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HK1220633B - Pharmaceutical preparation comprising aminopyrazole derivative - Google Patents

Pharmaceutical preparation comprising aminopyrazole derivative Download PDF

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Publication number
HK1220633B
HK1220633B HK16108800.5A HK16108800A HK1220633B HK 1220633 B HK1220633 B HK 1220633B HK 16108800 A HK16108800 A HK 16108800A HK 1220633 B HK1220633 B HK 1220633B
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HK
Hong Kong
Prior art keywords
group
amino
methyl
pharmaceutical preparation
benzoimidazol
Prior art date
Application number
HK16108800.5A
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Chinese (zh)
Other versions
HK1220633A1 (en
Inventor
仁平润
冈崎健介
吉村志保
Original Assignee
中外制药株式会社
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Application filed by 中外制药株式会社 filed Critical 中外制药株式会社
Priority claimed from PCT/JP2014/070154 external-priority patent/WO2015016295A1/en
Publication of HK1220633A1 publication Critical patent/HK1220633A1/en
Publication of HK1220633B publication Critical patent/HK1220633B/en

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Description

Pharmaceutical preparation containing aminopyrazole derivatives
Technical Field
The present invention relates to pharmaceutical formulations containing aminopyrazole derivatives.
Background art
Many substances expected as molecular target drugs for cancer at present are, for example, inhibitors of receptor-type tyrosine kinases such as erlotinib (エルロチニブ) and lapatinib (ラパチニブ). In addition, many of them have high drug effects on cancers that show mutation, gene amplification, and overexpression of a target gene. However, these molecular target drugs cannot exhibit a drug effect on cancer in which a gene of a target gene other than the molecular target drug itself is changed, and an effective therapeutic method for such cancer has not yet been established. That is, it is expected that inhibitors against new genes that change in cancer will contribute greatly to the treatment of cancer patients for which there has been no effect so far.
Fibroblast Growth Factor Receptors (FGFRs) are kinases belonging to the receptor type tyrosine kinase family, which are composed of FGFR1, FGFR2, FGFR3, FGFR 4. The ligand is a Fibroblast Growth Factor (FGF), a family of 22 structurally similar proteins (ファミリー). FGFR is known to be activated by overexpression, gene amplification, mutation, and transposition, respectively, and to cause cancer, and it is known that the signal of FGFR flows into the MAPK pathway and the PI3K/AKT pathway, and is involved in cell proliferation, angiogenesis, cell migration, infiltration, metastasis, and the like in cancer. (non-patent document 1).
It is strongly suggested that all of these FGFR family kinases are involved in cancer, and it is considered that inhibition of these FGFR family kinases in cancer tissues can provide a promising therapeutic approach for the above-mentioned cancer types.
In contrast, the present applicant and others have already provided low-molecular-weight compounds that can inhibit Fibroblast Growth Factor Receptor (FGFR) family kinases in cancer tissues (patent document 1).
In providing a drug, for example, a preparation needs to be efficiently absorbed in vivo, and an effective preparation is also required for the pyrazole compound described in patent document 1. For example, in the form of a preparation, since the active ingredient (drug) is enclosed in a small space in a capsule preparation and administered, it is important to disperse the drug (drug) after the capsule is disintegrated.
Documents of the prior art
Patent document
Patent document 1 WO2011/0165528
Non-patent document
Non-patent document 1, Cytokine & Growth Factor Reviews 16 (2005) 139-149.
Disclosure of Invention
The present inventors have tried to formulate an aminopyrazole compound having an indole ring to be used in the present invention. Specifically, a preparation produced using an unpulverized material of "[ 5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone" (compound 1 described in example 1 of the present application) disintegrates and disperses, but since the particle size is large, the subsequent elution is slow, and there is a concern that the absorption in the living body is caused. On the other hand, when the compound powder is pulverized, the dissolution rate in water increases, and before the capsule is completely disintegrated, the surfaces of the compound particles are brought into contact with water to be gelled, and the particles are bonded to each other, so that it has been found that the compound powder in the capsule preparation cannot be effectively disintegrated, and the dissolution rate becomes slower than that of the raw drug which is not pulverized.
Further, attempts have been made to improve the dissolution properties by improving the production method and adding a surfactant, but similarly, the dissolution rate of the drug substance becomes high, and gelation occurs before the disintegration of the preparation, and the disintegration is suppressed, and thus effective preparation is difficult.
That is, the present invention aims to improve the dissolution property of a pharmaceutical preparation containing an aminopyrazole compound used in the present invention.
The present inventors have made extensive studies to solve the above problems, and as a result, have found that an aminopyrazole compound used in the present invention can be formed into a preparation having excellent elution properties without causing gelation of compound particles by adding an alkyl sulfate to the preparation, thereby completing the present invention.
Namely, the present invention is as follows.
[ 1] A pharmaceutical preparation comprising an alkyl sulfate salt and a compound represented by the following general formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
[ in the formula, R1～R4Each independently represents the following group;
R1represents hydrogen, hydroxy, halogen, cyano, nitro, C1-4Haloalkyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl radical, C6-10Aryl radical C1-4Alkyl, -OR5、-NR6R7、-(CR8R9)nZ1、-C(O)NR12R13、-SR14、-SOR15、-SO2R16、-NR17SO2R18COOH, C which may be substituted by one or more groups independently selected from the group P6-10Aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclyl which may be substituted with one or more groups independently selected from group Q, -COR19、-COOR20、-OC(O)R21、-NR22C(O)R23、-NR24C(S)R25、-C(S)NR26R27、-SO2NR28R29、-OSO2R30、-SO3R31or-Si (R)32)3；
R2Represents hydrogen, hydroxy, halogen, cyano, nitro, C1-4Haloalkyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-7Cycloalkyl radical, C6-10Aryl radical C1-4Alkyl, -OR5、-NR6R7、-(CR8R9)nZ1、-C(O)NR12R13、-SR14、-SOR15、-SO2R16、-NR17SO2R18COOH, C which may be substituted by one or more groups independently selected from the group P6-10Aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclyl which may be substituted with one or more groups independently selected from group Q, -COR19、-COOR20、-OC(O)R21、-NR22C(O)R23、-NR24C(S)R25、-C(S)NR26R27、-SO2NR28R29、-OSO2R30、-SO3R31or-Si (R)32)3；
Or R1And R2Together with the atoms to which they are bonded form a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the heterocyclic group or the heteroaryl group may be substituted with halogen;
R3represents hydrogen, C1-5Alkyl radical, C6-10Aryl radical C1-6Alkyl or C1-4A haloalkyl group;
R4represents hydrogen, halogen, C1-3Alkyl radical, C1-3Perfluoroalkyl radical, cyanogenA group, methanesulfonyl, hydroxy, alkoxy, or amino;
R5is represented by C1-5Alkyl radical, C3-7Cycloalkyl radical, C3-7Cycloalkyl radical C1-3Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C1-3Alkoxy radical C1-4Alkoxy radical C1-4Alkyl radical, C1-4Aminoalkyl radical, C1-4Alkylamino radical C1-4Alkyl, di (C)1-4Alkyl) amino C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-3Alkyl, 3-to 10-membered heterocyclic group C which may be substituted with one or more groups independently selected from group Q1-3Alkyl, 3-to 10-membered heterocyclic group, 5-to 10-membered heteroaryl C1-3Alkyl radical, C1-6Monohydroxyalkyl group, C1-6Dihydroxyalkyl or C1-6A trihydroxyalkyl group;
R6and R7May be the same or different and each represents hydrogen or C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C6-10Aryl radical C1-3Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl radical, C1-6Monohydroxyalkyl group, C1-6Dihydroxyalkyl radical, C1-6Trihydroxyalkyl, 3-to 10-membered heterocyclic group, C1-4Aminoalkyl radical, C1-4Alkylamino radical C1-4Alkyl, di (C)1-4Alkyl) amino C1-4Alkyl or cyano (C)1-3Alkyl) or R6And R7Together with the nitrogen atom to which they are bonded form a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group;
n represents 1 to 3;
R8and R9May be the same or different and each represents hydrogen or C1-4Alkyl or halogen, or R8And R9May form esters together with the carbon atoms to which they are bondedA ring family ring;
Z1represents hydrogen, NR10R11-OH, or a 3-10 membered heterocyclyl or 5-10 membered heteroaryl group which may be substituted with one or more groups independently selected from group Q;
R10and R11May be the same or different and each represents C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl, cyano (C)1-3Alkyl) or C1-3Alkylsulfonyl radical C1-4Alkyl, or R10And R11May form a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group together with the nitrogen atom to which they are bonded;
R12and R13May be the same or different and each represents hydrogen or C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C6-10Aryl, 5-to 10-membered heteroaryl, 3-to 10-membered heterocyclic group, C6-10Aryl radical C1-4Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl, cyano (C)1-3Alkyl group), C1-3Alkylsulfonyl radical C1-4An alkyl group, a 3-to 10-membered alicyclic ring, a 5-to 10-membered heteroaryl group or a 3-to 10-membered heterocyclic group, or R12And R13May form, together with the nitrogen atom to which they are bonded, a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group, which may be substituted with one or more groups independently selected from group Q;
R14is represented by C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C which may be substituted with one or more groups independently selected from group P6-10Aryl, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q;
R15is represented by C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C which may be substituted with one or more groups independently selected from group P6-10Aryl, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q;
R16is represented by C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C which may be substituted with one or more groups independently selected from group P6-10Aryl, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q;
R17represents hydrogen or C1-4An alkyl group;
R18is represented by C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C which may be substituted with one or more groups independently selected from group P6-10Aryl, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q;
R19represents hydrogen, C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10Aryl, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q;
R20is represented by C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10An aryl group, a 5-to 10-membered heteroaryl group or a 3-to 10-membered heterocyclic group;
R21is represented by C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10An aryl group, a 5-to 10-membered heteroaryl group or a 3-to 10-membered heterocyclic group;
R22represents hydrogen, C1-4Alkyl or C1-4A haloalkyl group;
R23represents hydrogen, C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10An aryl group, a 5-to 10-membered heteroaryl group or a 3-to 10-membered heterocyclic group;
R24represents hydrogen, C1-4Alkyl or C1-4A haloalkyl group;
R25is represented by C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10An aryl group, a 5-to 10-membered heteroaryl group or a 3-to 10-membered heterocyclic group;
R26and R27May be the same or different and each represents hydrogen or C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C6-10Aryl, 5-to 10-membered heteroaryl, 3-to 10-membered heterocyclic group, C6-10Aryl radical C1-4Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl, cyano (C)1-3Alkyl group), C1-3Alkylsulfonyl radical C1-4Alkyl, or 3-to 10-membered alicyclic ring, or R26And R27May form a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group together with the nitrogen atom to which they are bonded;
R28and R29May be the same or different and each represents hydrogen or C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C6-10Aryl, 5-to 10-membered heteroaryl, 3-to 10-membered heterocyclic group, C6-10Aryl radical C1-4Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl, cyano (C)1-3Alkyl group), C1-3Alkylsulfonyl radical C1-4Alkyl, or 3-to 10-membered alicyclic ring, or R28And R29May form a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group together with the nitrogen atom to which they are bonded;
R30is represented by C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10An aryl group, a 5-to 10-membered heteroaryl group or a 3-to 10-membered heterocyclic group;
R31is represented by C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10An aryl group, a 5-to 10-membered heteroaryl group or a 3-to 10-membered heterocyclic group;
R32is represented by C1-4Alkyl or C6-10An aryl group;
< group P >
Halogen, C1-4Alkyl radical, C1-4Haloalkyl, -OH, C1-3Alkoxy radical, C1-3Haloalkoxy, 3-to 10-membered heterocyclylamino, -SO2R16、-CN、-NO2And a 3-to 10-membered heterocyclic group.
< group Q >
Halogen, C1-4Alkyl radical, C1-4Haloalkyl, -OH, C1-3Alkoxy radical, C1-6Monohydroxyalkyl group, C1-6Dihydroxyalkyl or C1-6Trihydroxyalkyl, 3-to 10-membered heterocyclylamine, -SO2R16、-CN、-NO2、C3-7Cycloalkyl, -COR19And can be substituted by C1-4An alkyl-substituted 3-to 10-membered heterocyclic group. And (c) a temperature sensor.
