in formula (a), R^a1And R^a2Any one of be hydrogen atom, another one be can have substituent group and C with ehter bond_2-12Alkyl (preferably 1- ethyoxyl -2- propyl, 1,3- dimethoxy -2- propyl, 1,3- diethoxy Base -2- propyl), R^a1And R^a2Any one of be hydrogen atom, another one be-R^a3- Cy¹(R^a3: it preferably can be by halogen original The C that son replaces_1-6Alkylidene, Cy¹: it preferably can have 4~7 yuan of cyclic ether group (preferably THP trtrahydropyranyl) of substituent group, or Person R^a1And R^a2Any one of be hydrogen atom, another one is 5~6 yuan of heteroaryl (the preferably pyridine that can have substituent group Base)

2)R⁸For group shown in formula (b), m 0, Het are 6 pi-electron system nitrogen heterocycles (preferably pyrazolyl)

3)R⁸For group shown in formula (d), R^d1For hydrogen atom, R^d2For the C that can have substituent group_1-7Alkyl (preferably methyl, four Hydrogen pyranylmethyl)

4)R⁸For group shown in formula (e), R^e1For hydrogen atom, R^e2For the C that can have substituent group_1-7Alkyl (preferably methyl)

Pyridone carboxylic acid derivatives of the invention can form base addition salts.It should be noted that the salt also includes foring and boronation Close the salt of the chelate salt of object.As base addition salts, such as the salt of the alkali metal such as (A) and sodium, potassium, (B) and calcium, magnesium etc. can be enumerated The salt of alkaline-earth metal, (C) ammonium salt, (D) and trimethylamine, triethylamine, tri-n-butylamine, pyridine, N, accelerine, N- methyl piperazine Pyridine, N-methylmorpholine, diethylamine, 2- aminoethane -1- alcohol, N- methyl amino ethanol, N, N- dimethylaminoethanol, 1,1,3,3- tetramethylguanidine, diethanol amine, triethanolamine, dicyclohexyl amine, cyclohexylamine, procaine, dibenzylamine, N- benzyl- β-phenyl ethylamine, 1- ephenamine, N, N '-dibenzyl-ethylenediamin, aminoglucose, N-METHYL-ALPHA-L-GLUCOSAMINE, 1- carbamyl are sub- Amine amide-N, N- dimethyl carboximidamide (1- カ Le バ system イミ De アミ De-N, N- ジメチ Le メタ Application イミ De アミ De) etc. the basic amino acids such as the salt of nitrogenous organic bases, (E) and arginine, lysine, ornithine salt.In addition, as boron Compound can enumerate the low-grade acyloxies boron such as the halogenations such as boron fluoride boron, acetoxyl group boron.

Pyridone carboxylic acid derivatives of the invention or its salt can not only exist in the form of unsolvated type, can also be with hydration The form of object or solvate exists.Therefore, pyridone carboxylic acid derivatives of the invention or its salt include its whole crystal type With hydration or solvate.

Pyridone carboxylic acid derivatives of the invention or its salt can exist in the form of optical isomer.These optical isomers Included in the compound of the present invention.In turn, pyridone carboxylic acid derivatives of the invention or its salt can be different with different solids The form of structure body (cis-, trans-) exists.These stereoisomers are also included in the present invention.

Pyridone carboxylic acid derivatives of the invention or its salt can substantially be manufactured by the method for following processes 1~3, root Type according to substituent group etc. and suitably change, can be manufactured by meeting its arbitrary method.

(process 1)

(in formula, R^9aIndicate low alkyl group, low-grade alkenyl or aralkyl, R¹³、R¹⁴And R¹⁵Respectively indicate low alkyl group, L¹Indicate halogen Plain atom, L²Indicate halogen atom, sulfide base or sulfoxide group, R¹、R², X and Y indicate and above-mentioned R¹、R², X and the same base of Y Group.〕

That is, react the orthoformic acid such as ethyl orthoformate or original acid A ester esters (II) with compound (I), the compound made It is reacted with aromatic amine (III) after compound (IV) is made, its is made to carry out cyclization, obtain compound (V).

Here, as R^9aShown in " low alkyl group ", can preferably enumerate C_1-4Alkyl, more preferably methyl, ethyl, tertiary fourth Base.As " low-grade alkenyl ", C can be preferably enumerated_2-4Alkenyl, more preferably vinyl, allyl, 1- acrylic etc..As " aralkyl ", preferably C_7-14Aralkyl can more preferably enumerate benzyl, phenethyl, benzhydryl etc..

As R¹³、R¹⁴、R¹⁵Shown in " low alkyl group ", preferably C_1-3Alkyl, further preferably ethyl.

As L¹And L²Shown in " halogen atom ", can preferably enumerate fluorine atom or chlorine atom.

Compound (I) is usually carried out at 0~160 DEG C, preferably 50~150 DEG C with reacting for orthoformic acid esters (II), the reaction time Usually 10 minutes~48 hours, preferably 1~10 hour.In addition, the usage amount of orthoformic acid esters is relative to compound (I) It is more than equimolar, particularly preferably about 1~10 times mole.

It is carried out in reaction dissolvent appropriate with reacting for aromatic amine (III).As long as solvent as used herein is not to the reaction It impacts, then can be used, such as aromatic hydrocarbon, ether, tetrahydrofuran, two such as can enumerate toluene, dimethylbenzeneAlkane etc. The halogenated hydrocarbons such as the aliphatic hydrocarbons such as ethers, pentane, hexane, methylene chloride, chloroform, carbon tetrachloride, acetonitrile, N, N- dimethyl The alcohol such as the aprotic polar solvents such as formamide, dimethyl sulfoxide, n-methylpyrrolidin-2-one, methanol, ethyl alcohol, propyl alcohol Deng.This reaction is usually at 0~150 DEG C, preferably in 0~100 DEG C of progress, and the reaction time is usually 10 minutes~48 hours, preferably It is 1~10 hour.

The cyclization of compound (IV) carries out in the presence of alkali compounds or in the presence of non-in solvent appropriate.As Solvent used in this reaction, as long as not impacted to the reaction, can be used, such as toluene, dimethylbenzene can be enumerated etc. It is aromatic hydrocarbon；Ether, tetrahydrofuran, twoThe ethers such as alkane；The aliphatic hydrocarbons such as pentane, hexane；Methylene chloride, chloroform, four The halogenated hydrocarbons such as chlorination carbon；The aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide；Methanol, ethyl alcohol, third Alcohol such as alcohol etc..In addition, alkali metal as metallic sodium, metallic potassium can be enumerated as used alkali compounds；Sodium hydride, The metal hydrides such as calcium hydride；The inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate；Sodium methoxide, The alcohol salt such as sodium ethoxide, potassium tert-butoxide；The metal fluorides such as sodium fluoride, potassium fluoride；Triethylamine, N- crassitude, 1,1,3, The organic bases such as 3- tetramethylguanidine, 11 carbon -7- alkene (DBU) of 1,8- diazabicyclo [5.4.0].This reaction is usually 0 ~200 DEG C, preferably carry out in room temperature~120 DEG C, the reaction time usually terminated at 10 minutes~48 hours.

