WO2011016472A1

WO2011016472A1 - Pyridine and pyrimidine derivatives having ttk-inhibiting activity

Info

Publication number: WO2011016472A1
Application number: PCT/JP2010/063153
Authority: WO
Inventors: 兼一日下部; 奈緒子山口; 恭典三岡
Original assignee: オンコセラピー・サイエンス株式会社
Priority date: 2009-08-06
Filing date: 2010-08-04
Publication date: 2011-02-10
Also published as: TW201109331A; JP2012197231A

Abstract

Disclosed are: an effective inhibitor of TTK protein kinase; and an effective medicinal agent. Specifically disclosed are: a compound; and inventions relating to the compound (e.g., a pharmaceutical composition, a TTK inhibitor, and others). Novel compounds are discovered, each of which can inhibit the activity of TTK kinase and has specific properties particularly useful for the formulation of a medicinal agent that can treat the diseases. Therefore, the compounds are useful for diseases for which the inhibition of the activity of TTK kinase is believed to be effective.

Description

Pyridine and pyrimidine derivatives having TTK inhibitory action

The present invention relates to pyridine and pyrimidine derivatives having an inhibitory / suppressing action on TTK (TTK protein kinase) activity. In another aspect, the present invention relates to a medicament comprising this pyridine and pyrimidine derivative.

Protein kinases are enzymes that add (phosphorylate) phosphate groups to other protein molecules. Protein kinases have an activity of transferring a phosphate group from ATP to a hydroxyl group at an amino acid residue in a protein molecule to covalently bond it. Many protein kinases react with hydroxyl groups of serine and threonine in protein molecules (serine / threonine kinase), react with hydroxyl groups of tyrosine (tyrosine kinase), react with all three types (dual specificity) Kinase). The activity of protein kinases is precisely regulated, and protein kinases themselves may be regulated by phosphorylation. These modulations are caused by binding of other activating (or suppressing) proteins and low molecular weight compounds, localization changes in cells, and the like. Kinase dysfunction often causes illness.

TTK protein kinase is a bispecific kinase that phosphorylates serine, threonine and tyrosine residues in a protein serving as a substrate (see, for example, Non-Patent Document 1). Kinase domains required for expressing kinase activity are known (see, for example, Non-Patent Documents 1 and 2). As endogenous substrates, Mad1 (for example, see Non-Patent Document 3), Spcl10p (Nuflp) (for example, Non-Patent Document 4), CHK2 (for example, Non-Patent Document 5), Borealin (for example, Non-Patent Document 6) For example). TTK expression correlates with cell proliferation and plays a role in cell cycle control. Patent Document 1 describes that TTK is expressed in malignant ovarian cancer and a screening method including a step of measuring the expression level of TTK. Patent Document 2 discloses an application relating to a method for identifying cancer cells by detecting TTK activity and a method for identifying a drug that suppresses tumor growth, and TTK using tau, cdc25, and their partial peptides as a substrate as a screening method. An activity measurement method is described. Patent Document 3 describes a method for measuring TTK activity using a partial peptide of p38MAPK as a substrate as a method for cleaning TTK activity. Examples of the TTK inhibitor include those described in Patent Documents 4 and 5.

Examples of pyridine and pyrimidine derivatives include those described in Patent Documents 6 to 59 and Non-Patent Documents 7 to 20, but none are known as TTK inhibitors, and Patent Document 60 discloses TTK inhibitory activity. Is not described.