[ 2] the pharmaceutical preparation according to [ 1], wherein R is3Is C1-4An alkyl group.
[ 3] the pharmaceutical preparation according to [ 1] or [ 2], wherein R is as defined above4Is hydrogen.
[ 4 ] the pharmaceutical preparation according to any one of [ 1] to [ 3], wherein R is as defined above1And R2Is hydrogen.
[5 ] the pharmaceutical preparation according to any one of [ 1] to [ 4 ], wherein the compound represented by the formula (I) is as follows:
a compound shown or a tautomer thereof.
[ 6 ] the pharmaceutical preparation according to any one of [ 1] to [5 ], wherein the alkyl sulfate salt is C10-14An alkyl sulfate.
[ 7 ] the pharmaceutical preparation according to any one of [ 1] to [ 6 ], wherein the alkyl sulfate salt is lauryl sulfate.
The pharmaceutical preparation according to any one of [ 1] to [ 7 ], wherein the pharmaceutical preparation is a solid preparation.
The pharmaceutical preparation according to [ 8 ], wherein the solid preparation is a capsule, tablet, powder, granule, or dry syrup.
[ 10 ] the pharmaceutical preparation according to any one of [ 1] to [ 9 ], wherein the compound represented by the general formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof is particles, and the average particle diameter of the particles is 10 μm or less.
The pharmaceutical preparation according to any one of [ 1] to [ 10 ], which further comprises a disintegrant.
[ 12 ] the pharmaceutical preparation according to [ 11 ], wherein the disintegrant is a super disintegrant.
The pharmaceutical preparation according to [ 11 ], wherein the disintegrant is at least 1 selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, corn starch, and soybean polysaccharide.
The pharmaceutical preparation according to any one of [ 1] to [ 13 ], wherein the pharmaceutical preparation is a capsule, and 1 capsule contains the compound represented by the formula (I), a tautomer thereof, or a pharmaceutically acceptable salt thereof in a content ratio of 10% by weight or less in terms of free form relative to the total amount of the pharmaceutical preparation (excluding the weight of the capsule).
The pharmaceutical preparation according to [ 14 ], wherein the 1 capsule contains 20mg or more of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof in a total amount in terms of free bodies.
The pharmaceutical preparation according to any one of [ 1] to [ 15 ], wherein the pharmaceutical preparation is a capsule, and crystalline cellulose is added (not added later) as an external preparation.
The pharmaceutical preparation according to any one of [ 1] to [ 13 ], wherein the pharmaceutical preparation is a tablet.
[ 18 ] the pharmaceutical preparation according to [ 17 ], which comprises
The following:
the compound comprises the compound shown in the specification or a tautomer thereof or a pharmaceutically acceptable salt thereof, sodium dodecyl sulfate and a super disintegrant.
The pharmaceutical preparation according to [ 17 ] or [ 18 ], wherein the tablet contains 1 to 50% by weight of the compound represented by the formula (I), a tautomer thereof, or a pharmaceutically acceptable salt thereof, in terms of free bodies, relative to the total amount of the tablet.
The pharmaceutical preparation according to any one of [ 17 ] to [ 19 ], wherein the weight ratio of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof to the alkyl sulfate salt is 1: 10-8: 1.
the pharmaceutical preparation according to any one of [ 17 ] to [ 20 ], wherein the content (by weight) of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof is 1 to 500mg in terms of free form.
A process for producing a solid pharmaceutical preparation containing the pharmaceutical preparation according to [ 1], which comprises
A step of providing a mixture containing an alkyl sulfate ester salt and a compound represented by the general formula (I) described in [ 1] or a tautomer thereof or a pharmaceutically acceptable salt thereof;
a step of adding purified water to the mixture in a proportion of 25 wt% or less with respect to the total weight of the mixture without adding water to the mixture, and granulating the mixture; and
and a step of drying the granulated mixture to provide a dry powder.
The production method according to [ 22 ], which further comprises a step of granulating the dried powder to provide a granulated powder;
mixing the whole grain powder () And an additive containing magnesium stearate to provide a blended powder) A step (2); and
and (3) tableting the blended powder to form a pharmaceutical preparation in the form of a tablet according to any one of [ 17 ] to [ 21 ].
[ 24 ] alkyl sulfate salt as an agent for preventing gelation of a solid pharmaceutical preparation: () The use of (1).
[ 25 ] use of an alkyl sulfate salt as an agent for preventing gelation of a solid pharmaceutical preparation containing the compound represented by the formula (I) described in [ 1] or a tautomer thereof or a pharmaceutically acceptable salt thereof.
[ 26 ] the pharmaceutical preparation according to any one of [ 1] to [ 21 ] for use in the prevention or treatment of cancer.
A method for the prophylaxis or treatment of cancer, which comprises administering a pharmaceutically effective amount of the pharmaceutical preparation according to any one of [ 1] to [ 21 ] to a patient in need of prophylaxis or treatment of cancer.
Use of the pharmaceutical preparation according to any one of [ 28 ] to [ 1] to [ 21 ] for the production of a prophylactic or therapeutic agent for cancer.
The pharmaceutical preparation according to any one of [ 1] to [ 21 ] for use in the prevention or treatment of cancer.
The present invention also includes a "composition" containing the same constituent elements as those of the "pharmaceutical preparation" of the present invention, and such a "composition" exerts the same effects as those of the "pharmaceutical preparation".
ADVANTAGEOUS EFFECTS OF INVENTION
Since the pharmaceutical preparation containing the aminopyrazole compound used in the present invention contains an alkyl sulfate salt, the compound particles are not gelled and have excellent elution properties.
Brief description of the drawings
FIG. 1 is a graph showing the elution profiles of capsules in which the content of sodium lauryl sulfate was constant (10.0 mg) and the content of Compound 1 (in terms of free body) was 1.0mg, 5.0mg and 10.0mg (examples 2,3 and 4).
FIG. 2 is a graph showing the elution profiles of capsules in the presence and absence of crystalline cellulose when the content of Compound 1 (in terms of the amount of free form) in the capsules was 20.0mg (examples 5 and 6).
FIG. 3 is a graph showing the dissolution profiles of tablets obtained when the content of Compound 1 (in terms of the amount of free substance) in the tablets was 50.0mg and 100.0mg (examples 9 and 10).
Detailed Description
The pharmaceutical preparation according to the present invention (hereinafter, sometimes referred to as "pharmaceutical composition") contains a compound represented by the general formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof (hereinafter, sometimes referred to as "compound suitable for use in the present invention"), and an alkyl sulfate salt.
Compound or tautomer thereof, or pharmaceutically acceptable salt thereof
The "alkyl group" in the present specification is a 1-valent group derived by arbitrarily removing 1 hydrogen atom from an aliphatic hydrocarbon, which does not contain a hetero atom or an unsaturated carbon-carbon bond in the skeleton, and has a hydrocarbon group or a subset of hydrocarbon group structures containing hydrogen and carbon atoms. The alkyl group has a linear or branched structure. The alkyl group preferably has 1 to 6 carbon atoms (C)1-6The following are, for example, "Cp-q"means an alkyl group having p to q carbon atoms), C1-5Alkyl radical, C1-4Alkyl radical, C1-3Alkyl groups, and the like.
Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a 2, 3-dimethylpropyl group, a 3, 3-dimethylbutyl group, and a hexyl group.
The "alkenyl group" in the present specification is a 1-valent hydrocarbon group having at least 1 double bond (2 adjacent SP2 carbon atoms), and includes a linear or branched alkenyl group. Depending on the configuration of the double bond and the substituted moiety (when present), of the double bondThe geometrical morphology may be in the E configuration (E) or Z configuration (Z), or in the cis or trans configuration. Alkenyl is preferably C2-6Alkenyl groups, and the like.
Specific examples of the alkenyl group include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis-form and trans-form), 3-butenyl, pentenyl, and hexenyl.
The "alkynyl group" in the present specification is a 1-valent hydrocarbon group having at least 1 triple bond (2 adjacent SP carbon atoms), and includes a linear or branched alkynyl group. Preferred are C2-6Alkynyl.
Specific examples of the alkynyl group include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl and the like.
The alkenyl or alkynyl group may have 1 or 2 or more double or triple bonds, respectively.
The term "cycloalkyl" as used herein refers to a saturated or partially saturated cyclic 1-valent aliphatic hydrocarbon group containing a monocyclic ring, a bicyclic ring or a spiro ring. Cycloalkyl is preferably C3-7Cycloalkyl groups, and the like. Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "cycloalkylalkyl" as used herein refers to a group obtained by substituting any hydrogen atom in the "alkyl" group defined above with the "cycloalkyl" group defined above. Cycloalkylalkyl radicals are preferably C3-7Cycloalkyl radical C1-3Examples of the alkyl group include a cyclopropylmethyl group and a cyclopropylethyl group.
The "hetero atom" in the present specification means a nitrogen atom (N), an oxygen atom (O) or a sulfur atom (S).
The "halogen" in the present specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The "haloalkyl group" in the present specification means the same or different, preferably 1 to 9, and more preferably 1 to 5 groups in which the "halogen atom" is bonded to the "alkyl group".
Specific examples thereof include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, perfluoroalkyl (e.g., trifluoromethyl, -CF)2CF3Etc.), 2,2, 2-trifluoroethyl, etc.
The "alkoxy" in the present specification means an oxy group to which the "alkyl" defined above is bonded, and preferably C is mentioned1-4Alkoxy radical, C1-3Alkoxy, and the like. Specific examples of the alkoxy group include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
The "haloalkoxy group" in the present specification means the same or different, preferably 1 to 9, and more preferably 1 to 5 groups in which the "halogen atom" is bonded to the "alkoxy group".
Specific examples thereof include chloromethoxy, trichloromethoxy and trifluoromethoxy.
The "aryl" in the present specification means an aromatic hydrocarbon ring having a valence of 1, and preferably C is exemplified6-10Aryl, and the like. Specific examples of the aryl group include a phenyl group and a naphthyl group (e.g., 1-naphthyl group and 2-naphthyl group).
The "alicyclic ring" in the present specification means a non-aromatic hydrocarbon ring having a valence of 1. The alicyclic ring may have an unsaturated bond in the ring, or may be a polycyclic group having 2 or more rings. In addition, carbon atoms constituting the ring may be oxidized to form a carbonyl group. The number of atoms constituting the alicyclic ring is preferably 3 to 10 (3-to 10-membered alicyclic ring). Examples of the alicyclic ring include a cycloalkyl ring, a cycloalkenyl ring, and a cycloalkynyl ring.
The term "heteroaryl" as used herein refers to an aromatic 1-valent heterocyclic group containing preferably 1 to 5 heteroatoms in the atoms constituting the ring. The heteroaryl group may be partially saturated, and may be a single ring or a fused ring (e.g., a bicyclic heteroaryl group fused to a phenyl ring or a monocyclic heteroaryl ring). The number of atoms constituting the ring is preferably 5 to 10 (5-to 10-membered heteroaryl).
Specific examples of the heteroaryl group include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazo, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzooxadiazolyl, benzimidazolyl, indolyl, isoindolyl, azaindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridinyl, and the like.
The term "heterocyclic group" as used herein means a non-aromatic 1-valent heterocyclic group containing preferably 1 to 5 hetero atoms in the atoms constituting the ring. The heterocyclic group may have a double bond or a triple bond in the ring, and a carbon atom may be oxidized to form a carbonyl group, and may be a single ring or a condensed ring. The number of atoms constituting the ring is preferably 3 to 10 (3 to 10-membered heterocyclic group).
Specific examples of the heterocyclic group include oxetanyl, dihydrofuranyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyl, azetidinyl, oxazolidinonyl, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, and the like.