It should be noted that commercially available product can be bought as the compound (I) that raw material uses and used, or text below can be passed through It offers the method for middle record or is manufactured according to its method.

1) Japanese Unexamined Patent Publication 2-282384

2) Japanese Unexamined Patent Application Publication 2006-514964

(process 2)

(in formula, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R^9a、L², X or Y indicate and above-mentioned R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R^9a、 L², X or the same group of Y.〕

That is, by the R of compound (V)^9aProtecting group be detached from and compound (VI) is made, with compound (VII) carry out aromatic series take Generation reaction, to obtain compound (IX).In addition, progress compound (V) is same as compound (VII) as other methods Substitution reaction after, then by R^9aProtecting group be detached from, thus also available compound (IX).

Aromatic series substitution reaction is in esters such as ethyl acetate, aromatic hydrocarbon, ethers, aliphatic hydrocarbon, halogenated hydrocarbon, non-proton In the solvent that property polar solvent or alcohol etc. do not impact the reaction, as needed in deoxidier, such as sodium carbonate, carbonic acid Calcium, sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0], N- first Base pyrrolidines, 1, in the presence of 1,3,3- tetramethylguanidine, sodium hydride etc., usually 0~80 DEG C, preferably carry out in 0 DEG C~room temperature. Reaction time terminates in a few minutes~48 hour.

The usage amount of compound (VII) is equimolar~5 times mole relative to compound (V) or compound (VI).In addition, This reaction is also reacted in the presence of as lithium salts such as weak lewis acidic lithium chlorides sometimes.

In addition, also carrying out aromatic series when importing azelidinyl using the compound (VII) with protecting group sometimes and replacing instead It answers.For example, importing tert-butyl 2,6- diaza spiroheptane -2- carboxylate, tert-butyl -1,6- diaza spiro [3.3] it when heptane -1- carboxylate, by making acid compound be detached from tert-butoxycarbonyl (Boc) base, obtains as target The compound for being imported with azelidinyl.As used acid compound, the inorganic acids such as hydrochloric acid, trifluoroacetic acid can be enumerated (TFA) organic acids such as.This reaction usually 0~80 DEG C, preferably 0 DEG C~room temperature carry out, the reaction time be usually a few minutes~ 48 hours.

The deprotection reaction of compound (VIII) for example can be using general used hydrolysis, for example, can be molten in alcohol In liquid, carried out using inorganic bases such as sodium hydroxide, potassium hydroxide.This reaction is usually at 0~150 DEG C, preferably in room temperature~100 DEG C It carries out, the reaction time is usually 10 minutes~48 hours.

In addition, other deprotection reactions as compound (VIII), as described below.

That is, for example, being detached from methyl, ethyl or tert-butyl in acetic acid solution by acid compound, obtaining target chemical combination Object.As used acid compound, the organic acids such as the inorganic acids such as hydrochloric acid, trifluoroacetic acid (TFA) can be enumerated.This reaction is logical It is often carried out in room temperature~150 DEG C, the reaction time is usually a few houres~3 day.

The deprotection reaction of compound (V) can for example apply general used hydrolysis, for example, in acetic acid solution, It is detached from methyl, ethyl or tert-butyl by acid compound, obtains target compound.As used acid compound, The organic acids such as the inorganic acids such as hydrochloric acid, trifluoroacetic acid (TFA) can be enumerated.This reaction is usually in room temperature~150 DEG C progress, reaction Between be usually a few houres~3 day.

(process 3)

(in formula, R^9bIndicate ester residue, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸, X or Y indicate and above-mentioned R¹、R²、R³、R⁴、R⁵、R⁶、 R⁷、R⁸, X or the same group of Y.〕

Here, R^9bShown in " ester residue " can enumerate and be easier to be broken and generate any group of corresponding free carboxy, such as The C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, amyl, hexyl, heptyl can be enumerated_1-7Alkyl；Ethylene The C such as base, allyl, 1- acrylic, cyclobutenyl, pentenyl, hexenyl, heptenyl_2-7Alkenyl；Benzyl, diphenyl methyl (hexichol Methyl) aralkyl such as base；Aryl such as phenyl, naphthalene etc. under conditions of hydrolysis or catalysis reduction etc. are mild and being handled The C such as the group or acetoxy-methyl of disengaging, oxy acid methyl neopentyl_1-7Alkanoyloxy C_1-4Low alkyl group；Methoxyl group carbonyl The C such as base oxygroup methyl, 1- ethoxycarbonyloxyethyl_1-4Alkoxy-carbonyl oxy C_1-4Alkyl；The C such as methoxy_1-4Alkane Oxygroup methyl；The lactone groups such as phthalein ketone group；Two C such as 1- dimethyl aminoethyl_1-4Alkyl amino C_1-4Alkyl；Methoxy ethoxy The R such as ethoxyethyl group¹⁸O- (CH₂CH₂O)_p- R¹⁹(here, R¹⁸Indicate C_1-4Alkyl, R¹⁹Indicate C_1-4Alkylidene, p indicate 0 ~4 integer)；(5- methyl -2- oxo -1,3- dioxole -4- base) methyl etc. is detached from vivo Group etc..

That is, obtaining compound (X) by importing (esterification) for carrying out ester residue to compound (IX).

Esterification can enumerate Theodora W.Greene, Peter G.M.Wuts, " Protective Groups in The method recorded in Organic Synthesis " 4th.ed., John Wiley&Sons, Inc., 2007, as esterifying agent, example Alkyl halide or 4- halogenated methyl -5- methyl -2- oxo -1,3- dioxolane, acetoxyl group first can such as be enumerated Base halide, oxy acid methyl neopentyl halide.

Alkali compounds can be added in this reaction and carry out.

As alkali compounds, such as the metal hydrides such as sodium hydride, calcium hydride can be enumerated；Sodium hydroxide, potassium hydroxide, carbonic acid The inorganic bases such as sodium, potassium carbonate；Triethylamine, N, N- diisopropylethylamine, N-methylmorpholine, N- crassitude, 1,1,3, The organic bases such as 3- tetramethylguanidine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0].

As solvent used in this reaction, as long as not impacted to reaction, can be used, such as aromatic hydrocarbon can be enumerated Class, ethers, esters, aliphatic hydrocarbon, halogenated hydrocarbon, aprotic polar solvent.This reaction usually at room temperature~100 DEG C into Row, reaction time are a few minutes~48 hour.

(process 4-1)

The X of the aromatic amine (III) used as raw material is that the compound (III-1) of nitrogen-atoms can buy commercially available product and make With, or can be manufactured by arbitrary method, if given an example, as described below.

(in formula, R¹It indicates and above-mentioned R¹Same group.〕

That is, making ammonium chloride reaction obtain carbonamidine (XII) after reacting alkoxide with nitrile (XI), so that it is carried out cyclization, obtain Aromatic amine (III).As other methods, after reacting hydrogen halides with nitrile (XI), ammonia reaction is made to obtain carbonamidine (XII), So that it is carried out cyclization, obtains aromatic amine (III-1).