International Publication No. 01/94629 Pamphlet International Publication No. 02/068444 Pamphlet JP 2007-104911 A International Publication No. 2009/024824 Pamphlet International Publication No. 2009/032694 Pamphlet International Publication No. 2009/073575 Pamphlet International Publication No. 2008/129255 Pamphlet International Publication No. 2008/054292 Pamphlet International Publication No. 2008/053812 Pamphlet International Publication No. 2006/118231 Pamphlet International Publication No. 2006/087538 Pamphlet International Publication No. 2006/083392 Pamphlet International Publication No. 2006/117560 Pamphlet International Publication No. 2009/007029 Pamphlet International Publication No. 2008/156726 Pamphlet International Publication No. 2007/109355 Pamphlet International Publication No. 2006/081388 Pamphlet International Publication No. 2006/0776646 Pamphlet International Publication No. 2006/042289 Pamphlet International Publication No. 2007/077005 Pamphlet International Publication No. 2003/080564 Pamphlet German Patent Invention Application No. 3111937 British Patent No. 1405308 International Publication No. 98/28257 Pamphlet International Publication No. 94/15936 Pamphlet International Publication No. 98/37150 Pamphlet International Publication No. 95/07318 Pamphlet International Publication No. 94/20469 Pamphlet German Patent Invention Publication No. 3528759 German Patent Invention Application No. 3201268 European Patent No. 43575 European Patent Application No. 35172 German Patent Application Publication No. 2454492 German Patent Invention Application No. 2438130 Polish Provisional Patent No. 133955 Specification Japanese Examined Patent Publication No. 49-094677 German patent invention No. 22602727 US Pat. No. 3,853,895 German Patent Invention Application No. 2230392 International Publication No. 2003/002544 Pamphlet International Publication No. 2004/014382 Pamphlet French Patent Invention Application No. 2042360 Specification DE Patent Application Publication No. 2015955 Specification International Publication No. 2009/012421 Pamphlet International Publication No. 2008/107096 Pamphlet International Publication No. 2004/056786 Pamphlet International Publication No. 2004/048343 Pamphlet International Publication No. 2003/063794 Pamphlet International Publication No. 2003/037877 Pamphlet International Publication No. 2003/032997 Pamphlet International Publication No. 2003/002544 Pamphlet European Patent No. 135472 International Publication No. 2007/071455 Pamphlet International Publication No. 2007/003596 Pamphlet JP 2006-241089 A International Publication No. 2006/034872 Pamphlet International Publication No. 2002/096887 Pamphlet International Publication No. 2002/004429 Pamphlet International Publication No. 2004/065378 Pamphlet International Publication No. 2009/0675547 Pamphlet

An object of the present invention is to provide an effective inhibitor of TTK protein kinase, and thus to provide an effective medicine.

The above problems have been solved by the compounds provided in the present invention and related inventions (for example, pharmaceutical compositions, TTK inhibitors, etc.).

The Applicant has discovered a novel series of compounds with specific properties that inhibit the action of TTK kinase and are particularly useful in formulating pharmaceuticals for treating the above diseases. Therefore, the present compounds are useful in diseases that are considered effective by inhibiting the action of TTK kinase.

Therefore, for example, the present invention provides the following items.

(1A) Formula (I):

Wherein X is ═C (R ⁴ ) — or ═N—, and A is a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (provided that a substituted or unsubstituted aromatic ring Except for pyrazole or fused pyrazole.), A substituted or unsubstituted non-aromatic hydrocarbon ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR ^1A R ^{1A ′} or a group represented by the formula: —OR ^1B ;
R ^1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl or substituted or Unsubstituted saturated heterocyclyl,
R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A substituted saturated heterocyclyl;
R ^1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted Of saturated heterocyclyl
R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino, halogen, carboxy or hydrogen, or
R ¹ and R ² together with the adjacent carbon atom
Formula (II):