The term "arylalkyl" as used herein refers to a group wherein any hydrogen atom in the "alkyl" group defined above is replaced with the "aryl" group defined above. Arylalkyl is preferably C6-10Aryl radical C1-4Alkyl radical, C6-10Aryl radical C1-3Alkyl groups, and the like. Specific examples thereof include benzyl, phenethyl, and naphthylmethyl.
The "heteroarylalkyl group" in the present specification is a group obtained by substituting any hydrogen atom in the "alkyl group" defined above with the "heteroaryl group" defined above. Preferred heteroarylalkyl groups include 5-to 10-membered heteroaryl C1-3Examples of the alkyl group include a pyrrolylmethyl group, an imidazolylmethyl group, a thienylmethyl group, a pyridylmethyl group, a pyrimidinylmethyl group, a quinolylmethyl group, and a pyridylethyl group.
The term "heterocyclylalkyl" as used herein refers to a group obtained by substituting any hydrogen atom in the "alkyl" group defined above with the "heterocyclyl" group defined above. Preferable examples of the heterocyclylalkyl group include a 3-to 10-membered heterocyclyl group C1-3Examples of the alkyl group include a morpholinomethyl group, a morpholinoethyl group, a thiomorpholinylmethyl group, a pyrrolidinylmethyl group, a piperidinylmethyl group, a piperazinylmethyl group, a piperazinylethyl group, and an oxetanylmethyl group.
The term "monohydroxyalkyl group" as used herein refers to a group obtained by substituting 1 hydrogen atom in any of the "alkyl groups" defined above with 1 hydroxyl group. Monohydroxyalkyl is preferably C1-6Monohydroxyalkyl group, C2-6Monohydroxyalkyl groups and the like, specifically, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and the like are contained therein.
The term "dihydroxyalkyl group" as used herein refers to a group obtained by substituting 2 or more hydrogen atoms in any of the above-defined "alkyl groups" with 2 or more hydroxyl groups. As the dihydroxyalkyl group, C is preferably mentioned1-6Dihydroxyalkyl radical, C2-6Dihydroxyalkyl groups and the like, and specifically, 1, 2-dihydroxyethyl, 1, 2-dihydroxypropyl, 1, 3-dihydroxypropyl, and the like are included, for example.
The term "trihydroxyalkyl" as used herein refers to a group obtained by substituting 3 hydroxyl groups for any 3 hydrogen atoms in the "alkyl" defined above. Preferred examples of the trihydroxyalkyl group include C1-6Trihydroxyalkyl radical, C2-6Trihydroxyalkyl, and the like.
"alkoxyalkyl group" in the present specification"is a group obtained by substituting any hydrogen atom in the" alkyl group "defined above with the" alkoxy group "defined above. Alkoxyalkyl is preferably C1-3Alkoxy radical C1-4Alkyl radical, C1-3Alkoxy radical C2-4Alkyl groups and the like, specifically, for example, methoxyethyl groups and the like are contained therein.
The term "alkoxyalkoxyalkyl" as used herein refers to a group obtained by substituting any hydrogen atom in the terminal alkyl group in the above-mentioned definition of "alkoxyalkyl" with the above-mentioned definition of "alkoxy". As the alkoxyalkoxyalkyl group, there may be preferably mentioned C1-3Alkoxy radical C1-4Alkoxy radical C1-4Alkyl radical, C1-3Alkoxy radical C2-4Alkoxy radical C2-4Alkyl groups, and the like.
The term "aminoalkyl" as used herein refers to a group wherein any hydrogen atom in the above definition of "alkyl" is replaced with an amino group. Aminoalkyl is preferably listed under C1-4Aminoalkyl radical, C2-4Aminoalkyl groups, and the like.
The term "alkylamino" as used herein refers to an amino group to which 1 "alkyl" as defined above is bonded. As the alkylamino group, there may be preferably mentioned C1-4Alkylamino, and the like.
"dialkylamino" in the present specification means an amino group to which 2 "alkyl" groups defined above are bonded, and the alkyl groups may be the same or different. As the dialkylamino group, a di (C) group is preferably mentioned1-4Alkyl) amino, and the like.
The "alkylaminoalkyl group" in the present specification means a group obtained by substituting any hydrogen atom in the "alkyl group" defined above with the "alkylamino group" defined above. As alkylaminoalkyl group, there may be preferably mentioned C1-4Alkylamino radical C1-4Alkyl radical, C1-4Alkylamino radical C2-4Alkyl groups, and the like.
The term "dialkylaminoalkyl" as used herein refers to a group in which any hydrogen atom in an "alkyl" group as defined above is replaced with a "dialkylamino" group as defined above. MakingAs the dialkylaminoalkyl group, a di (C) group is preferably mentioned1-4Alkyl) amino C1-4Alkyl, di (C)1-4Alkyl) amino C2-4Alkyl groups, and the like.
The term "heterocyclylamino" as used herein refers to an amino group to which 1 "heterocyclyl" as defined above is bonded. As the heterocyclic amino group, a 3-to 10-membered heterocyclic amino group and the like are preferable.
The "cyanoalkyl group" in the present specification means a group obtained by substituting any hydrogen atom in the "alkyl group" defined above with a cyano group. Preferred cyanoalkyl group is cyano (C)1-3Alkyl), and the like.
"alkylsulfonyl" in the present specification means a sulfonyl group (i.e., alkyl-SO) to which "alkyl" as defined above is bonded2-). Alkylsulfonyl is preferably C1-3Alkylsulfonyl and the like, specifically, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl and the like are included therein.
The "alkylsulfonylalkyl" in the present specification is a group obtained by substituting any hydrogen atom in the "alkyl" defined above with the "alkylsulfonyl" defined above. Alkylsulfonylalkyl is preferably C1-3Alkylsulfonyl radical C1-4Alkyl radical, C1-3Alkylsulfonyl radical C2-4Alkyl groups, and the like.
The compound to be used in the present invention may be an episome or a pharmacologically acceptable salt thereof, and is included in the present invention. Examples of such "salts" include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, and acidic or basic amino acid salts.
"free form" refers to the compound itself without forming salts, hydrates, solvates, and the like.
Preferred examples of the inorganic acid salt include hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and preferred examples of the organic acid salt include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, malate, stearate, benzoate, methanesulfonate, p-toluenesulfonate and the like. A particularly preferred salt in the present invention is malate.
Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt, and preferred examples of the organic base salt include diethylamine salt, diethanolamine salt, meglumine salt and N, N-dibenzylethylenediamine salt.
Preferred examples of the acidic amino acid salt include aspartic acid salt and glutamic acid salt, and preferred examples of the basic amino acid salt include arginine salt, lysine salt and ornithine salt.
The compound to be used in the present invention may be allowed to stand in the atmosphere to absorb water or to be adsorbed with water to form a hydrate, and such a hydrate is also included in the salt of the present invention.
Further, the compound to which the present invention is applied may absorb some other solvent to form a solvate, and such a solvate is also included in the salt of the present invention.
All other isomers (geometric isomers, optical isomers, stereoisomers, tautomers and the like) and isomer mixtures which arise structurally from the compounds suitable for use in the present invention are encompassed by the present invention.
Polymorphism sometimes occurs in compounds useful in the present invention, and all polymorphs thereof are included in the present invention.
The compounds suitable for use in the present invention include prodrugs thereof. The prodrug is a derivative of the compound of the present invention, which has a chemically or metabolically decomposable group and returns to the original compound after administration to an organism and shows the original drug effect.
The compound to be used in the present invention includes a compound in which 1 or more atoms in the molecule are replaced with an isotope. In the present invention, isotopes refer to atoms having the same atomic number (proton number) and different mass numbers (the sum of the numbers of protons and neutrons). Examples of the atom to be replaced by an isotope contained in the compound of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, a chlorine atom and the like, and isotopes thereof include2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl, and the like. In particular, it is possible to use, for example,3H、14a radioactive isotope such as C, which emits radioactive energy and decays, is useful for in vivo tissue distribution tests of drugs or compounds, and the like. The stable isotope does not decay, is present in an amount that hardly changes, and has no radioactivity, and thus can be safely used. Isotopic replacements of the compounds of the present invention can be changed by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes according to conventional methods.
The compound represented by the above formula (I) of the present invention is suitably as described below.
R is as defined above1Preferably hydrogen, hydroxy, halogen, cyano, C1-4Haloalkyl, C1-6Alkyl radical, C2-6Alkynyl, C3-7Cycloalkyl radical, C6-10Aryl radical C1-4Alkyl, -OR5、-NR6R7、-(CR8R9)nZ1、-C(O)NR12R13、-SR14、-SO2R16、-NR17SO2R18COOH, C which may be substituted by one or more groups independently selected from the group P6-10Aryl, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q. As the 5-to 10-membered heteroaryl group, specifically, imidazolyl, thienyl, and pyranyl are particularly preferablePyridyl, pyridazinyl and pyrazolyl, and the 3-to 10-membered heterocyclic group is particularly preferably morpholinyl, tetrahydropyridyl and piperidyl.
R is as defined above1More preferably hydrogen.
R is as defined above2Preferably hydrogen, halogen, C1-4Haloalkyl, C1-6Alkyl, -OR5C which may be substituted with one or more groups independently selected from group P6-10Aryl, 5-10 membered heteroaryl which may be substituted with one or more groups independently selected from group Q. As the 5-to 10-membered heteroaryl group mentioned therein, specifically, a pyridyl group is particularly preferable.
R is as defined above2More preferably hydrogen.
R is as defined above1And the above R2Preferably, they may form a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group together with the atoms to which they are bonded. Wherein the heterocyclic group or the heteroaryl group may have a halogen atom as a substituent. The 3 to 10-membered heterocyclic group formed together with the bonded atom is particularly preferably dioxolanyl or dioxanyl.
R is as defined above3Preferably hydrogen, C1-5Alkyl radical, C6-10Aryl radical C1-6Alkyl or C1-4Haloalkyl, more preferably hydrogen, or C1-4Alkyl, more preferably C1Alkyl, particularly preferably methyl.
R is as defined above4Preferably hydrogen, or halogen, more preferably hydrogen.
R is as defined above5Preferably C1-5Alkyl radical, C3-7Cycloalkyl radical, C3-7Cycloalkyl radical C1-3Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C1-3Alkoxy radical C1-4Alkoxy radical C1-4Alkyl radical, C1-4Aminoalkyl radical, C1-4Alkylamino radical C1-4Alkyl, di (C)1-4Alkyl) amino C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-3Alkyl, 3-to 10-membered heterocyclic group C which may be substituted with one or more groups independently selected from group Q1-3Alkyl, 3-to 10-membered heterocyclic group, 5-to 10-membered heteroaryl C1-3Alkyl radical, C1-6Monohydroxyalkyl group, C1-6Dihydroxyalkyl or C1-6A trihydroxyalkyl group.
R is as defined above5More preferably C1-5Alkyl radical, C3-7Cycloalkyl radical C1-3Alkyl radical, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-3Alkyl, 3-to 10-membered heterocyclic group C which may be substituted with one or more groups independently selected from group Q1-3Alkyl and 3-10 membered heterocyclic group. As the 3-to 10-membered heterocyclic alkyl, specifically, piperazinylethyl, oxetanylmethyl, morpholinylethyl is particularly preferable, and as the 3-to 10-membered heterocyclic group, specifically, oxetanyl, tetrahydropyranyl is particularly preferable.
R is as defined above6And the above R7Preferably, they may be the same or different and each represent hydrogen or C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C2-4Alkyl radical, C6-10Aryl radical C1-3Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl radical, C1-6Monohydroxyalkyl group, C1-6Dihydroxyalkyl radical, C1-6Trihydroxyalkyl, 3-to 10-membered heterocyclic group, C1-4Aminoalkyl radical, C1-4Alkylamino radical C1-4Alkyl, di (C)1-4Alkyl) amino C1-4Alkyl, or cyano (C)1-3Alkyl groups).
R is as defined above6And the above R7More preferably, each is independently hydrogen or C1-3Alkoxy radical C1-4Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl, or C1-6A dihydroxyalkyl group. As suchAs the 3-to 10-membered heterocyclylalkyl group, a morpholinoethyl group is particularly preferable, and as the 5-to 10-membered heteroarylalkyl group, a pyridylethyl group is particularly preferable.