It can be used, such as ether can be enumerated as with solvent used in the reacting of alkoxide as long as not impacted to reaction Class, aprotic polar solvent or alcohol etc. can preferably enumerate alcohol.This reaction usually -30~80 DEG C, preferably -20~ 40 DEG C of progress, the reaction time is usually 10 minutes~48 hours.

It can be used, such as can enumerate as with solvent used in the reacting of hydrogen halides as long as not impacted to reaction Halogenated hydrocarbon, ethers, aprotic polar solvent or alcohol etc. can preferably enumerate halogenated hydrocarbon, ethers or alcohol.As this reaction Used in hydrogen halides, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide can be enumerated, can preferably enumerate hydrogen chloride.This is anti- Should be usually at -30~80 DEG C, preferably in -20~40 DEG C of progress, the reaction time is usually a few houres~5 day.

As solvent used in cyclization, as long as not impacted to reaction, can be used, such as halogenated hydrocarbons can be enumerated Class, ethers, aprotic polar solvent or alcohol etc. can preferably enumerate alcohol.This reaction usually -30~80 DEG C, preferably - 20~40 DEG C of progress, the reaction time is usually 10 minutes~48 hours.

(process 4-2)

The X of aromatic amine (III) is C-R¹¹Compound (III-2) commercially available product can be bought and used, or can pass through Arbitrary method manufactures, if given an example, as described below.

(in formula, L³Indicate halogen atom, methanesulfonic acid ester group, tosylate group or trifluoromethanesulfonic acid ester group, R¹And R¹¹Indicate with Above-mentioned R¹And R¹¹Same group.〕

That is, compound (XIII) and compound (XIV) is made to carry out cyclization, aromatic amine (III-2) is obtained.

Here, as L³Shown in " halogen atom ", can preferably enumerate chlorine atom, bromine atom or iodine atom.

As solvent used in this reaction, as long as not impacted to reaction, can be used, such as ethers, non-can be enumerated Protic polar solvent, halogenated hydrocarbon or alcohol etc. can preferably enumerate ethyl alcohol, methanol, n,N-Dimethylformamide, chloroform.

Alkali compounds can be added in this reaction and carry out.

As alkali compounds, such as the organic bases such as triethylamine, n,N-diisopropylethylamine or potassium carbonate, carbonic acid can be enumerated The inorganic bases such as hydrogen sodium.

As long as the usage amount of alkali compounds is 1~5 times mole relative to compound (XIII) or its salt.

This reaction is usually carried out at 0~120 DEG C, and the reaction time is usually a few minutes~10 hour.

(process 5)

Raw material compound (VII) can be manufactured by arbitrary method, if given an example, as described below.

(in formula, R¹⁶Indicate amino protecting group, R³、R⁴、R⁵、R⁶、R⁷、R⁸It indicates and above-mentioned R³、R⁴、R⁵、R⁶、R⁷、R⁸Same base Group.〕

I.e., it is possible to by by the protecting group R of compound (XV)¹⁶It is detached from and obtains compound (VII).

Here, as R¹⁶Shown in " amino protecting group ", usually used amino in the field of Synthetic Organic Chemistry can be enumerated and protected Protect base, such as can enumerate elementary alkoxy carbonyl, benzyloxycarbonyl, benzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl, Benzhydryl etc. can preferably enumerate tert-butoxycarbonyl or benzhydryl.

The deprotection reaction of compound (XV) can enumerate Theodora W.Greene, Peter G.M.Wuts, " Protective The method recorded in Groups in Organic Synthesis " 4th.ed., John Wiley&Sons, Inc., 2007, example Such as, it in the case where tert-butoxycarbonyl, can carry out in the presence of acid in a solvent, it, can in the case where benzhydryl With in a solvent, in a hydrogen atmosphere, the presence of acid or it is non-in the presence of, carried out in the presence of metallic catalyst.

As solvent used in this reaction, as long as not impacted to reaction, can be used, such as aliphatic hydrocarbon can be enumerated Class, aprotic polar solvent, ethers, halogenated hydrocarbon, esters, alcohol etc. can preferably enumerate ethers, halogenated hydrocarbon, esters, alcohol Deng.

As acid, such as trifluoroacetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid or trifluoromethanesulfonic acid can be enumerated etc., preferably Trifluoroacetic acid, hydrochloric acid or hydrobromic acid can be enumerated.

The usage amount of acid is 1~30 equivalent, preferably 1~15 equivalent relative to compound (XV).- 30~120 DEG C, preferably It is carried out at 0~80 DEG C, the reaction time is usually 10 minutes~48 hours, preferably 1~12 hour.

As metallic catalyst, such as palladium catalyst, platinum catalyst can be enumerated, can preferably enumerate palladium catalyst.

It should be noted that commercially available product can be bought as the compound (XV) that raw material uses and used, or can be by below The method recorded in document is manufactured according to its method.

1) International Publication No. 2000/063168

2)Chemical Reviews 108,3988(2008)

3)Chemical and Pharmaceutical Bulletin 56,346(2008)

4)Science 351,241(2016)

(process 6-1)

The R of compound (XV)⁷Or R⁸It can be by any to can have the compound (XV-1) of the lower alkoxy of substituent group Method manufacture, if given an example, as described below.

(in formula, R¹⁷It indicates relative to R⁸The lower alkoxy that can have substituent group low alkyl group, L⁴Indicate that halogen is former Son, methanesulfonic acid ester group, tosylate group or trifluoromethanesulfonic acid ester group, R³、R⁴、R⁵、R⁶、R⁷、R¹⁶It indicates and above-mentioned R³、R⁴、R⁵、 R⁶、R⁷、R¹⁶Same group.〕

That is, compound (XV-1) can be obtained by the substitution reaction for carrying out compound (XVI) and compound (XVII).

Here, as R¹⁷Shown in " low alkyl group ", can preferably enumerate C_1-5Alkyl, can more preferably enumerate methyl, ethyl, Propyl, isopropyl, butyl, isobutyl group, sec-butyl or tert-butyl can further preferably enumerate methyl, ethyl or propyl.

As L⁴Shown in " halogen atom ", can preferably enumerate chlorine atom, bromine atom or iodine atom.

As solvent used in substitution reaction, as long as not impacted to reaction, can be used, such as can enumerate ethers, Aprotic polar solvent etc..

Alkali compounds can be added in this reaction and carry out.

As alkali compounds, such as sodium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, N, N- diisopropyl can be enumerated Base ethamine, N-methylmorpholine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0], 1,1,3,3- tetramethylguanidine or hydrogen Change sodium etc., can preferably enumerate sodium hydride etc..

As long as the usage amount of alkali compounds is 1~20 times mole, preferably 1~5 times relative to compound (XVII) or its salt Mole.

Usually at -30~150 DEG C, preferably in -10~100 DEG C of progress, the reaction time is usually that a few minutes~48 are small for this reaction When.

(process 6-2)

In addition, compound (XV) by R⁷And R⁸The compound (XV-2) for forming oximido can be manufactured by arbitrary method, If given an example, as described below.