Wherein R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted An acyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl, wherein R ^a and R ^b are each independently hydrogen or substituted or unsubstituted alkyl, and n is 0-3 Which may be an integer).
R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
R ⁴ is hydrogen or halogen;
R ^5A and R ^5B are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Carbamoyl, a group represented by the formula: —SO ₂ —R ′, a group represented by the formula: —SO—R ′, or a group represented by the formula: —SR ′;
R ′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl It is.
However,
(I) X is ═C (R ⁴ ) —, and A is substituted or unsubstituted piperidine, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted fused pyrimidine, substituted or unsubstituted When substituted condensed pyridine or substituted or unsubstituted tetrahydrofuran, R ² is cyano;
(Ii) when X is ═C (R ⁴ ) —, A is a substituted or unsubstituted aromatic hydrocarbon ring and R ² is nitro, R ¹ is of the formula: —NR ^1A R ^{1A ′} A group represented by formula (where R ^{1A ′} is phenylethyl) and a group represented by the formula: —OR ^1B (where R ^1B is methyl),
(Iii) When X is ═C (R ⁴ ) — and A is a substituted or unsubstituted non-aromatic hydrocarbon ring, R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (here R ^{1A ′} is substituted or unsubstituted alkyl) and a group represented by the formula: —OR ^1B (where R ^1B is substituted or unsubstituted alkyl),
(Iv) X is ═C (R ⁴ ) —, A is a substituted or unsubstituted aromatic hydrocarbon ring, R ² is cyano, and R ¹ is represented by the formula: —NR ^1A R ^{1A ′} R ³ is hydrogen, wherein R ^{1A ′} is a substituted or unsubstituted alkyl or a group of the formula: —OR ^1B (where R ^1B is methyl or ethyl),
(V) when X is ═C (R ⁴ ) — and A is a non-aromatic heterocyclic ring, R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (where R ^{1A ′} is Instead of substituted or unsubstituted alkyl)
(Vi) when X is = C (R ⁴ )-, the number of hydrogens in R ¹ , R ³ and R ⁴ is 2 or less;
(Vii) When X is ═N—, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine). , R ² is cyano, R ³ is hydrogen, and R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (where R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted Piperidinyl and substituted or unsubstituted cyclopropyl) and a group represented by the formula: —OR ^1B (where R ^1B is substituted or unsubstituted alkyl),
(Viii) When X is ═N—, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine). , R ² is cyano, R ³ is hydrogen and R ^5A is not substituted sulfinyl, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted morpholinyl and substituted sulfonyl.
) A compound represented by the following formula (however, the compound shown below:

except for. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.

(2A) R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} or a group represented by the formula: —OR ^1B (wherein R ^1A , R ^{1A ′} and R ^1B are as defined in item (1A)) Yes,
R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted The compound according to item (1A), its pharmaceutically acceptable salt, or a solvate thereof, which is carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.

(3A) The compound according to item (1A) or (2A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein A is a substituted or unsubstituted aromatic hydrocarbon ring.

(4A) The compound according to any one of items (1A) to (3A), wherein X is ═C (R ⁴ ) — (where R ⁴ has the same meaning as item (1A)), and a pharmaceutically acceptable salt thereof Salts or solvates thereof.

(5A) The compound according to any one of items (1A) to (4A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is = CH-.

(6A) R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted The compound according to any one of items (1A) to (5A), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is alkoxycarbonyl, substituted amino or carboxy.

(7A) The compound according to any one of items (1A) to (6A), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R ² is cyano.

(8A) The compound according to any one of items (1A) to (7A), a pharmaceutically acceptable salt or a solvate thereof, wherein R ³ is hydrogen.

(8′A) The compound according to any one of items (1A) to (7A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ³ is substituted or unsubstituted alkyl.

(9A) ^{R 1} has the formula: -NHR ^{1A 'in} a group represented by or formula group (wherein, ^{R 1A} represented by ^{-OR ^1B'} and ^{R 1B} item (1A) and synonymous) is, items (1A ) To (8A) and (8′A), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(10A) R ¹ is a group represented by the formula: —NHR ^{1A ′} , and R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated heterocyclyl. The compound according to any one of items (1A) to (8A), (8′A) and (9A), a pharmaceutically acceptable salt thereof or a solvate thereof.

(11A) ^{R 1} has the formula: a group represented by ^{-OR ^1B,} ^{R 1B} is a substituted or unsubstituted cycloalkyl, item (1A) ~ (8A), (8'A), and (9A) Or a pharmaceutically acceptable salt or solvate thereof.

(12A) Formula (III):

A group represented by
Formula (IV):

Any one of items (1A) to (8A), (8′A), and (9A) to (11A), wherein R ^5A and R ^5B are as defined in item (1A) Or a pharmaceutically acceptable salt or solvate thereof.

(13A) In any one of items (1A) to (8A), (8′A), and (9A) to (12A), wherein R ^5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl The described compounds, pharmaceutically acceptable salts or solvates thereof.