Or, the above R6And the above R7Preferably, they may form a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group together with the nitrogen atom to which they are bonded.
N represents an integer of 1 to 3, and preferably n is 1.
R is as defined above8And the above R9Preferably, they may be the same or different and are each hydrogen or C1-4Alkyl or halogen, more preferably hydrogen.
Or, the above R8And the above R9Preferably, they may form an alicyclic ring together with the carbon atom to which they are bonded.
Z above1Preferably hydrogen, NR10R11-OH, or a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group which may be substituted with one or more groups independently selected from Q, more preferably NR10R11or-OH, or a 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q. The 3-to 10-membered heterocyclic group is particularly preferably a pyrrolidinyl group, a piperazinyl group, a piperidinyl group or a morpholinyl group.
R is as defined above10And the above R11Preferably, they may be the same or different and each represents C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl, cyano (C)1-3Alkyl) or C1-3Alkylsulfonyl radical C1-4Alkyl, more preferably C1-4Alkyl radical, C2-6Alkynyl, or C1-3Alkoxy radical C2-4An alkyl group.
Or, the above R10And the above R11Preferably, they may form a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group together with the nitrogen atom to which they are bonded.
R is as defined above12And the above R13Preferably, they may be the same or different and each represent hydrogen or C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C6-10Aryl, 5-to 10-membered heteroaryl, 3-to 10-membered heterocyclic group, C6-10Aryl radical C1-4Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl, cyano (C)1-3Alkyl group), C1-3Alkylsulfonyl radical C1-4An alkyl group or a 3-to 10-membered alicyclic ring, more preferably hydrogen or C1-4Alkyl radical, C1-4A haloalkyl group.
Or, the above R12And the above R13Preferably, they may form, together with the nitrogen atom to which they are bonded, a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group, which may be substituted with one or more groups independently selected from group Q. Particularly preferred is a 3-to 10-membered heterocyclylalkyl group, and specifically more preferred is a piperazinyl group, a morpholinyl group, a pyrrolidinyl group, or a piperidinyl group.
R is as defined above14Is preferably C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C which may be substituted with one or more groups independently selected from group P6-10Aryl, or 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q, more preferably C1-4Alkyl radical, C1-4A haloalkyl group.
R is as defined above15Is preferably C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C which may be substituted with one or more groups independently selected from group P6-10Aryl, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q.
R is as defined above16Is preferably C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, one or more radicals which may be independently selected from the group PC substituted by radicals6-10Aryl, or 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q, more preferably C1-4An alkyl group.
R is as defined above17Preferably hydrogen or C1-4Alkyl, more preferably hydrogen.
R is as defined above18Is preferably C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C which may be substituted with one or more groups independently selected from group P6-10Aryl, or 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q, more preferably C1-4An alkyl group.
R is as defined above19Preferably hydrogen, C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10Aryl, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q, more preferably hydrogen, or a 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group which may be substituted with one or more groups independently selected from group Q. The 3-to 10-membered heterocyclic group is more preferably a piperazinyl group, a morpholinyl group, a pyrrolidinyl group or a piperidinyl group.
R is as defined above20Is preferably C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10Aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group.
R is as defined above21Preferably C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10Aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group.
R is as defined above22Preferably hydrogen, C1-4Alkyl or C1-4A haloalkyl group.
R is as defined above23Preferably hydrogen, C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10Aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group.
R is as defined above24Preferably hydrogen, C1-4Alkyl or C1-4A haloalkyl group.
R is as defined above25Preferably C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10Aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group.
R is as defined above26And the above R27Preferably, they may be the same or different and each represent hydrogen or C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C6-10Aryl, 5-to 10-membered heteroaryl, 3-to 10-membered heterocyclic group, C6-10Aryl radical C1-4Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl, cyano (C)1-3Alkyl group), C1-3Alkylsulfonyl radical C1-4An alkyl group, or a 3-to 10-membered alicyclic ring.
Or, the above R26And the above R27Preferably, they may form a 3-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group together with the nitrogen atom to which they are bonded.
R is as defined above28And the above R29Preferably, they may be the same or different and each represent hydrogen or C1-4Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-4Haloalkyl, C1-3Alkoxy radical C1-4Alkyl radical, C6-10Aryl, 5-to 10-membered heteroaryl, 3-to 10-membered heterocyclic group, C6-10Aryl radical C1-4Alkyl, 3-to 10-membered heterocyclic group C1-3Alkyl, 5-to 10-membered heteroaryl C1-3Alkyl, cyano (C)1-3Alkyl group), C1-3Alkylsulfonyl radical C1-4An alkyl group, or a 3-to 10-membered alicyclic ring.
Or, the above R28And the above R29Preferably, they may form a 3-to 10-membered heterocyclic group or a 5-to 10-membered hetero group together with the nitrogen atom to which they are bondedAnd (4) an aryl group.
R is as defined above30Preferably C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10Aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group.
R is as defined above31Is preferably C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Haloalkyl, C6-10Aryl, 5-to 10-membered heteroaryl or 3-to 10-membered heterocyclic group.
R is as defined above32Preferably C1-4Alkyl or C6-10And (4) an aryl group.
The substituent contained in the above group P is preferably halogen or C1-4Alkyl radical, C1-4Haloalkyl, -OH, C1-3Alkoxy radical, C1-3Haloalkoxy, 3-to 10-membered heterocyclylamino, -SO2R、-CN、-NO2Or 3-to 10-membered heterocyclic group, more preferably halogen, C1-4Haloalkyl, C1-3Alkoxy radical, C1-3A haloalkoxy group, or a 3-to 10-membered heterocyclic group. As the so-called 3 to 10-membered heterocyclic group herein, a morpholino group is particularly preferable.
The substituent contained in the above group Q is preferably halogen or C1-4Alkyl radical, C1-4Haloalkyl, -OH, C1-3Alkoxy radical, C1-6Monohydroxyalkyl group, C1-6Dihydroxyalkyl or C1-6Trihydroxyalkyl, 3-to 10-membered heterocyclylamino, -SO2R、-CN、-NO2、C3-7Cycloalkyl, -COR19Or can be C1-4An alkyl-substituted 3-to 10-membered heterocyclic group, more preferably halogen, C1-4Alkyl radical, C1-4Haloalkyl, -OH, C1-3Alkoxy radical, C1-6Monohydroxyalkyl, -SO2R16、C3-7Cycloalkyl, -COR19Or can be C1-4An alkyl-substituted 3-to 10-membered heterocyclic group. The 3-to 10-membered heterocyclic group is more preferably a piperazinyl group, a piperidyl group or a morpholinyl group.
Specific examples of the compound suitable for use in the present invention include the following compounds.
(1) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone (or [ 5-amino-1- (2-methyl-3H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone);
(2) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-pyrrolidin-1-ylmethyl-1H-indol-2-yl) -methanone;
(3) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-hydroxy-piperidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(5) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-piperazin-1-ylmethyl-1H-indol-2-yl) -methanone;
(6) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-morpholin-4-yl-ethoxy) -1H-indol-2-yl ] -methanone;
(7) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (tetrahydropyran-4-yloxy) -1H-indol-2-yl ] -methanone;
(8) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-chloro-1H-indol-2-yl) -methanone;
(9) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-bromo-1H-indol-2-yl) -methanone;
(10) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-iodo-1H-indol-2-yl) -methanone;
(11) 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indole-5-carbonitrile;
(12) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-bromo-5-fluoro-1H-indol-2-yl) -methanone;
(13) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-ethynyl-1H-indol-2-yl) -methanone;
(14) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-fluoro-phenyl) -1H-indol-2-yl ] -methanone;
(15) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-fluoro-phenyl) -1H-indol-2-yl ] -methanone;
(16) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-fluoro-phenyl) -1H-indol-2-yl ] -methanone;
(17) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-chloro-phenyl) -1H-indol-2-yl ] -methanone;
(18) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-chloro-phenyl) -1H-indol-2-yl ] -methanone;
(19) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-chloro-phenyl) -1H-indol-2-yl ] -methanone;
(20) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-trifluoromethyl-phenyl) -1H-indol-2-yl ] -methanone;
(21) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-trifluoromethyl-phenyl) -1H-indol-2-yl ] -methanone;
(22) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-trifluoromethyl-phenyl) -1H-indol-2-yl ] -methanone;
(23) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-bromo-1H-indol-2-yl) -methanone;
(24) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-fluoro-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(25) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-methyl-1H-indol-2-yl) -methanone;
(26) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (4, 4-difluoro-piperidine-1-carbonyl) -1H-indol-2-yl ] -methanone;
(27) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (3, 3-difluoro-piperidine-1-carbonyl) -1H-indol-2-yl ] -methanone;
(28) 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indole-5-carboxylic acid (2, 2, 2-trifluoro-ethyl) -amide;
(29) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (5-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(30) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (6-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(31) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (5-chloro-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(32) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-methyl-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(33) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-chloro-4-fluoro-phenyl) -1H-indol-2-yl ] -methanone;
(34) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(35) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-trifluoromethyl-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(36) [ 5-amino-1- (6-fluoro-2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(37) 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indole-6-carboxylic acid;
(38) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-hydroxymethyl-1H-indol-2-yl) -methanone;
(39) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - { 6- [ 2- (4-methyl-piperazin-1-yl) -ethoxy ] -1H-indol-2-yl } -methanone;
(40) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-methyl-oxetan-3-ylmethoxy) -1H-indol-2-yl ] -methanone;
(41) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-fluoro-piperidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(42) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6- { [ bis (2-methoxy-ethyl) -amino ] -methyl } -1H-indol-2-yl) -methanone;
(43) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - { 6- [ (methyl-prop-2-ynyl-amino) -methyl ] -1H-indol-2-yl } -methanone;
(44) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3, 3-difluoro-pyrrolidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(45) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2, 5-dimethyl-pyrrolidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(46) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3, 3-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(47) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- ((S) -3-methyl-morpholin-4-ylmethyl) -1H-indol-2-yl ] -methanone;
(48) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-bromo-1H-indol-2-yl) -methanone;
(49) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-iodo-1H-indol-2-yl) -methanone;
(51) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-bromo-6-trifluoromethyl-1H-indol-2-yl) -methanone;
(52) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-iodo-1H-indol-2-yl) -methanone;
(53) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-methyl-1H-indol-2-yl) -methanone;
(54) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-isopropyl-1H-indol-2-yl) -methanone;
(55) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (2-fluoro-phenyl) -1H-indol-2-yl ] -methanone;
(56) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-benzyl-1H-indol-2-yl) -methanone;
(57) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (2-trifluoromethyl-phenyl) -1H-indol-2-yl ] -methanone;
(58) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (3-fluoro-phenyl) -1H-indol-2-yl ] -methanone;
(59) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (3-trifluoromethyl-phenyl) -1H-indol-2-yl ] -methanone;
(60) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-ethynyl-1H-indol-2-yl) -methanone;
(61) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5H- [ 1, 3] dioxolo [ 4,5-f ] indol-6-yl) -methanone;
(62) [ 5-amino-1- (7-fluoro-2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(63) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (4-trifluoromethyl-phenyl) -1H-indol-2-yl ] -methanone;
(64) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-butoxy-1H-indol-2-yl) -methanone;
(65) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (1-methyl-piperidin-4-yl) -1H-indol-2-yl ] -methanone;
(66) n- { 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indol-6-yl } -methanesulfonamide;
(67) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (6-morpholin-4-yl-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(68) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-butyl-1H-indol-2-yl) -methanone;
(69) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (1-methyl-1H-pyrazol-4-yl) -1H-indol-2-yl ] -methanone;
(70) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (5-methoxy-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(71) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-methoxy-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(72) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-cyclopropyl-1H-indol-2-yl) -methanone;
(73) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-methoxy-phenyl) -1H-indol-2-yl ] -methanone;
(74) 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-phenyl-1H-indol-2-yl) -methanone;
(75) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (5-methanesulfonyl-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(76) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-isopropyl-1H-indol-2-yl) -methanone;
(77) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-pyridin-2-yl-1H-indol-2-yl) -methanone;
(78) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-cyclopropyl-1H-indol-2-yl) -methanone;
(79) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-pyridazin-3-yl-1H-indol-2-yl) -methanone;
(80) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-isopropoxy-1H-indol-2-yl) -methanone;
(81) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (2-methoxy-ethoxy) -1H-indol-2-yl ] -methanone;
(82) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-cyclopropylmethoxy-1H-indol-2-yl) -methanone;