(in formula, R³、R⁴、R⁵、R⁶、R¹⁰、R¹⁶It indicates and above-mentioned R³、R⁴、R⁵、R⁶、R¹⁰、R¹⁶Same group.〕

That is, obtaining compound (XV-2) by the condensation reaction for carrying out compound (XVIII) and compound (XIX) or its salt.

As solvent used in this reaction, as long as not impacted to reaction, can be used, such as aromatic hydrocarbon can be enumerated Class, esters, ethers, aliphatic hydrocarbon, halogenated hydrocarbon, protic polar solvent or aprotic polar solvent can preferably be lifted Halogenated hydrocarbon, protic polar solvent or aprotic polar solvent out.

Acid compound can be added in this reaction and carry out.

As acid compound, such as formic acid, acetic acid, hydrochloric acid can be enumerated etc., it can preferably enumerate acetic acid.

As long as the usage amount of acid compound is 0.05~1 times mole relative to compound (XIX) or its salt.

In addition, alkali compounds can be added in this reaction and carry out.

As alkali compounds, such as the inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate can be enumerated Class.

As long as the usage amount of alkali compounds is 1~10 times mole relative to compound (XIX) or its salt.

Usually at 0~110 DEG C, preferably in room temperature~80 DEG C progress, the reaction time is usually a few houres~8 day for this reaction.

(process 6-3)

In addition, the R of compound (XV)⁸Arbitrary side can be passed through for the raw material compound (XV-a) shown in formula (a) when group Method manufactures, if given an example, as described below.

(in formula, R³、R⁴、R⁵、R⁶、R⁷、R^a1、R^a2And R¹⁶It indicates and above-mentioned R³、R⁴、R⁵、R⁶、R⁷、R^a1、R^a2And R¹⁶Same base Group.〕

That is, compound (XV-a) can be obtained by the condensation reaction for carrying out compound (XX) and compound (XXI) or its salt.

As solvent used in this reaction, as long as not impacted to reaction, can be used, such as aromatic hydrocarbon can be enumerated Class, ethers, aliphatic hydrocarbon, halogenated hydrocarbon, aprotic polar solvent, alcohol etc. can preferably enumerate halogenated hydrocarbon and non-matter Sub- property polar solvent, can more preferably enumerate amides.

The usage amount of solvent is not particularly limited, as long as being 1~500 times of amount (v/w) relative to compound (XX).

Compound (XXI) as long as or its salt usage amount relative to compound (XX) be 1~50 times mole, preferably 1~5 times rub You.

As condensing agent used in this reaction, such as N can be enumerated, N '-diisopropylcarbodiimide (DIC), N, N '-two- Tert-butylcarbodiimide, N, N '-dicyclohexylcarbodiimide (DCC), N- (tert-butyl)-N '-ethyl carbodiimide (BEC), N- cyclohexyl-N '-(2- morpholinoethyl) carbodiimide (CMC) and N- (3- dimethylaminopropyl)- The carbodiimides classes such as N '-ethyl carbodiimide (EDC)；Two (1,2,4- of 1,1 '-carbonyl dimidazoles (CDI) and 1,1 '-carbonyl Triazole) imidazoles such as (CDT)Class；O- (benzotriazole -1- base)-N, N, N ', N '-tetramethylureaHexafluorophosphoric acid ester (HBTU), O- (7- azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylureaHexafluorophosphoric acid ester (HATU), O- Bis- (tetramethylene) ureas of (benzotriazole -1- base)-N, N, N ', N ' -Hexafluorophosphoric acid ester (HBPyU), O- (benzo three Azoles -1- base)-N, N, N ', bis- (pentamethylene) ureas of N ' -Hexafluorophosphoric acid ester (HBPipU), O- (6- chlorobenzotriazole- 1- yl)-N, N, N ', N '-tetramethylureaHexafluorophosphoric acid ester (HCTU), O- (3,4- dihydro -4- oxo -1,2,3- Phentriazine -3- base)-N, N, N ', N '-tetramethylureaHexafluorophosphoric acid ester (HDBTU), O- (2- oxo -1- (2H) Pyridyl group)-N, N, N ', N '-tetramethylureaHexafluorophosphoric acid ester (TPTU), O- { (ethoxy carbonyl) cyanomethylene ammonia Base }-N, N, N ', N '-tetramethylureaHexafluorophosphoric acid ester (HOTU), O- { (ethoxy carbonyl) cyanomethylene amino }- N, N, N ', N '-tetramethylureaTetrafluoroborate (TOTU), N, N, N ', N '-tetramethyl-O- (N- succinimido) UreaHexafluorophosphoric acid ester (HSTU), N, N, N ', N '-tetramethyl-O- (N- succinimido) ureaTetrafluoroborate (TSTU), bihyrrolidinyl (N- succinimide oxygroup) carbonHexafluorophosphoric acid ester (HSPyU), S- (1- oxo -2- pyrrole Piperidinyl)-N, N, N ', N '-tetramethyl thioureaTetrafluoroborate (TOTT) and ([{ (1- cyano -2- ethyoxyl -2- oxygen For ethylidene) amino } oxygroup] -4- morpholino methylene) ureas such as dimethyl ammonium hexafluorophosphoric acid ester (COMU)Class；1H- benzene And triazol-1-yl oxygroup three (dimethylamino)Hexafluorophosphoric acid ester (BOP), three pyrrole of 1H- benzotriazole -1- base oxygroup Cough up alkylHexafluorophosphoric acid ester (PyBOP), (7- azepine benzo triazol-1-yl oxygroup) tripyrrole alkylHexafluorophosphoric acid ester (PyAOP), chlorine tripyrrole alkylHexafluorophosphoric acid ester (PyCloP), bromine three (dimethylamino)Hexafluorophosphoric acid ester (Brop), - 4 (3H) -one (DEPBT) of 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine and (ethyl cyano (hydroxyl imido Base) acetic acid esters-O2)-three (1- pyrrolidinyls)Hexafluorophosphoric acid ester (PyOxim) etc.Class；2,4,6- tri- chloro- 1,3, 5- triazine (TCT), chlorine dimethoxy-triazine (CDMT), N- (3,5- dimethoxy-triazine base)-N-methylmorpholineChlorination The triazines such as object (DMT-MM) or dichloro methoxyl group triazine (DCMT), can preferably enumerate carbodiimide class, imidazolesClass, ureaClass or triazines can more preferably enumerate carbodiimide class, ureaClass or triazines, can further preferably enumerate EDC, COMU or DMT-MM.

As long as the usage amount of condensing agent is 1~50 times mole, preferably 1~5 times mole relative to compound (XX).

Alkali compounds can be added in this reaction and carry out.

As alkali compounds, such as triethylamine, n,N-diisopropylethylamine and N-methylmorpholine can be enumerated.

It rubs as long as the usage amount of alkali compounds is 1~50 times mole, preferably 1~5 times relative to compound (XXI) or its salt You.

When using carbodiimide class as condensing agent, it is preferably added to additive.