(14A) Items (1A) to (8A) wherein R ^5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl ), (8′A), and (9A) to (13A), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(15A) The compound according to any one of items (1A) to (8A), (8′A), and (9A) to (14A), wherein R ^5B is hydrogen or substituted or unsubstituted alkoxy, its pharmaceutical Top acceptable salts or solvates thereof.

(16A) X is = C (R ⁴ )-(where R ⁴ is synonymous with item (1A)),
R ¹ and R ² together with adjacent carbon atoms
Formula (II):

Wherein R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl,
n is an integer of 0 to 2, R ^a and R ^b are the same as defined in item (1A)), A is a substituted or unsubstituted aromatic hydrocarbon ring;
R ³ is hydrogen, the compound according to any one of items (1A) to (5A), (8A), (8′A), and (12A) to (15A), a pharmaceutically acceptable salt thereof, or Their solvates.

(17A) A pharmaceutical comprising the compound according to any one of items (1A) to (8A), (8'A), (9A) to (16A), a pharmaceutically acceptable salt thereof or a solvate thereof Composition.

(18A) The pharmaceutical composition according to item (17A), which is a TTK inhibitor.

(19A) Formula (I):

Wherein X is ═C (R ⁴ ) —, and A is a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (provided that a substituted or unsubstituted pyrazole or condensed pyrazole And substituted or unsubstituted thiophene), a substituted or unsubstituted non-aromatic hydrocarbon ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR ^1A R ^{1A ′} or a group represented by the formula: —OR ^1B ;
R ^1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl or substituted or Unsubstituted saturated heterocyclyl,
R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A substituted saturated heterocyclyl;
R ^1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted Of saturated heterocyclyl
R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino, halogen, carboxy or hydrogen, or
R ¹ and R ² together with the adjacent carbon atom
Formula (II):

(Where
R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted Or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl,
R ^a and R ^b are each independently hydrogen or substituted or unsubstituted alkyl;
n is an integer of 0 to 3. )
R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
R ⁴ is hydrogen or halogen;
R ^5A and R ^5B are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Carbamoyl, a group represented by the formula: —SO ₂ —R ′, a group represented by the formula: —SO—R ′, or a group represented by the formula: —SR ′;
R ′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl The pharmaceutical composition which has TTK inhibitory activity containing the compound which is these, its pharmaceutically acceptable salt, or those solvates.

(20A) The pharmaceutical composition according to any of items (17A) to (19A), which is a medicament for the treatment or prevention of a disease, disorder or condition associated with TTK.

(21A) The pharmaceutical composition according to any of items (17A) to (20A) for treatment and / or prevention of cancer.

(22A) administering the compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for preventing or treating cancer, comprising:

(23A) The compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A) for the manufacture of a therapeutic and / or prophylactic agent for cancer, its pharmaceutical Use of top acceptable salts or solvates thereof.

(24A) The compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A) for treating and / or preventing cancer, its pharmaceutically acceptable Salts or solvates thereof.

(25A) The compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof TTK inhibitor.

(26A) A compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof Anticancer drugs.

(27A) A compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof A therapeutic agent for immune system diseases.

(28A) A compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof Immunosuppressant.

(29A) A compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof A therapeutic agent for autoimmune diseases.

(30A) A compound according to any one of items (1A) to (8A), (8'A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof is produced. Methods, systems, devices, kits etc.

(31A) The compound according to any one of items (1A) to (8A), (8′A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof Methods, systems, devices, kits, etc. for preparing pharmaceutical compositions.

(32A) The compound according to any one of items (1A) to (8A), (8'A), (9A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof is used. Methods, systems, devices, kits etc.

(33A) A method for preventing or treating cancer, comprising administering the pharmaceutical composition having TTK inhibitory activity according to item (19A).