(83) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (2, 2-difluoro-5H- [ 1, 3] dioxolo [ 4,5-f ] indol-6-yl) -methanone;
(84) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-chloro-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(85) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (5-fluoro-pyridin-2-yl) -1H-indol-2-yl ] -methanone;
(86) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (6-morpholin-4-yl-pyridazin-3-yl) -1H-indol-2-yl ] -methanone;
(87) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-chloro-6-cyclopropylmethoxy-1H-indol-2-yl) -methanone;
(88) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2, 4-difluoro-phenyl) -1H-indol-2-yl ] -methanone;
(89) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-pyridazin-4-yl-1H-indol-2-yl) -methanone;
(90) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (3-fluoro-1H-indol-2-yl) -methanone;
(91) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (1-isopropyl-piperidin-4-yl) -6-trifluoromethyl-1H-indol-2-yl ] -methanone;
(92) 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indole-6-carbonitrile;
(93) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (1, 2,3, 6-tetrahydro-pyridin-4-yl) -1H-indol-2-yl ] -methanone;
(94) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-piperidin-4-yl-1H-indol-2-yl) -methanone;
(95) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- ((R) -3-fluoro-pyrrolidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(96) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-fluoro-5-piperidin-4-yl-1H-indol-2-yl) -methanone;
(97) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6-fluoro-5- (1-methyl-piperidin-4-yl) -1H-indol-2-yl ] -methanone;
(98) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (1-isopropyl-piperidin-4-yl) -1H-indol-2-yl ] -methanone;
(99) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6-fluoro-5- (1-isopropyl-piperidin-4-yl) -1H-indol-2-yl ] -methanone;
(100) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-pyridin-3-yl-1H-indol-2-yl) -methanone;
(101) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (6-morpholin-4-yl-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(102) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-pyridin-3-yl-1H-indol-2-yl) -methanone;
(103) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (6-piperazin-1-yl-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(104) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (6-hydroxy-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(105) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6-fluoro-5- (4-methyl-piperazin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(106) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-fluoro-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl) -methanone;
(107) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (1-methyl-piperidin-4-yl) -1H-indol-2-yl ] -methanone;
(108) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-morpholin-4-yl-phenyl) -1H-indol-2-yl ] -methanone;
(109) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3, 4,5, 6-tetrahydro-2H- [ 1,2 '] bipyridinyl-5' -yl) -1H-indol-2-yl ] -methanone;
(110) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (6-piperazin-1-yl-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(111) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (6-methoxy-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(112) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- ((S) -3-methyl-morpholin-4-ylmethyl) -1H-indol-2-yl ] -methanone;
(113) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- ((R) -3-fluoro-pyrrolidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(114) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (2, 5-dimethyl-pyrrolidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(115) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (3-fluoro-piperidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(116) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (3, 3-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(117) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - { 6- [ 2- (4-methyl-piperazin-1-yl) -pyridin-4-yl ] -1H-indol-2-yl } -methanone;
(118) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-pyridin-4-yl-1H-indol-2-yl) -methanone;
(119) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (4-fluoro-piperidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(120) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (4, 4-difluoro-piperidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(121) [ 5-amino-1- (2-difluoromethyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (1-methyl-piperidin-4-yl) -1H-indol-2-yl ] -methanone;
(122) [ 5-amino-1- (2-difluoromethyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(123) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (3, 3-difluoro-pyrrolidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(124) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (1-cyclopentyl-piperidin-4-yl) -1H-indol-2-yl ] -methanone;
(125) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (1-cyclohexyl-piperidin-4-yl) -1H-indol-2-yl ] -methanone;
(132) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-morpholin-4-ylmethyl-1H-indol-2-yl) -methanone;
(133) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 4- (2-morpholin-4-yl-ethylamino) -1H-indol-2-yl ] -methanone;
(134) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (4-methyl-piperazine-1-carbonyl) -1H-indol-2-yl ] -methanone;
(135) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-morpholin-4-yl-ethylamino) -1H-indol-2-yl ] -methanone;
(136) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (piperazine-1-carbonyl) -1H-indol-2-yl ] -methanone;
(137) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 4- (2-methoxy-ethylamino) -1H-indol-2-yl ] -methanone;
(138) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 4- (2-hydroxy-1-hydroxymethyl-ethylamino) -1H-indol-2-yl ] -methanone;
(139) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 4- (2-pyridin-4-yl-ethylamino) -1H-indol-2-yl ] -methanone;
(140) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-methoxy-ethylamino) -1H-indol-2-yl ] -methanone;
(141) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-morpholin-4-yl-1H-indol-2-yl) -methanone;
(142) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-morpholin-4-yl-1H-indol-2-yl) -methanone;
(143) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-morpholin-4-ylmethyl-1H-indol-2-yl) -methanone;
(144) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-morpholin-4-ylmethyl-1H-indol-2-yl) -methanone;
(145) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (morpholine-4-carbonyl) -1H-indol-2-yl ] -methanone;
(146) [ 5-amino-1- (2-isopropyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(147) [ 5-amino-1- (2-propyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(148) [ 5-amino-1- (1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(149) [ 5-amino-1- (2-trifluoromethyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(150) [ 5-amino-1- (2-ethyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(151) [ 5-amino-1- (2-benzyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone;
(152) 1- (4- { 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indol-5-ylmethyl } -piperazin-1-yl) -ethanone;
(153) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (4-methanesulfonyl-piperazin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(154) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-piperazin-1-ylmethyl-1H-indol-2-yl) -methanone;
(155) 1- (4- { 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indol-6-ylmethyl } -piperazin-1-yl) -ethanone;
(156) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-methyl-piperazin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(157) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (4-methyl-piperazin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(158) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-pyrrolidin-1-ylmethyl-1H-indol-2-yl) -methanone;
(159) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-fluoro-1H-indol-2-yl) -methanone;
(160) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-fluoro-1H-indol-2-yl) -methanone;
(161) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-fluoro-1H-indol-2-yl) -methanone;
(163) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-fluoro-6-morpholin-4-ylmethyl-1H-indol-2-yl) -methanone;
(164) 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indole-5-carboxylic acid;
(165) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-methoxy-1H-indol-2-yl) -methanone;
(166) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4, 6-dimethoxy-1H-indol-2-yl) -methanone;
(167) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-methoxy-1H-indol-2-yl) -methanone;
(168) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-methoxy-1H-indol-2-yl) -methanone;
(169) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4, 6-dimethyl-1H-indol-2-yl) -methanone;
(170) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-tert-butyl-1H-indol-2-yl) -methanone;
(171) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-isopropyl-1H-indol-2-yl) -methanone;
(172) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-benzyloxy-1H-indol-2-yl) -methanone;
(173) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-benzyloxy-1H-indol-2-yl) -methanone;
(174) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5, 6-dimethoxy-1H-indol-2-yl) -methanone;
(175) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-tert-butyl-1H-indol-2-yl) -methanone;
(176) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-fluoro-4-trifluoromethyl-1H-indol-2-yl) -methanone;
(177) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-phenoxy-1H-indol-2-yl) -methanone;
(178) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-methylsulfanyl-1H-indol-2-yl) -methanone;
(179) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-tert-butyl-1H-indol-2-yl) -methanone;
(180) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-methyl-1H-indol-2-yl) -methanone;
(181) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-ethyl-1H-indol-2-yl) -methanone;
(182) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-fluoro-6-trifluoromethyl-1H-indol-2-yl) -methanone;
(183) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-fluoro-5-methoxy-1H-indol-2-yl) -methanone;
(184) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-chloro-5-methoxy-1H-indol-2-yl) -methanone;
(185) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-chloro-6-methoxy-1H-indol-2-yl) -methanone;
(186) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-isopropoxy-1H-indol-2-yl) -methanone;
(187) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-benzyloxy-1H-indol-2-yl) -methanone;
(188) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4-isopropoxy-1H-indol-2-yl) -methanone;
(189) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (2, 3-dihydro-6H- [ 1,4 ] dioxino [ 2,3-f ] indol-7-yl) -methanone;
(190) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4, 6-di-tert-butyl-1H-indol-2-yl) -methanone;
(191) 2- [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazole-4-carbonyl ] -1H-indole-4-carbonitrile;
(192) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-imidazol-1-yl-1H-indol-2-yl) -methanone;
(193) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-trifluoromethylsulfanyl-1H-indol-2-yl) -methanone;
(194) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-methylsulfanyl-1H-indol-2-yl) -methanone;
(195) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-methanesulfonyl-1H-indol-2-yl) -methanone;
(196) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4, 4-difluoro-piperidin-1-ylmethyl) 1H-indol-2-yl ] -methanone;
(197) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-fluoro-piperidin-1-ylmethyl) -1H-indol-2-yl ] -methanone;
(198) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (oxetan-3-yloxy) -1H-indol-2-yl ] -methanone;
(199) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-hydroxy-1H-indol-2-yl) -methanone;
(200) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-methanesulfonyl-1H-indol-2-yl) -methanone;
(204) [ 5-amino-1- (2-methyl-3H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-chloro-1H-indol-2-yl) -methanone;
(205) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-chloro-1H-indol-2-yl) -methanone;
(206) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-3-yl) -methanone;
(207) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-6-yl) -methanone;
(208) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-bromo-6-fluoro-1H-indol-2-yl) -methanone;
(209) [ 5-amino-1- (2-ethyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-bromo-6-fluoro-1H-indol-2-yl) -methanone;
(210) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-trifluoromethyl-1H-indol-2-yl) -methanone;
(211) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-trifluoromethoxy-1H-indol-2-yl) -methanone;
(212) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4, 6-dichloro-1H-indol-2-yl) -methanone;
(213) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-bromo-4-fluoro-1H-indol-2-yl) -methanone;
(214) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-trifluoromethoxy-1H-indol-2-yl) -methanone;
(215) [ 5-amino-1- (2-ethyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-trifluoromethoxy-1H-indol-2-yl) -methanone;
(216) [ 5-amino-1- (2-ethyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5-trifluoromethyl-1H-indol-2-yl) -methanone;
(217) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (5, 6-dichloro-1H-indol-2-yl) -methanone;
(218) [ 5-amino-1- (2-ethyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-bromo-5-fluoro-1H-indol-2-yl) -methanone;
(219) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4, 5-dichloro-1H-indol-2-yl) -methanone;
(220) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (4, 6-difluoro-1H-indol-2-yl) -methanone;
(221) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-chloro-pyridin-4-yl) -1H-indol-2-yl ] -methanone;
(222) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (6-methyl-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(223) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (5-fluoro-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(224) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-trifluoromethyl-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(225) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (5-chloro-2-methoxy-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(226) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (5-chloro-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(227) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-thiophen-3-yl-1H-indol-2-yl) -methanone;
(228) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (4-chloro-pyridin-3-yl) -1H-indol-2-yl ] -methanone;
(229) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - (6-thiophen-2-yl-1H-indol-2-yl) -methanone;
(230) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (3-fluoro-pyridin-4-yl) -1H-indol-2-yl ] -methanone;
(231) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [ 6- (2-trifluoromethyl-pyridin-4-yl) -1H-indol-2-yl ] -methanone;
(232) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (3, 3-difluoro-pyrrolidine-1-carbonyl) -1H-indol-2-yl ] -methanone;
(233) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (2, 6-dimethyl-morpholine-4-carbonyl) -1H-indol-2-yl ] -methanone;
(234) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- ([ 1,4 '] bipiperidinyl-1' -carbonyl) -1H-indol-2-yl ] -methanone;
(235) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - { 5- [ 4- (2, 2, 2-trifluoro-ethyl) -piperazine-1-carbonyl ] -1H-indol-2-yl } -methanone;
(236) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - { 5- [ 4- (2-hydroxy-ethyl) -piperazine-1-carbonyl ] -1H-indol-2-yl } -methanone;
(237) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- (3, 3,4, 4-tetrafluoro-pyrrolidine-1-carbonyl) -1H-indol-2-yl ] -methanone;
(238) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -1H-indol-2-yl ] -methanone;
(239) [ 5-amino-1- (2-methyl-1H-benzoimidazol-5-yl) -1H-pyrazol-4-yl ] - [5- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -1H-indol-2-yl ] -methanone;
among them, preferred is (1) [ 5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone; or a tautomer thereof.