As additive, such as I-hydroxybenzotriazole (HOBt), 1- hydroxyl -7- azepine benzotriazole can be enumerated (HOAt), the chloro- I-hydroxybenzotriazole of 6- (6-Cl-HOBt), 1- hydroxyl -6- nitrobenzene and triazolam (6-NO2- HOBt), 6- Trifluoromethyl-1-hydroxybenzotriazole (6-CF3-HOBt), 3,4- dihydro-3-hydroxy-4- oxygen Generation -1,2,3- phentriazine (HODhbt), 3- hydroxyl -4- oxo -3,4- dihydro -5- azepine benzo -1,2,3- Triazenes (HODhat), n-hydroxysuccinimide (HOSu), N- hydroxyl -5- norbornene -2,3- dicarboxyl acyl are sub- Amine (HONB) and ethyl (oxyimino) cyan-acetic ester (Oxyma), can preferably enumerate HOBt.

As long as the usage amount of additive is 1~50 times mole, preferably 1~5 times mole relative to general formula (XX).

As long as this reaction -50~100 DEG C, preferably 0~50 DEG C implement 15 minutes~48 hours.

In addition, other autofrettages as compound (XV-a), can enumerate the following method.

That is, by compound (XX) and etheride, acid anhydrides or 2- ethyoxyl -1- ethoxy carbonyl -1,2- dihydroquinoline (EEDQ) after mixing, react compound (XXI) or its salt, so as to obtain compound (XV-a).

As solvent used in condensation reaction, as long as not impacted to reaction, can be used, such as aromatic series can be enumerated Hydro carbons, ethers, aliphatic hydrocarbon, halogenated hydrocarbon, aprotic polar solvent can preferably enumerate ethers and aprotic polar Solvent can more preferably enumerate ethers.

The usage amount of solvent is not particularly limited, as long as being 1~500 times of amount (v/w) relative to compound (XX).

Compound (XXI) as long as or its salt usage amount relative to compound (XX) be 1~50 times mole, preferably 1~5 times rub You.

As etheride used in condensation reaction, for example, can enumerate methylchloroformate, ethyl chloroformate, propyl chlorocarbonate, The chloro-carbonic acids esters such as butyl chlorocarbonate and isobutyl chlorocarbonate；And mesyl chloride, ethyl sulfonic chloride, benzene sulfonyl chloride and to toluene sulphur The sulfonic acid chlorides class such as acyl chlorides.

As acid anhydrides used in condensation reaction, such as the carboxylic acid anhydrides such as acetic anhydride can be enumerated；With di-tert-butyl dicarbonate ((Boc)₂The carbonates such as O).

As etheride used in reaction or acid anhydrides, etheride can be preferably enumerated, can more preferably enumerate chloro-carbonic acid Esters and sulfonic acid chloride class, can further preferably enumerate ethyl chloroformate, isobutyl chlorocarbonate, particularly preferably can enumerate chloromethane Sour isobutyl ester.

As long as the usage amount of etheride or acid anhydrides is 1~50 times mole, preferably 1~5 times mole relative to compound (XX) .

This reaction is preferably added to alkali compounds.

As alkali compounds, such as triethylamine, n,N-diisopropylethylamine, pyridine, N-methylmorpholine, 1- first can be enumerated Base imidazoles and N, N- dimethyl benzyl amine can preferably enumerate N-methylmorpholine.

As long as the usage amount of alkali compounds is 1~50 times mole, preferably 1~5 times mole relative to compound (XX).

As long as this reaction at -50~100 DEG C, preferably in -30~50 DEG C of implementation a few minutes~5 day, preferably 10 minutes~72 small When.

(process 6-4)

The R of compound (XV)⁸It can be manufactured by arbitrary method for the compound (XV-b) of group shown in formula (b), such as Fruit is given an example, then as described below.

(in formula, L^bIndicate halogen atom, methanesulfonic acid ester group, tosylate group or trifluoromethanesulfonic acid ester group, Het, R^b1、R³、 R⁴、R⁵、R⁶、R⁷、R¹⁶It is indicated and above-mentioned Het, R with m^b1、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶Group same with m.〕

That is, compound can be obtained by the substitution reaction for carrying out compound (XXII) and compound (XXIII) or its salt (XV-b).

Here, as L^bShown in " halogen atom ", can preferably enumerate chlorine atom, bromine atom or iodine atom.

As solvent used in substitution reaction, as long as not impacted to reaction, can be used, such as can enumerate ethers, Aprotic polar solvent etc..

Alkali compounds can be added in this reaction and carry out.

As long as the usage amount of alkali compounds is 1~20 times mole, preferably 1~5 times relative to compound (XXIII) or its salt Mole.

As long as this reaction at -30~150 DEG C, preferably -10~100 DEG C of implementation a few minutes~48 hour.

(process 6-5)

The R of compound (XV)⁸For group (R shown in formula (c)^c1Arbitrary method can be passed through for the compound (XV-c1) of CO) It manufactures, if given an example, as described below.

(in formula, M indicates metal, X^cIndicate halogen atom, R^c2、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶It indicates and above-mentioned R^c2、R³、R⁴、R⁵、 R⁶、R⁷、R¹⁶Same group.〕

That is, can be obtained by reacting compound (XXIV) with organometallic reagent (XXV) or organometallic reagent (XXVI) Compound (XV-c1).

Here, as X^cShown in " halogen atom ", can preferably enumerate chlorine atom, bromine atom or iodine atom.

As solvent used in this reaction, such as aromatic hydrocarbon, ethers or aliphatic hydrocarbon can be enumerated, can preferably enumerated Ethers can more preferably enumerate tetrahydrofuran.

As organometallic reagent used in this reaction, Grignard Reagent handbook (HANDBOOK OF GRIGNARD can be passed through REAGENTS), the method recorded in 1996 etc. manufactures, such as can enumerate organomagnesium reagent as Grignard Reagent or have Machine lithium reagent can preferably enumerate alkyl magnesium halide, halogenation ring group magnesium, halogenation heterocycle magnesium, halogenated aryl magnesium, halogenation heteroaryl Magnesium, lithium alkylide or aryl lithium, can more preferably enumerate alkyl magnesium chloride, alkyllmagnesiurn bromide, chlorination aryl magnesium, bromination aryl magnesium, Lithium alkylide can further preferably enumerate methylmagnesium-bromide, ethyl-magnesium-bromide, bromination cyclopenta magnesium, pyridinium chloride base magnesium, bromination Benzyl magnesium, n-BuLi.

As long as this reaction at -100~50 DEG C, preferably -80~30 DEG C of implementation a few minutes~24 hour.

(process 6-6)

The R of compound (XV)⁸For group (R shown in formula (c)^c1For SO or SO₂) compound (XV-c2) can be by any Method manufacture, if given an example, as described below.

(in formula, L^cIndicate halogen atom, methanesulfonic acid ester group, tosylate group or trifluoromethanesulfonic acid ester group, n^cIndicate 1 or 2 Integer, R^c2、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶It indicates and above-mentioned R^c2、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶Same group.〕

That is, making it after compound (XXIX) is made by the substitution reaction for carrying out compound (XXVII) and compound (XXVIII) Oxidation reaction is carried out, compound (XV-c2) is obtained.