(1B) Formula (I):

(Where
X is = C (R ⁴ )-or = N-
A represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyrazole or fused pyrazole), a substituted or unsubstituted non-aromatic hydrocarbon ring. Or a substituted or unsubstituted non-aromatic heterocycle,
R ¹ is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR ^1A R ^{1A ′} or a group represented by the formula: —OR ^1B ;
R ^1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl or substituted or Unsubstituted saturated heterocyclyl,
R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted saturated heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
R ^1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Saturated heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl , Substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino, halogen, carboxy or hydrogen, or
R ¹ and R ² together with the adjacent carbon atom
Formula (II):

(Where
R ^{1A ″} and R ^{2A ″} each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl Substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl,
R ^a and R ^b are each independently hydrogen or substituted or unsubstituted alkyl;
n is an integer of 0 to 3. ) May be formed,
R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
R ⁴ is hydrogen or halogen;
R ^5A and R ^5B are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted carbamoyl, a group represented by the formula: —SO ₂ —R ′, a group represented by the formula: —SO—R ′, or a group represented by the formula: —SR ′;
R ′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl It is.
However,
(I) X is ═C (R ⁴ ) —, and A is substituted or unsubstituted piperidine, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted fused pyrimidine, substituted or unsubstituted When substituted condensed pyridine or substituted or unsubstituted tetrahydrofuran, R ² is cyano;
(Ii) when X is ═C (R ⁴ ) —, A is a substituted or unsubstituted aromatic hydrocarbon ring and R ² is nitro, R ¹ is of the formula: —NR ^1A R ^{1A ′} A group represented by formula (where R ^{1A ′} is phenylethyl) and a group represented by the formula: —OR ^1B (where R ^1B is methyl),
(Iii) When X is ═C (R ⁴ ) — and A is a substituted or unsubstituted non-aromatic hydrocarbon ring, R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (here R ^{1A ′} is substituted or unsubstituted alkyl) and a group represented by the formula: —OR ^1B (where R ^1B is substituted or unsubstituted alkyl),
(Iv) X is ═C (R ⁴ ) —, A is a substituted or unsubstituted aromatic hydrocarbon ring, R ² is cyano, and R ¹ is represented by the formula: —NR ^1A R ^{1A ′} R ³ is hydrogen, wherein R ^{1A ′} is a substituted or unsubstituted alkyl or a group of the formula: —OR ^1B (where R ^1B is methyl or ethyl),
(V) when X is ═C (R ⁴ ) — and A is a non-aromatic heterocyclic ring, R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (where R ^{1A ′} is Instead of substituted or unsubstituted alkyl)
(Vi) when X is = C (R ⁴ )-, the number of hydrogens in R ¹ , R ³ and R ⁴ is 2 or less;
(Vii) When X is ═N—, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine). , R ² is cyano, R ³ is hydrogen, and R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (where R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted Piperidinyl and substituted or unsubstituted cyclopropyl) and a group represented by the formula: —OR ^1B (where R ^1B is substituted or unsubstituted alkyl),
(Viii) When X is ═N—, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine). , R ² is cyano, R ³ is hydrogen and R ^5A is not substituted sulfinyl, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted morpholinyl and substituted sulfonyl.
) A compound represented by the following formula (however, the compound shown below:

(2B) R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} or a group represented by the formula: —OR ^1B (where R ^1A , R ^{1A ′} and R ^1B are as defined in item (1B)) Yes,
R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl , A substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy, a pharmaceutically acceptable salt thereof or a solvent thereof Japanese products.

(3B) The compound according to item (1B) or (2B), pharmaceutically acceptable salt or solvate thereof, wherein A is a substituted or unsubstituted aromatic hydrocarbon ring.

(4B) The compound according to any one of items (1B) to (3B), wherein X is ═C (R ⁴ ) — (where R ⁴ is synonymous with item (1B)), and a pharmaceutically acceptable salt thereof Salts or solvates thereof.

(5B) The compound according to any one of items (1B) to (4B), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is = CH-.

(6B) R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted The compound according to any one of items (1B) to (5B), a pharmaceutically acceptable salt thereof or a solvate thereof, which is acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.

(7B) The compound according to any one of items (1B) to (6B), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R ² is cyano.

(8B) The compound according to any one of items (1B) to (7B), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ³ is hydrogen.