As the compound, the following compounds or tautomers thereof are particularly preferable. (hereinafter, the following compound will be referred to as "Compound 1").
Such a compound suitable for use in the present invention is known as described in patent document 1 (WO 2011/16528), and can be prepared by the method described in patent document 1.
Among the compounds applicable in the present invention, various isomers (e.g., geometric isomers, asymmetric carbon-based optical isomers, rotamers, stereoisomers, tautomers, etc.) can be purified and separated by using a conventional separation method, such as recrystallization, diastereomer salt method, enzyme resolution method, various chromatographies (e.g., thin layer chromatography, column chromatography, high performance liquid chromatography, gas chromatography, etc.).
When the compound to be used in the present invention is obtained as a free form, the compound can be converted into a state of a salt or a hydrate thereof which the compound can form according to a conventional method. When the compound of the present invention is obtained as a salt or hydrate of the compound, the compound can be converted into a free form of the compound according to a conventional method.
As described in patent document 1 (WO 2011/16528), the compound suitable for use in the present invention is useful as a compound having an inhibitory activity on a Fibroblast Growth Factor Receptor (FGFR) family kinase, and is useful for the prevention and/or treatment of cancer (for example, breast cancer, acute myelogenous leukemia, pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer, angiogenesis, gastric cancer, uterine cancer, ovarian cancer, brain tumor (including glioblastoma), large intestine cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), thyroid cancer, and the like).
Alkyl sulfate salt
The "alkyl sulfate salt" in the present specification is alkyl-OSO2A salt of OH.
As the alkyl group, C is preferably mentioned10-14(straight chain) alkyl, more preferably C12An alkyl group.
The salt is preferably an inorganic base salt as defined above, and examples of the salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt, and examples of the organic base salt include diethylamine salt, diethanolamine salt, meglumine salt and N, N-dibenzylethylenediamine salt.
Among the salts, sodium salts are preferred.
The "alkyl sulfate" is more preferably lauryl sulfate, and particularly preferably sodium lauryl sulfate.
Since the pharmaceutical preparation according to the present invention contains an alkyl sulfate salt, when the compound represented by the formula (I), a tautomer thereof, or a salt thereof is formulated, gelation of the contained compound when the preparation is dissolved in water or the like can be prevented or suppressed, and the elution property can be improved.
In this case, the weight ratio of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof to the alkyl sulfate salt in the pharmaceutical preparation according to the present invention is preferably 1: 10-8: 1. more preferably 1: 2-8: 1. more preferably 1: 1-5: 1. more preferably 1: 1-3: 1. more preferably 2: 1.
in the pharmaceutical preparation according to the present invention, the weight ratio of compound 1 or its tautomer or its pharmaceutically acceptable salt (preferably malate) to sodium lauryl sulfate is preferably 1: 10-8: 1. more preferably 1: 2-8: 1. more preferably 1: 1-5: 1. more preferably 1: 1-3: 1. more preferably 2: 1.
therefore, the above-mentioned alkyl sulfate salt is extremely useful as an agent for preventing gelation of a pharmaceutical preparation containing the compound represented by the above formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, particularly a pharmaceutical solid preparation thereof.
Pharmaceutical preparation
The pharmaceutical preparation contains a compound shown in a general formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and an alkyl sulfate.
Such a pharmaceutical preparation is preferably a solid preparation, and the solid preparation can be formulated as a tablet, powder, fine granule, coated tablet, capsule, dry syrup, lozenge, suppository, or the like.
Among these, the pharmaceutical preparation according to the present invention is preferably formed into a capsule, tablet, granule or dry syrup, and more preferably formed into a capsule or tablet. These preparations may have any shape, size, hardness, etc. of the components and ranges generally used in the field of preparation, and the forms thereof are not particularly limited.
For example, capsules such as japanese pharmacopoeia capsules/No. 5 to No. 00/gelatin, which are generally used for capsule preparations, can be used.
In addition, as the tablet, a tablet in the form of 5 to 15mm in diameter, 3 to 5mm in thickness, 60N (Newton) to 100N in hardness, or the like, which is generally used as a tablet, can be used.
The compound suitable for use in the present invention contained in such a pharmaceutical preparation is preferably a particle. The average particle diameter of the particles is preferably 10 μm or less, more preferably 1 μm to 10 μm.
The pharmaceutical preparation according to the present invention contains the above-mentioned alkyl sulfate salt and the compound represented by the above general formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and may preferably further contain a disintegrant.
Examples of the disintegrant include croscarmellose sodium, carboxymethylcellulose calcium, crospovidone, sodium carboxymethyl starch, low-substitution hydroxypropyl cellulose, corn starch, and soybean polysaccharide.
Further, in the disintegrant of the present invention, the swelling ratio (swelling ratio) ((R))) Swelling disintegrants known as "super disintegrants" are up to 200%.
Examples of the super-disintegrant include croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, sodium carboxymethyl starch, and soybean polysaccharide, and preferably, croscarmellose sodium.
When the pharmaceutical preparation according to the present invention is a capsule, the weight ratio of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof to the alkyl sulfate salt is preferably 1: 10-8: 1. more preferably 1: 2-8: 1. more preferably 1: 1-5: 1. more preferably 1: 1-3: 1. more preferably 2: 1.
in addition, when the pharmaceutical preparation according to the present invention is a capsule, the weight ratio of the compound 1 or its tautomer or its pharmaceutically acceptable salt (preferably malate) to sodium lauryl sulfate is preferably 1: 10-8: 1. more preferably 1: 2-8: 1. more preferably 1: 1-5: 1. more preferably 1: 1-3: 1. more preferably 2: 1.
the alkyl sulfate to be added to the capsule of the present invention may be 0.5 to 10% by weight, preferably 1 to 5% by weight, and particularly preferably 4 to 5% by weight.
The sodium lauryl sulfate, which is a preferable alkyl sulfate to be added to the capsule of the present invention, may be 0.5 to 10% by weight, preferably 1 to 5% by weight, and particularly preferably 4 to 5% by weight.
In 1 capsule, the content ratio of the compound represented by the formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in terms of free bodies, relative to the total amount of the pharmaceutical preparation (excluding the weight of the capsule; hereinafter, the same applies to the total amount of the pharmaceutical preparation when the pharmaceutical preparation is a capsule in the present specification) is desirably 10% by weight or less, more preferably 0.1 to 10% by weight, still more preferably 0.5 to 10% by weight, and particularly preferably 0.5 to 8% by weight.
The content ratio of the compound 1 or its tautomer or its pharmaceutically acceptable salt (preferably malate) in terms of free form to the total amount of the pharmaceutical preparation (excluding the weight of the capsule; hereinafter, the same applies to the total amount of the pharmaceutical preparation when the pharmaceutical preparation is a capsule in the present specification) is desirably 10% by weight or less, more preferably 0.1 to 10% by weight, even more preferably 0.5 to 10% by weight, and particularly preferably 0.5 to 8% by weight.
When the pharmaceutical preparation according to the present invention is a capsule, the content of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof in terms of free bodies relative to the total amount of the capsule is preferably 1 to 500mg, more preferably 10 to 200mg, and still more preferably 20 to 100mg per 1 capsule.
In addition, when the pharmaceutical preparation according to the present invention is a capsule, the content of the compound 1 or its tautomer or its pharmaceutically acceptable salt (preferably malate) in terms of free bodies relative to the total amount of capsules is preferably 1 to 500mg, more preferably 10 to 200mg, and still more preferably 20 to 100mg per 1 capsule.
In such a capsule, when the amount of the compound represented by the formula (I), a tautomer thereof, or a pharmaceutically acceptable salt thereof is 20mg or more in terms of free form, the concentration thereof is particularly preferably 10% by weight or less.
In addition, when the amount of compound 1, a tautomer thereof, or a pharmaceutically acceptable salt thereof (preferably malate salt) is 20mg or more in terms of free body, the concentration is particularly preferably 10% by weight or less.
The super-disintegrant such as croscarmellose sodium added to the capsule of the present invention may be 1 to 10 wt%, preferably 2 to 8 wt%, and particularly preferably 4 to 6 wt%, based on the total weight of the capsule.
In the capsule formulation, when the content ratio of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof is in such a range, gelation of the compound during administration can be suppressed, and excellent elution properties can be exhibited.
When the pharmaceutical preparation according to the present invention is a tablet, the content of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof in terms of free bodies relative to the total amount of the tablet is preferably 1 to 500mg, more preferably 10 to 200mg, and still more preferably 50 to 100mg per 1 tablet.
In addition, when the pharmaceutical preparation according to the present invention is a tablet, the content of the compound 1 or its tautomer or its pharmaceutically acceptable salt (preferably malate) in terms of free bodies relative to the total amount of the tablet is preferably 1 to 500mg, more preferably 10 to 200mg, and still more preferably 50 to 100mg per 1 tablet.
In the pharmaceutical preparation according to the present invention, when the content of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof is a high content ratio in the preparation, for example, 10% by weight or more in terms of free form relative to the total amount of the pharmaceutical preparation, the pharmaceutical preparation is preferably a tablet.
When the pharmaceutical preparation according to the present invention is a tablet, the content of the compound 1 or its tautomer or its pharmaceutically acceptable salt (preferably malate) is high in the preparation, and when the content is 10 wt% or more based on the total amount of the pharmaceutical preparation in terms of free form, for example, the pharmaceutical preparation is preferably a tablet.
When the total amount of the compounds to be used in the present invention is 10% by weight or more, the pharmaceutical preparation can be improved in disintegration property and dissolution property as compared with a capsule when the pharmaceutical preparation is a tablet.
The content of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof in the tablet is preferably 1 to 50% by weight, and more preferably 1 to 40% by weight, in terms of free bodies, per 1 tablet, relative to the total amount of the tablet.
The content of the compound 1, a tautomer thereof, or a pharmaceutically acceptable salt thereof (preferably malate salt) in the tablet is preferably 1 to 50 wt%, more preferably 1 to 40 wt%, in terms of free bodies, per 1 tablet, relative to the total amount of the tablet.
When the pharmaceutical preparation is a tablet, the weight ratio of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof to the alkyl sulfate salt is preferably 1: 10-8: 1. more preferably 1: 2-8: 1. more preferably 1: 1-5: 1. more preferably 1: 1-3: 1. more preferably 2: 1.
in addition, when the pharmaceutical preparation is a tablet, the weight ratio of the compound 1 or its tautomer or its pharmaceutically acceptable salt (preferably malate) to sodium lauryl sulfate is preferably 1: 10-8: 1. more preferably 1: 2-8: 1. more preferably 1: 1-5: 1. more preferably 1: 1-3: 1. more preferably 2: 1.
the alkyl sulfate to be added to the tablet of the present invention may be 4 to 40% by weight, preferably 5 to 20% by weight, and particularly preferably 10 to 20% by weight.
The sodium lauryl sulfate, which is a preferable alkyl sulfate to be added to the tablet of the present invention, may be 4 to 40% by weight, preferably 5 to 20% by weight, and particularly preferably 10 to 20% by weight.
When a disintegrant is added in the present invention, the use of a super disintegrant instead of a usual disintegrant is particularly preferable in view of the improvement of the disintegration property and the further improvement of the dissolution property of a pharmaceutical preparation, in comparison with the case of a capsule.