Here, as L^cShown in " halogen atom ", can preferably enumerate chlorine atom, bromine atom or iodine atom.

As solvent used in substitution reaction, as long as not impacted to reaction, can be used, such as can enumerate ethers, Aprotic polar solvent etc..

Alkali compounds can be added in substitution reaction and carry out.

As long as the usage amount of alkali compounds is 1~20 times mole, preferably 1~5 times mole relative to compound (XXVIII) .

As long as this reaction at -30~150 DEG C, preferably -10~100 DEG C of implementation a few minutes~48 hour.

As solvent used in oxidation reaction, as long as not impacted to reaction, can be used, such as halogenated hydrocarbons can be enumerated Class, ethers, protic polar solvent or aprotic polar solvent can preferably enumerate halogenated hydrocarbon, ethers, alcohols or second Acid.As oxidant used in this reaction, for example, can enumerate mCPBA, oxone (Oxone), hydrogen peroxide and 3- phenyl -2- (phenyl sulfonyl) -1,2- oxaza propane.

Usually at 0~110 DEG C, preferably in room temperature~80 DEG C progress, the reaction time is usually a few houres~8 day for this reaction.

(process 6-7)

The R of compound (XV)⁸It can be manufactured by arbitrary method for the compound (XV-d) of group shown in formula (d), such as Fruit is given an example, then as described below.

(in formula, R^d1、R^d2、R³、R⁴、R⁵、R⁶、R¹⁶It indicates and above-mentioned R^d1、R^d2、R³、R⁴、R⁵、R⁶、R¹⁶Same group.〕

That is, by progress compound (XXX) and the condensation reaction of amine (XXXI) or its salt and the reduction reaction of obtained oxime, So as to obtain compound (XV-d).

As solvent used in condensation reaction, as long as not impacted to reaction, can be used, such as aromatic series can be enumerated Hydro carbons, esters, ethers, aliphatic hydrocarbon, halogenated hydrocarbon, protic polar solvent or aprotic polar solvent, preferably may be used Halogenated hydrocarbon, protic polar solvent or aprotic polar solvent are enumerated, alcohols or halogenated hydrocarbon can be more preferably enumerated.

Acid compound can be added in condensation reaction and carry out.

As acid compound, such as formic acid, acetic acid, hydrochloric acid can be enumerated etc., it can preferably enumerate acetic acid.

As long as the usage amount of acid is 0.05~1 times mole relative to compound (XXX).

In addition, alkali compounds can be added in this reaction and carry out.

As alkali compounds, such as the inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate can be enumerated Class.

As long as the usage amount of alkali compounds is 1~10 times mole relative to compound (XXXI) or its salt.

Usually at 0~120 DEG C, preferably in 0~80 DEG C of progress, the reaction time is usually 10 minutes~48 hours, excellent for condensation reaction It is selected as 1~24 hour.

As solvent used in reduction reaction, as long as not impacted to reaction, can be used, such as aromatic series can be enumerated Hydro carbons, halogenated hydrocarbon, ethers, esters, aprotic polar solvent, alcohol etc. can preferably enumerate alcohol or halogenated hydrocarbon.

As reducing agent used in reduction reaction, such as lithium borohydride and sodium borohydride, lithium aluminium hydride reduction, cyano boron hydrogen can be enumerated Change sodium, sodium triacetoxy borohydride or similar hydride donor compound, can preferably enumerate sodium borohydride or triacetyl oxygen Base sodium borohydride.

The usage amount of reducing agent is preferably equimolar or more relative to compound (XXX), and particularly preferably about 1~10 times mole.

For reduction reaction usually at 0~120 DEG C, preferably in 0~80 DEG C of progress, the reaction time is usually 10 minutes~72 hours, excellent It is selected as 1~48 hour.

(process 6-8)

The R of compound (XV)⁸For the compound (XV-e1), compound (XV-e2) or compound of group shown in formula (e) (XV-e3) it can be manufactured by arbitrary method, if given an example, as described below.

(in formula, L^eIndicate halogen atom, methanesulfonic acid ester group, tosylate group or trifluoromethanesulfonic acid ester group, R^e1、R^e2、R³、R⁴、 R⁵、R⁶、R⁷、R¹⁶It indicates and above-mentioned R^e1、R^e2、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶Same group.〕

That is, obtaining compound (XV-e1) by the substitution reaction for carrying out compound (XXXII) and compound (XXXIII) or changing It closes object (XV-e2), by carrying out the substitution reaction of compound (XV-e1) and compound (XXXIV), so as to obtain chemical combination Object (XV-e3).

Here, as L^eShown in " halogen atom ", can preferably enumerate chlorine atom, bromine atom or iodine atom.

As solvent used in this reaction, as long as not impacted to reaction, can be used, such as aliphatic hydrocarbon can be enumerated Class, aprotic polar solvent, ethers, halogenated hydrocarbon etc., preferably ethers or aprotic polar solvent can more preferably be enumerated Aprotic polar solvent.

This reaction is preferably added to alkali compounds.

As alkali compounds, such as the metallic hydrogens such as alkali metal, sodium hydride, calcium hydride as metallic sodium, metallic potassium can be enumerated The alkoxide such as the inorganic bases such as compound, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide The metal fluorides such as class, sodium fluoride, potassium fluoride, triethylamine, N- crassitude, 1,1,3,3- tetramethylguanidine, 1,8- phenodiazine The organic bases such as miscellaneous bicyclic [5.4.0] 11 carbon -7- alkene, can preferably enumerate sodium hydride, potassium carbonate or triethylamine.

The usage amount of alkali compounds is preferably equimolar or more relative to compound (XXXII) and (XV-e1), particularly preferably It is about 1~10 times mole.

For reduction reaction usually at 0~120 DEG C, preferably in 0~80 DEG C of progress, the reaction time is usually 10 minutes~48 hours, excellent It is selected as 1~24 hour.

(process 6-9)

The R of compound (XV)⁸For the compound (XV-f1), compound (XV-f2) or compound of group shown in formula (f) (XV-f3) it can be manufactured by arbitrary method, if given an example, as described below.

(in formula, L^fIndicate halogen atom or trifluoromethanesulfonic acid ester group, n^fIndicate 0, an integer of 1 or 2, R^f1、R^f2、R³、R⁴、R⁵、R⁶、 R⁷、R¹⁶It indicates and above-mentioned R^f1、R^f2、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶Same group.〕

That is, being obtained by the substitution reaction for carrying out compound (XXXV) and compound (XXXVI) in the presence of metallic catalyst To compound (XV-f1) or compound (XV-f2), by carried out in the presence of metallic catalyst compound (XV-f1) with The substitution reaction of compound (XXXVII), so as to obtain compound (XV-f3).

Here, as L^fShown in " halogen atom ", can preferably enumerate chlorine atom, bromine atom or iodine atom, more preferably may be used Enumerate bromine atom or iodine atom.