(9B) The item (1B) wherein R ¹ is a group represented by the formula: —NHR ^{1A ′} or a group represented by the formula: —OR ^1B (wherein R ^{1A ′} and R ^1B have the same ^{meanings as} the item (1B)) ) To (8B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(10B) R ¹ is a group represented by the formula: —NHR ^{1A ′} , and R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated heterocyclyl. The compound according to any one of items (1B) to (9B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(11B) ^{R 1} has the formula: a group represented by ^{-OR ^1B,} ^{R 1B} is a substituted or unsubstituted cycloalkyl A compound according to any of items (1B) ~ (10B), a pharmaceutically Acceptable salts or solvates thereof.

(12B) Formula (III):

A group represented by
Formula (IV):

Or a pharmaceutically acceptable salt thereof, or a compound thereof according to any one of items (1B) to (11B), wherein R ^5A and R ^5B are as defined in item (1B) Solvate.

(13B) The compound according to any one of items (1B) to (12B), a pharmaceutically acceptable salt thereof, or a solvent thereof, wherein R ^5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl Japanese products.

(14B) Items (1B) to (13B), wherein R ^5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.

(15B) The compound according to any one of items (1B) to (14B), wherein R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof Acceptable salts or solvates thereof.

(16B) X is = C (R ⁴ )-(where R ⁴ is synonymous with item (1B)),
R ¹ and R ² together with adjacent carbon atoms
Formula (II):

Wherein R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl,
n is an integer of 0 to 2, and R ^a and R ^b are the same as defined in item (1B)),
A is a substituted or unsubstituted aromatic hydrocarbon ring,
The compound according to any one of items (1B) to (15B), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ³ is hydrogen.

(17B) A pharmaceutical composition comprising the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(18B) The pharmaceutical composition according to item (17B), which is a TTK inhibitor.

(19B) Formula (I):

(Where
X is = C (R ⁴ )-
A represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyrazole or fused pyrazole and substituted or unsubstituted thiophene), substituted or unsubstituted A non-aromatic hydrocarbon ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR ^1A R ^{1A ′} or a group represented by the formula: —OR ^1B ;
R ^1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl or substituted or Unsubstituted saturated heterocyclyl,
R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A substituted saturated heterocyclyl;
R ^1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted Of saturated heterocyclyl
R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl , Substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino, halogen, carboxy or hydrogen, or
R ¹ and R ² together with the adjacent carbon atom
Formula (II):

(20B) The pharmaceutical composition according to any of items (17B) to (19B), which is a medicament for the treatment or prevention of a disease, disorder or condition associated with TTK.

(21B) The pharmaceutical composition according to any of items (17B) to (20B) for the treatment and / or prevention of cancer.

(22B) A method for preventing or treating cancer, comprising administering the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(23B) Use of the compound according to any one of items ((1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic and / or prophylactic agent for cancer. .

(24B) The compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof for the treatment and / or prevention of cancer.

(25B) A TTK inhibitor containing the compound according to any one of items ((1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(26B) An anticancer agent comprising the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(27B) A therapeutic agent for immune system diseases comprising the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(28B) An immunosuppressant comprising the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(29B) An autoimmune disease therapeutic agent comprising the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(30B) A method, system, apparatus, kit, etc. for producing the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(31B) Method, system, apparatus, kit and the like for preparing a pharmaceutical composition containing the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof .

(32B) A method, system, apparatus, kit or the like using the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(33B) A method for preventing or treating cancer, comprising administering the pharmaceutical composition having TTK inhibitory activity according to item (19B).

Thus, these and other advantages of the present invention will be apparent upon reading the following detailed description.

The present invention provides an effective inhibitor of TTK protein kinase, and thus provides an effective medicament for diseases, disorders or conditions related to TTK such as cancer.

Hereinafter, the present invention will be described while showing the best mode. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. Therefore, it is understood that singular modifiers (for example, articles such as “a”, “an”, “the” in the case of English, etc.) also include the plural concept unless otherwise stated. Should be. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the above field unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

The meaning of each term used in this specification is explained below. In the present specification, each term is used in a unified meaning, and is used in the same meaning when used alone or in combination with other terms.

The abbreviations used in this specification are listed below.

In the present specification, “halogen” includes fluorine, chlorine, bromine and iodine.

In the present specification, “alkyl” includes a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. For example, alkyl having 1 to 6 or 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl, isohexyl can be mentioned.