The super-disintegrant such as croscarmellose sodium added to the tablet of the present invention may be 1 to 10% by weight, preferably 2 to 8% by weight, and particularly preferably 4 to 6% by weight, based on the total weight of the tablet.
The pharmaceutical preparation according to the present invention may contain, in addition to the above components, as a carrier generally used, for example, an excipient, a binder, a lubricant, a coloring agent, a flavoring agent, and an additive containing a stabilizer, an emulsifier, an absorption enhancer, a surfactant, a pH adjuster, a preservative, an antioxidant, and the like as necessary. These substances can be formulated into preparations by blending components generally used as raw materials for pharmaceutical preparations.
The content of the carrier in the pharmaceutical preparation according to the present invention may be the balance obtained by subtracting the total content of the compound, the alkyl sulfate salt and the disintegrant which may be contained in the pharmaceutical preparation according to the present invention from the total amount of the pharmaceutical preparation.
For example, the content of the carrier varies depending on the form of the preparation, and in the case of a capsule, the content is 0.1 to 99.4% by weight relative to the total amount of the capsule, and in the case of a disintegrant, the content is preferably 0.1 to 98.4% by weight.
In the case of a tablet, the content ratio of the super disintegrant to the total amount of the tablet is preferably 0.1 to 95% by weight per 1 tablet, and in the case of a tablet containing the super disintegrant, 0.1 to 94% by weight.
For example, in the case of producing an oral preparation, the compound of the present invention or a pharmacologically acceptable salt thereof or an alkyl sulfate salt is added, if necessary, a disintegrant and a carrier, for example, an excipient, and if necessary, a binder, a lubricant, a coloring agent, a taste-modifying agent, and the like are added, and then the mixture is formed into a powder, a fine granule, a tablet, a coated tablet, a capsule, and the like by a conventional method.
Examples of such components include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetearyl alcohol and behenyl alcohol; a silicone resin; a silicone oil; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oils, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate, and purified water.
Examples of the excipient include lactose, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide.
Examples of the binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth gum, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol, polyoxyethylene, and meglumine.
Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, and the like.
The colorant can be added into the medicine, and the flavoring agent can be cocoa powder, menthol, aromatic powder, oleum Menthae Dementholatum, Borneolum Syntheticum, cortex Cinnamomi Japonici powder, etc.
Of course, these tablets/granules may be sugar-coated, and other suitable coatings may be applied as necessary. In addition, in the case of producing a liquid preparation such as syrup, an injection preparation, or the like, a pH adjuster, a dissolving agent, an isotonic agent, or the like, and if necessary, a dissolution aid, a stabilizer, or the like are added to the compound of the present invention or a pharmacologically acceptable salt thereof to form a preparation.
The dose of the pharmaceutical preparation according to the present invention can be appropriately selected depending on the degree of symptoms, age, sex, body weight, administration method/type of salt, specific type of disease, and the like.
The dose varies significantly depending on the type of disease, the degree of symptoms of the patient, the age, sex, sensitivity to drugs, and the like of the patient, but generally about 0.03 to 1000mg, preferably 0.1 to 500mg, and more preferably 0.1 to 100mg is administered to an adult in an administration form of 1 to several times per 1 day.
Method for producing pharmaceutical preparation
The process for producing a pharmaceutical preparation according to the present invention comprises the steps of providing a mixture containing an alkyl sulfate salt and the above-mentioned compound suitable for use in the present invention;
granulating the mixture without adding water to the mixture or adding purified water to the mixture in an amount of 25 wt% or less based on the total weight of the mixture; and
and a step of drying the granulated mixture to provide a dry powder.
The compound to be used in the present invention is preferably supplied to the mixture in a state of being formed into particles in advance.
The particles of the compound can be prepared by a conventional method, and for example, the particles can be obtained by a method such as high-pressure jet pulverization like a jet mill.
In the step of supplying the mixture, the mixture containing the alkyl sulfate salt and the compound suitable for use in the present invention is more preferably obtained by charging each component of the alkyl sulfate salt and the compound suitable for use in the present invention, and if necessary, the above-mentioned components generally used as a raw material of a drug, into a known stirring mixing granulator or the like and mixing them.
The mixing temperature and mixing time are not particularly limited as long as they are within a range that does not adversely affect the components, and are, for example, preferably 0 to 50 ℃ and preferably about 5 to 15 minutes.
In the step of granulating the mixture, there are a method of granulating the mixture obtained without adding water, and a method of granulating the mixture by adding purified water to the mixture in an amount of 25 wt% or less based on the total weight of the mixture.
As a method for granulating the mixture without adding water, for example, a dry granulation method can be cited. The dry granulation method is a granulation method in which a large stress (pressure) is applied to the obtained mixture and granulation is performed without adding water. A typical example of the dry granulation method is a method of granulating a mixed powder by compression molding using a roller mill (ローラーコンパクター). The compression molding pressure at this time is preferably 5 to 9kN/cm, more preferably 6 to 8 kN/cm.
As a method of adding water to granulate the mixture, for example, a wet granulation method can be cited. The wet granulation method is a method of adding purified water to the obtained mixture while stirring, and granulating the mixture.
The purified water is desirably added in a proportion of 25 wt% or less, preferably 15 to 25 wt%, more preferably 18 to 23 wt%, and further preferably 20 to 22 wt% with respect to the total weight of the mixture.
It is generally known that if the stress is increased, a small amount of water is required, and if the stress is small, a large amount of water is required, and therefore the amount of water is not limited.
The temperature and time in the granulation step are not particularly limited depending on the stirring conditions and the like, and are preferably, for example, about 0 to 50 ℃, and more preferably about 3 to 5 minutes, within a range not adversely affecting the components.
In the step of providing the dry powder, the granulated mixture is dried by a conventional method such as vacuum drying, and a dry powder can be obtained.
The drying temperature and drying time are not particularly limited as long as they are within a range that does not adversely affect the components, and are, for example, preferably 50 to 80 ℃ and preferably about 30 minutes to 2 hours.
The method for producing a pharmaceutical preparation according to the present invention may further comprise the following steps.
Granulating the dried powder to provide a granulated powder;
mixing the whole granule powder with an additive containing magnesium stearate to provide a blended powder; and
and tabletting the blended powder to form a pharmaceutical preparation in the form of tablets.
In the step of granulating the dried powder to provide the granulated powder, the granulating method is not particularly limited, and the granulation can be performed by a conventional method using a sieve, a granulator, or the like.
The obtained whole-grain powder may be mixed with additional additives such as magnesium stearate, talc, and stearic acid, if necessary, to obtain a blended powder.
The mixing temperature and time are not particularly limited as long as they are within a range that does not adversely affect the components, and are, for example, preferably 0 to 50 ℃ and preferably about 3 to 5 minutes.
The above blended powder can be filled into capsules to form capsules.
Further, the blended powder is tableted by a conventional method to obtain a tablet.
All prior art documents cited in this specification are incorporated herein by reference.
Examples
The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to these. All starting materials and reagents were obtained from commercial suppliers or synthesized using well-known methods.
The capsules used in the following examples are those generally used in capsule preparations (japanese medicine capsule, No. 2, gelatin).
In addition, the tablets were prepared in a form generally used as tablets (diameter 9mm, thickness 3.5mm to 4.5mm, hardness 60N (Newton) to 100N).
1. Production of Compound 1
A malate salt of compound 1 (hereinafter referred to as [ 5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone) was prepared according to the method described in example 1A and the like described in publicly known International publication No. 2011/16528.
Example 1A
Synthesis of [ 5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone L-malate salt
[ 5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone hydrate (190 g, 0.507 mol) and L-malic acid (68 g, 0.507 mol) were weighed, dissolved in dimethyl sulfoxide (0.418L, 2.2 v/w) and acetone (0.418L, 2.2 v/w), and then filtered using a Tung mountain funnel (Tung mountain ロート) (No 4 filter paper), and added to a 10L separable flask equipped with a cannula, and then the reaction solution was dissolved at 50 ℃.
L-malic acid (544.4 g, 4.06 mol) was weighed, dissolved in acetone (1.25L, 6.6 v/w) and acetic acid (0.418L, 2.2 v/w), filtered through a Kiriya funnel (No 4 filter paper), and introduced into a 10L separable flask with a cannula so that the internal temperature was not lower than 45 degrees, and seed crystals (0.95 g, 0.5%) were suspended in acetone (7.5 mL) and introduced into a 10L separable flask with a cannula.
After 7 hours, the suspension was cooled to 25 degrees, the crystals were filtered using a Kiriya funnel, and after washing the crystals 2 times with acetone (0.85L, 5 v/w), the resulting wet powder was added to a 10L removable flask with a cannula. Acetone (2.85L, 15 v/w) was added, the suspension was stirred at 50 ℃ for 3 hours, and after the crystals were filtered using a Kiriya funnel, the crystals were washed 2 times with acetone (0.85L, 5 v/w). The wet powder was dried under reduced pressure at 40 degrees external temperature for 3 hours to give [ 5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl ] - (1H-indol-2-yl) -methanone L-malate salt (556.9 g, 73%).
2. Usefulness of Sodium Lauryl Sulfate (SLS) in comparison to other surfactants
(production of pharmaceutical preparation)
Each component described in table 1 (except magnesium stearate) was put into a mortar and premixed. To the mixture was added purified water in an amount corresponding to 20% by weight (based on the ratio of the mixture), and the mixture was granulated with stirring and then dried to obtain a dry powder.
The dried powder was granulated with a sieve, and the obtained granulated powder and magnesium stearate were mixed in a mortar to obtain a blended powder.
The blended powder is filled into capsules to produce capsules.
(formulation evaluation)
For example 1 and comparative examples 1 to 5, the dissolution test solution 1 of the japanese pharmacopoeia was used, and the disintegration property in the dissolution test apparatus was visually observed. The results are shown in Table 2. The dissolution property of a preparation (capsule, tablet, etc.) contributes to the evaluation of the content of the preparation, that is, the absorbability of a drug. In addition, since the preparation disintegrates and dissolves in an aqueous solution, the evaluation of the disintegration property is a simple evaluation of the dissolution property.
(Effect of surfactant)
The surfactant concentration was adjusted to 5% using the surfactant shown in Table 3 and the Japanese pharmacopoeia dissolution test solution 1. Compound 1 malate salt was added thereto thoroughly and stirred, and the solubility after 24 hours was measured.
Although the surfactant increased the solubility of compound 1, polysorbate 80 and polyoxyethylene (10) octylphenyl ether, which increased the solubility of compound 1 to the same extent as or greater than sodium lauryl sulfate, did not improve disintegration.
Therefore, it is suggested that the increase in solubility by the surfactant does not promote the disintegration.
3. Confirmation of elution Property of Compound 1
The disintegration of the preparation was confirmed as described above, and the dissolution property was confirmed.
As shown in table 4, capsules containing 1mg, 5mg, 10mg, and 20mg of compound 1 (hereinafter referred to as "1 mg preparation and 20mg preparation") were produced and confirmed by an elution test. The 1-10 mg preparation had no problem and the release of the ingredient was immediate, but the 20mg preparation was considered to have a delayed dissolution.
This is presumably because, although the capsule is disintegrated, the particles of compound 1 dispersed in the test solution are larger in the 20mg preparation than in the 1 to 10mg preparation. That is, this is because the concentration of compound 1 is high for a 20mg preparation, and therefore, the binding between particles cannot be sufficiently broken.
Therefore, in the case of a 20mg preparation, by further adding crystalline cellulose as an excipient (not added later) in an additional manner, the binding between the drug particles is prevented, and thereby the dissolution can be improved.
(preparation of preparation)
Examples 2 to 4 and 6
The components shown in table 4 (except for magnesium stearate) were put into a high-speed mixer-granulator and premixed. To the mixture was added purified water in an amount corresponding to 22% by weight (based on the ratio of the mixture), and the mixture was granulated with stirring and then dried under vacuum to obtain a dry powder. The dried powder was granulated by a granulator, and the obtained granulated powder and magnesium stearate were mixed by a mixer to obtain a blended powder. The blended powder is filled into capsules to produce capsules.