As solvent used in this reaction, as long as not impacted to reaction, can be used, such as aromatic hydrocarbon can be enumerated Class, aliphatic hydrocarbon, aprotic polar solvent, ethers, esters, halogenated hydrocarbon, alcohol etc. can preferably enumerate aromatic hydrocarbon Class.

As metallic catalyst, such as tetrakis triphenylphosphine palladium, tris(dibenzylideneacetone) dipalladium, bis- (dibenzylidenes can be enumerated Acetone) palladium (0), acid chloride, palladium chloride, bis- (benzonitrile) palladium chlorides or bis- (Diphenyl phosphino ferrocene) palladium chloride dichloromethanes The palladium catalysts such as alkane complex compound, copper catalyst can preferably enumerate acid chloride.

As long as the usage amount of metallic catalyst is 0.005~1 times mole relative to compound (XXXV).

This reaction can be added phosphine compound and carry out.

As phosphine compound, such as 2 can be enumerated, 2 '-bis- (diphenylphosphino) -1,1 '-dinaphthalene (BINAP), Xantphos (trade mark) (Strem Chemicals Inc.) or related phosphine based ligand, can preferably enumerate BINAP.

As long as the usage amount of phosphine compound is 0.01~1 times mole relative to compound (XXXV).

This reaction is preferably added to alkali compounds.

As alkali compounds, such as the metallic hydrogens such as alkali metal, sodium hydride, calcium hydride as metallic sodium, metallic potassium can be enumerated The alkoxide such as the inorganic bases such as compound, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide The metal fluorides such as class, sodium fluoride, potassium fluoride, triethylamine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0] etc. are organic Bases can preferably enumerate potassium tert-butoxide.

The usage amount of alkali compounds is preferably equimolar or more relative to compound (XXXV), and particularly preferably about 1~10 times Mole.

Usually at 0~150 DEG C, preferably in 50~120 DEG C of progress, the reaction time is usually 10 minutes~72 hours, excellent for this reaction It is selected as 1~48 hour.

(process 6-10-1)

The R of compound (XV)⁸It can be by appointing for the compound (XV-g1) or compound (XV-g2) of group shown in formula (g) The method of meaning manufactures, if given an example, as described below.

(in formula, n^gIndicate an integer of 1 or 2, L^gIndicate halogen atom, R^g1、R^g3、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶It indicates and above-mentioned R^g1、 R^g3、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶Same group.〕

That is, by the condensation reaction for carrying out compound (XXXVIII) or its salt and compound (XXXIX) or compound (XXXX), So as to obtain compound (XV-g1) or compound (XV-g2).

Here, as L^gShown in " halogen atom ", can preferably enumerate chlorine atom, bromine atom or iodine atom, more preferably may be used Enumerate chlorine atom.

As solvent used in condensation reaction, as long as not impacted to reaction, can be used, such as aromatic series can be enumerated Hydro carbons, ethers, esters, aliphatic hydrocarbon, halogenated hydrocarbon, aprotic polar solvent, alcohol etc. can preferably enumerate halogenated hydrocarbon And amides.

The usage amount of compound (XXXIX) or compound (XXXX) preferably etc. is rubbed relative to compound (XXXVIII) or its salt More than you, particularly preferably about 1~10 times mole.

Alkali compounds can be added in this reaction and carry out.

As alkali compounds, such as the organic bases such as triethylamine, n,N-diisopropylethylamine and N-methylmorpholine can be enumerated Or the inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.

As long as the usage amount of alkali compounds is 1~50 times mole, preferably 1~5 relative to compound (XXXVIII) or its salt Times mole.

Usually at -30~80 DEG C, preferably in -20~40 DEG C of progress, the reaction time is usually 10 minutes~72 hours for this reaction, Preferably 1~48 hour.

(process 6-10-2)

As other autofrettages of compound (XV-g1), as described below.

(in formula, R^g1、R^g3、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶It indicates and above-mentioned R^g1、R^g3、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶Same group.〕

That is, compound can be obtained by the condensation reaction for carrying out compound (XXXVIII) or its salt and compound (XXXXI) (XV-g1).

The usage amount of compound (XXXXI) is equimolar or more relative to compound (XXXVIII) or its salt, particularly preferably about 1~10 times mole.

As condensing agent used in condensation reaction, such as condensing agent same as above-mentioned condensing agent can be enumerated, can preferably lifted Carbodiimide class out can more preferably enumerate EDC.

The usage amount of condensing agent is preferably equimolar or more relative to compound (XXXVIII) or its salt, particularly preferably about 1~ 10 times moles.

Alkali compounds can be added in this reaction and carry out.

As long as the usage amount of alkali compounds is 1~50 times mole, preferably 1~5 relative to compound (XXXVIII) or its salt Times mole.

Usually at -30~80 DEG C, preferably in -20~40 DEG C of progress, the reaction time is usually 10 minutes~72 hours for this reaction, Preferably 1~48 hour.

In addition, other autofrettages as compound (XV-g1), as described below.

That is, by compound (XXXXI) and etheride, acid anhydrides or 2- ethyoxyl -1- ethoxy carbonyl -1,2- dihydro quinoline After quinoline (EEDQ) mixing, react compound (XXXVIII) or its salt, so as to obtain compound (XV-a).

Compound (XXXXI) if usage amount relative to compound (XXXVIII) or its salt be 1~50 times mole, preferably 1 ~5 times moles.

As etheride used in condensation reaction or acid anhydrides, such as acyl same as above-mentioned etheride or acid anhydrides can be enumerated Halide or acid anhydrides can preferably enumerate chloro-carbonic acid esters, can more preferably enumerate isobutyl chlorocarbonate.

It rubs as long as the usage amount of etheride or acid anhydrides is 1~50 times mole, preferably 1~5 times relative to compound (XXXXI) You.

This reaction is preferably added to alkali compounds.

As long as the usage amount of alkali compounds is 1~50 times mole, preferably 1~5 times mole relative to compound (XXXXI) It can.

This reaction -50~100 DEG C, preferably -30~50 DEG C carry out, the reaction time is usually a few minutes~72 hour, excellent It is selected as 10 minutes~48 hours.

(process 6-10-3)

The R of compound (XV)⁸For group (R shown in formula (g)^g2It can be by arbitrary for the compound (XV-g3) of CO or CS) Method manufactures, if given an example, as described below.

(in formula, R^g4Indicate O or S, R^g1、R^g3、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶It indicates and above-mentioned R^g1、R^g3、R³、R⁴、R⁵、R⁶、R⁷、R¹⁶ Same group.〕

That is, by carrying out reacting for compound (XXXVIII) and compound (XXXXII) or compound (XXXXIII), so as to Access compound (XV-g3).

As solvent used in this reaction, as long as not impacted to reaction, can be used, such as aromatic hydrocarbon can be enumerated Class, ethers, esters, aliphatic hydrocarbon, halogenated hydrocarbon, aprotic polar solvent, protic polar solvent etc. can preferably be lifted Halogenated hydrocarbon out.

The usage amount of compound (XXXXII) or compound (XXXXIII) is preferably relative to compound (XXXVIII) or its salt It is more than equimolar, particularly preferably about 1~10 times mole.