Example 5
Each of the components shown in Table 4 (except for crystalline cellulose (added (or not added)) and magnesium stearate) was put into a high-speed stirring mixer-granulator and premixed. Purified water was added to the mixture in an amount corresponding to 23 wt% (based on the mixture ratio), and the mixture was granulated by stirring and then dried under vacuum to obtain a dry powder. The dried powder was granulated by a granulator, and the obtained granulated powder, crystalline cellulose (added) and magnesium stearate were mixed by a mixer to obtain a blended powder. The blended powder is filled into capsules to produce capsules.
(formulation evaluation)
In examples 2 to 5 and 6, 900mL of the Japanese pharmacopoeia dissolution test solution 1 containing 1% of polyoxyethylene (10) octylphenyl ether was used as a test solution, and dissolution curves when the test was performed at 75 rpm by the Japanese pharmacopoeia dissolution test paddle method are shown in FIGS. 1 and 2.
As shown in FIG. 1, examples 2,3 and 4 are capsule preparations each containing 1mg, 5mg and 10mg, and show immediate-release preparations. As shown in fig. 2, when a capsule preparation of 20mg was produced in the same manner, the dissolution tended to decrease as in example 6. As in example 5, by adding crystalline cellulose in an external manner (without adding it later), a preparation with immediate release properties can be formed.
4. Dissolution and tableting of Compound 1 at high concentration
In order to prepare capsules in an amount of 20mg or more, the concentration of the drug substance is generally increased or the capsules are enlarged. However, as shown in examples 5 and 6, it was difficult to increase the concentration of the drug substance, and it was difficult to swallow a large capsule, and thus it was not acceptable in the market. Therefore, other dosage forms are preferred when developing formulations with a content higher than 20 mg.
The reason why the dissolution failure of the high content capsule occurs is due to the disintegration failure. That is, the disintegrant does not act effectively, and the preparation cannot be disintegrated sufficiently. In general, disintegrants are classified into a capillary (wetting with water, breaking the bonding force between particles) system and a Swelling (Swelling) system (absorbing water, Swelling, breaking the bonding between particles). The poor disintegration of compound 1 is caused by adsorption of moisture between particles, and is considered to be a high effect of the swelling-type disintegrant.
On the other hand, the swelling type disintegrating agent is required to swell sufficiently and break the bond between particles. Super disintegrants such as croscarmellose sodium are disintegrants having a swelling ratio of more than 200%. According to the studies of the present inventors, it was found that even when such a disintegrant is used, it is difficult to disintegrate a capsule containing 20mg or more per 1 capsule in the case of compound 1.
The inventors of the present application have clarified that the reason is voids generated when the capsule is filled with the powder. That is, this is because the swollen disintegrant escapes into the voids, and disperses the force that breaks the bonding between particles.
Therefore, in order to eliminate the voids, tableting was attempted. As described below, by using a disintegrant having a high swelling ratio and a formulation in which voids are eliminated, excellent disintegration properties and dissolution properties can be obtained even for a high-content formulation.
(preparation of preparation)
Examples 7 and 8 and reference examples 1 and 2
The components shown in table 5 (except for magnesium stearate) were put into a mortar and premixed. To the mixture was added purified water in an amount corresponding to 20% by weight (based on the ratio of the mixture), and the mixture was granulated with stirring and then dried to obtain a dry powder. The dried powder was granulated with a sieve, and the obtained granulated powder and magnesium stearate were mixed in a mortar to obtain a blended powder. Examples 7 and 8 are examples in which the blended powder is tableted to form a tablet, and examples 1 and 2 are examples in which the blended powder is filled into a capsule to form a capsule.
(formulation evaluation)
For examples 7 and 8 and reference examples 1 and 2, the japanese pharmacopoeia dissolution test solution 1 was used, and the disintegration property in the dissolution tester was visually observed. The results are shown in Table 6.
Further, since a disintegrated preparation was obtained by forming a tablet as described above, a tablet was produced by a machine as shown in examples 9 and 10 below, and the dissolution property was confirmed. In consideration of convenience, tablets having a main drug content of 50mg and 100mg were prepared by adding 1.25 times the amount of the powder.
(preparation of preparation)
Examples 9 and 10
The respective components (except for magnesium stearate) shown in table 7 were charged into a high-speed stirring mixer-granulator and premixed. To the mixture, purified water corresponding to 20 wt% (ratio to the mixture) was added for example 9, and purified water corresponding to 18 wt% was added for example 10, and the mixture was stirred, granulated, and vacuum-dried to obtain a dry powder. The dried powder was granulated by a granulator, and the obtained granulated powder was mixed with magnesium stearate by a mixer to obtain a blended powder. Examples of tablets formed by tableting the blended powder are shown in examples 9 and 10.
(formulation evaluation)
For examples 9 and 10, 900mL of the Japanese Kokai dissolution test solution 1 containing 1% polyoxyethylene (10) octylphenyl ether was used as a test solution, and the test was carried out by the Japanese Kokai dissolution test paddle method at 75 rotations per minute, and the dissolution curve at the time of carrying out the test is shown in FIG. 3.
5. Evaluation on combination of SLS and super disintegrant for Compound 1
The combination of SLS with a super disintegrant is highly suitable, as may also be suggested by the comparative examples below.
As is clear from examples 7 and 8, and 9 and 10, when SLS was used, even a high-content preparation of 50 to 100mg of compound 1 was disintegrated by tableting. On the other hand, as shown in comparative examples 6 and 7 below, when tablets were prepared using another surfactant instead of SLS, the tablets did not disintegrate within 60 minutes even in the presence of a super disintegrant and even at a low content of compound 1 of 20 mg. This shows the superiority of not only the addition of SLS but also the combination of SLS with a super disintegrant for a pharmaceutical preparation containing compound 1.
(preparation of preparation)
Each component described in table 8 (except magnesium stearate) was put into a mortar and premixed. To the mixture was added purified water in an amount corresponding to 20% by weight (based on the ratio of the mixture), and the mixture was granulated with stirring and then dried to obtain a dry powder. The dried powder was granulated with a sieve, and the obtained granulated powder and magnesium stearate were mixed in a mortar to obtain a blended powder.
The blended powder is tabletted to prepare tablets.
(formulation evaluation)
For comparative examples 6 and 7, the disintegration property in the dissolution tester was visually observed using the japanese pharmacopoeia dissolution test solution No. 1. The results are shown in Table 9.
6. Manufacturing method
In the preparation of compound 1, which is a poorly soluble drug, attempts have been made to improve the dissolution property by optimizing the granulation method, but in the case of general granulation, disintegration does not occur. As described above, by adding SLS, the disintegration property is improved.
(preparation of preparation)
Examples 11 to 14
The respective components (except for magnesium stearate) shown in table 10 were charged into a high-speed stirring mixer-granulator and premixed. Purified water (ratio to the mixture) was added to the mixture in the weight ratio shown in table 10, and the mixture was granulated with stirring and then vacuum-dried to obtain a dry powder. The dried powder was granulated by a granulator, and the obtained granulated powder and magnesium stearate were mixed by a mixer to obtain a blended powder. Tabletting the mixed powder to obtain tablet.
(formulation evaluation)
In examples 9 and 11 to 14, the disintegration property in the dissolution test apparatus was visually observed using the Japanese pharmacopoeia dissolution test solution No. 1. The results are shown in Table 11.
From the above results, it is found that the proportion of purified water to the mixture is preferably 25% by weight or less.
Industrial applicability
The pharmaceutical preparation of the present invention contains an alkyl sulfate salt, and therefore, the compound particles are not gelled and have excellent elution properties, and therefore, the pharmaceutical preparation is extremely useful as a pharmaceutical preparation.

Claims (19)

1. Pharmaceutical preparation containing C10-14An alkyl sulfate, a disintegrant, and a compound represented by the following general formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
in the formula, R1And R2Is hydrogen, R3Is C1-4Alkyl, and R4Is hydrogen.
2. The pharmaceutical formulation of claim 1, wherein the compound of formula (I) is the following:
a compound shown or a tautomer thereof.
3. The pharmaceutical preparation according to any one of claims 1 to 2, wherein the alkyl sulfate salt is dodecyl sulfate.
4. The pharmaceutical preparation according to any one of claims 1 to 2, wherein the pharmaceutical preparation is a solid preparation.
5. The pharmaceutical preparation according to claim 4, wherein the solid preparation is a capsule, a tablet, a powder, a granule, or a dry syrup.
6. The pharmaceutical preparation according to any one of claims 1 to 2, wherein the compound represented by the general formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof is particles having an average particle diameter of 10 μm or less.
7. The pharmaceutical formulation according to any one of claims 1 to 2, wherein the disintegrant is a super disintegrant.
8. The pharmaceutical preparation according to any one of claims 1 to 2, wherein the disintegrant is at least 1 selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, corn starch, and soybean polysaccharide.
9. The pharmaceutical preparation according to any one of claims 1 to 2, wherein the pharmaceutical preparation is a capsule, and 1 capsule contains the compound represented by the formula (I), a tautomer thereof, or a pharmaceutically acceptable salt thereof in an amount of 10% by weight or less in terms of free bodies relative to the total amount of the pharmaceutical preparation excluding the weight of the capsule.
10. The pharmaceutical preparation according to claim 9, wherein the 1 capsule contains 20mg or more of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof in a total amount in terms of free bodies.
11. The pharmaceutical preparation according to any one of claims 1 to 2, wherein the pharmaceutical preparation is a capsule, and crystalline cellulose is added as an external additive.
12. The pharmaceutical preparation according to any one of claims 1 to 2, wherein the pharmaceutical preparation is a tablet.
13. The pharmaceutical formulation of claim 12, comprising:
the compound comprises the compound shown in the specification or a tautomer thereof or a pharmaceutically acceptable salt thereof, sodium dodecyl sulfate and a super disintegrant.
14. The pharmaceutical preparation according to claim 12, wherein the tablet contains 1 to 50% by weight of the compound represented by the formula (I), a tautomer thereof, or a pharmaceutically acceptable salt thereof, in terms of free bodies, relative to the total amount of the tablet.
15. The pharmaceutical preparation according to claim 12, wherein the compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, and C10-14The weight ratio of the alkyl sulfate is 1: 10-8: 1 in terms of free form of the compound represented by the formula (I) or the tautomer thereof or the pharmaceutically acceptable salt thereof.
16. The pharmaceutical preparation according to claim 12, wherein the content (by weight) of the compound represented by the formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof is 1 to 500mg in terms of free body.
17. A process for producing a solid pharmaceutical preparation comprising the pharmaceutical preparation according to claim 1, which comprises
Providing a catalyst containing C10-14A step of mixing an alkyl sulfate, a disintegrant, and a compound represented by the general formula (I) described in claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof;
a step of adding purified water to the mixture in a proportion of 25 wt% or less with respect to the total weight of the mixture without adding water to the mixture, and granulating the mixture; and
and a step of drying the granulated mixture to provide a dry powder.
18. The production method according to claim 17, further comprising a step of granulating the dried powder to provide a granulated powder;
mixing the whole granule powder with an additive containing magnesium stearate to provide a blended powder; and
a step of tableting the blended powder to form a pharmaceutical preparation of the tablet according to any one of claims 12 to 16.
19.C10-14Alkyl sulfates as compounds containing the formula (I) according to claim 1Or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a gelation inhibitor for a solid pharmaceutical preparation.
HK16108800.5A 2013-07-31 2014-07-31 Pharmaceutical preparation comprising aminopyrazole derivative HK1220633B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2013159521 2013-07-31
JP2013-159521 2013-07-31
PCT/JP2014/070154 WO2015016295A1 (en) 2013-07-31 2014-07-31 Pharmaceutical preparation comprising aminopyrazole derivative

Publications (2)

Publication Number Publication Date
HK1220633A1 HK1220633A1 (en) 2017-05-12
HK1220633B true HK1220633B (en) 2019-02-01

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