Alkali compounds can be added in this reaction and carry out.

As alkali compounds, such as triethylamine, pyridine, n,N-diisopropylethylamine, 1,8- diazabicyclo can be enumerated The organic bases such as [5.4.0] 11 carbon -7- alkene and N-methylmorpholine；Sodium hydroxide, potassium hydroxide, sodium bicarbonate, carbonic acid The inorganic bases such as sodium, potassium carbonate；The organometallic reagents such as n-BuLi；The alcohol salt such as potassium tert-butoxide.

As long as the usage amount of alkali compounds is 1~50 times mole, preferably 1~5 relative to compound (XXXVIII) or its salt Times mole.

Usually in -30~80 DEG C, preferably -20~40 DEG C of progress of son, the reaction time is usually 10 minutes~72 small for this reaction When, preferably 1~48 hour.

Raw material compound used in above-mentioned preparation method can directly use commercially available product sometimes, by using commercially available product and can also answer With the method recorded in aftermentioned Production Example, to those skilled in the art obvious method or their deformation side Method manufactures.

Compound (IX) or synthetic intermediate compound can be with free compound, its salt, hydrate, solvate or polycrystalline The form of the substance of type is separated, is purified.The salt of compound (IX) or synthetic intermediate compound can also be normal by carrying out The salt-forming reaction of rule method manufactures.

Isolation, purifying can be using commonization such as extraction, fractional crystallization, various classification chromatographies, evaporation, drying, filtering, centrifugations Operation is learned to carry out.

Various isomers can be manufactured by selecting raw material compound appropriate, or can use physico between isomers The difference of property is learned to separate.For example, optical isomer can be by the general optical resolution method of racemic modification (for example, with light Learn active alkali or acid form the fractional crystallization of diastereomeric salt, using chromatography of chiral column etc. etc.) and obtain, in addition, It can also be manufactured by optically active raw material compound appropriate.

Shown in the pyridone carboxylic acid derivatives of the invention or its salt test example as be described hereinafter obtained in this way, to Non-small cell lung carcinoma Cell strain and people's Ji Gu Marrow leukemia cell line have excellent anti-tumor activity, move in human prostate cancer cell line xenogenesis It plants in piece tumor model, plays excellent tumor proliferation inhibitory effect.On the other hand, low to the cytotoxicity of normal cell.

Therefore, pyridone carboxylic acid derivatives of the invention or its salt is highly-safe, can become the prevention to various cancers or control Treat useful antitumor agent.

It is not particularly limited, such as can lift as the cancer that can be utilized antitumor agent of the invention and be applied to treat or prevent Cancer, lymthoma, blastoma, sarcoma and leukaemia or lymphoid malignancy out can enumerate neural mother as a more specific example Cytoma, intestinal cancer, such as carcinoma of the rectum, colorectal cancer, familial colorectal polyp cancer and something lost hereditary nonpolyposis colorectal cancer, colorectum Cancer, cancer of the esophagus, lip cancer, laryngocarcinoma, hypopharyngeal cancer, tongue cancer, salivary-gland carcinoma, gastric cancer, malignant adenoma, medullary carcinoma of thyroid gland, mamillary Thyroid cancer, kidney, carcinoma of renal parenchyma, oophoroma, head and neck cancer, carcinoma of uterine body, carcinoma of endometrium, choriocarcinoma, cancer of pancreas, forefront Gland cancer, carcinoma of testis, breast cancer, urinary system cancer, malignant mela noma, brain tumor, such as glioblastoma, astrocyte Tumor, meningioma, medulloblastoma and nerve ending ectoderm tumour, hodgkin's lymphomas, non Hodgkin lymphom, primary Base spy lymthoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myelogenous leukemia (AML), Man Gu Marrow leukaemia (CML), adult T-cell leukemia-lymphoma, diffusivity large B cell lymphoid tumor (DLBCL), marrow increase Raw exception syndrome is ((MDS), hepatocellular carcinoma, gallbladder Nang cancer, bronchial asthma cancer, Small Cell Lung Cancer, non-small cell lung cancer, multiple Property myeloma, basal cell tumor, teratoma, retinoblastoma, malignant melanoma of choroid, seminoma, band Muscle tumor, craniopharyngioma, osteosarcoma, chondrosarcoma, muscle tumor, embryonal-cell lipoma, fibrosarcoma, ewing's sarcoma and plasmacytoma And primary unknown cancer.

When using pyridone carboxylic acid derivatives or its salt of the invention as drug (composite medicine), can with for injecting, Admissible carrier is together in the pharmacy of the oral administration of the non-oral administrations such as per rectum, solid, semisolid or liquid form etc. Match prescription as composition.

As the form of the composition of the invention for injection, can enumerate admissible sterile water in pharmacy, non-aqueous solution, Suspension or emulsion.As the example of nonaqueous carrier appropriate, diluent, solvent or vehicle, propylene glycol, poly- second can be enumerated The organic ester of the injectables such as the vegetable oil such as glycol, olive oil, ethyl oleate.Such composition can also be containing preservative, wet Moisten the adjuvants such as agent, emulsifier, dispersing agent.These compositions can be sterilized by operating as follows: for example by using carefully Bacterium retains filter and is filtered, or will can be dissolved in front of use aqua sterilisa or it is some it is other can sterile injection The form of aseptic solid composite of medium be mixed into bactericidal agent.

As the solid pharmaceutical preparation for oral administration, can enumerate capsule, tablet, pill, containing tablet, powder, granule etc..In When preparing the solid pharmaceutical preparation, on one side by the compounds of this invention and at least one kind of non-activated thinner, such as sucrose, lactose, starch Deng mixing.Said preparation can also containing it is common it is formulation in addition in addition to non-activated thinner substance, such as lubricate Agent (such as magnesium stearate etc.).It can also include buffer in the case where capsule, tablet and pill.It can also be further Enteric solubility envelope is further implemented to tablet and pill.

As the liquid preparation for oral administration, inactive diluents usually used between those skilled in the art can be enumerated Agent, such as emulsion admissible in the pharmacy containing water, solution, suspending agent, syrup, elixir.Except the non-activated thinner In addition, the adjuvants such as wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, flavouring agent can also be cooperated in the composition.In In the case where preparation for per rectum administration, also assigned containing cocoa butter, suppository wax etc. preferably in addition to the compounds of this invention Shape agent.

Character, administration route, phase of the dosage of pyridone carboxylic acid derivatives of the invention or its salt by the compound being administered During the disposition of prestige and other principal elements influence, generally in the case of intravenous administration, preferably daily about 0.1~ 1000mg/m²(body surface area), in the case where intramuscular adminstration, preferably daily about 1~1000mg/m²(body surface area), and In the case where oral administration, preferably from about 5~500mg/m²(body surface area).Alternatively, it is also possible to according to expectation by a staggering amount It is divided into 2~4 times to be administered.

The present invention is further concretely demonstrated hereinafter, enumerating reference example and embodiment.It should be noted that for including interconversion The compound of the group of isomers, for convenience, using the Description Method of a side of these tautomers, i.e. name and formula come It indicates.

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