In the present specification, “alkenyl” includes straight-chain or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”. 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like.

In the present specification, “alkynyl” includes linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds in the above “alkyl”, and includes, for example, ethynyl, Examples include propynyl and butynyl. Furthermore, it may have one or more double bonds.

In the present specification, “cycloalkyl” includes a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon. Group, spiro hydrocarbon group and the like. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group.

In the present specification, the “bridged cyclic hydrocarbon group” refers to hydrogen from an aliphatic ring having 5 to 12 carbon atoms in which two or more rings share two or more atoms. Includes groups that can be removed. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl, bicyclo [3.3.1] nonane, 1-adamantyl, 2-adamantyl and the like.

In addition, in this specification, the “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings are configured to share one carbon atom. Specific examples include spiro [3.4] octyl.

In the present specification, “cycloalkenyl” includes a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.

In the present specification, “aryl” includes a monocyclic or condensed aromatic hydrocarbon ring. This may be condensed with the above “cycloalkyl” at all possible positions. Whether aryl is a single ring or a fused ring, it can be attached at all possible positions. Examples include phenyl, 1-naphthyl, 2-naphthyl, anthryl, tetrahydronaphthyl and the like. Examples include phenyl, 1-naphthyl and 2-naphthyl. An example is phenyl.

In the present specification, the “aromatic hydrocarbon ring” includes an aromatic 5- to 8-membered ring containing only a carbon atom in the ring or a ring in which two or more of them are condensed. The monocyclic aromatic hydrocarbon ring includes a ring derived from a 6-membered aromatic hydrocarbon ring and optionally having a bond at any substitutable position. The condensed aromatic hydrocarbon ring has a bond at any substitutable position where the 6-membered aromatic hydrocarbon ring is condensed with 1 to 4 6-membered aromatic hydrocarbon rings. Includes an optional ring. For example, a 6-membered aromatic hydrocarbon ring is mentioned. Examples of the aromatic hydrocarbon ring include a benzene ring, a naphthalene ring, an anthracene ring, and a tetrahydronaphthalene ring. For example, a benzene ring and a naphthalene ring are mentioned.

In the present specification, the “non-aromatic hydrocarbon ring” includes a non-aromatic 3- to 8-membered ring containing only a carbon atom in the ring or a ring in which two or more of them are condensed. The monocyclic non-aromatic hydrocarbon ring includes a group derived from a 3- to 8-membered non-aromatic hydrocarbon ring and optionally having a bond at any substitutable position. A fused non-aromatic hydrocarbon ring is any substitutable position where a 5- to 8-membered non-aromatic hydrocarbon ring is fused with 1 to 4 5- to 8-membered non-aromatic hydrocarbon rings Includes a group which may have a bond. If it is non-aromatic, it may be saturated or unsaturated. For example, a 5- to 6-membered non-aromatic hydrocarbon ring can be mentioned. Examples of the non-aromatic hydrocarbon ring include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclopropene ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, and a cycloheptene ring. Can be mentioned. Examples thereof include a cyclopentane ring, a cyclohexane ring, a cyclopentene ring, and a cyclohexene ring.

In the present specification, “heteroaryl” includes an optionally selected 5- to 8-membered aromatic hydrocarbon ring containing at least one oxygen atom, sulfur atom, and / or nitrogen atom in the ring. This may be condensed with the above “cycloalkyl”, the above “aryl”, the following “heterocyclyl”, or other heteroaryl at all possible positions. Whether the heteroaryl is a single ring or a fused ring, it can be attached at all possible positions. For example, pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), imidazolyl (eg, 2 -Imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxazolyl), oxazolyl (eg 2-oxazolyl) 4-oxazolyl, 5-oxazolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (eg 2- Pyrazinyl), pyrimidinyl (eg 2-pyrimidini) 4-pyrimidinyl), pyridazinyl (eg 3-pyridazinyl), tetrazolyl (eg 1H-tetrazolyl), oxadiazolyl (eg 1,3,4-oxadiazolyl), thiadiazolyl (eg 1,3,4-thiadiazolyl), Indolizinyl (eg, 2-indolidinyl, 6-indolidinyl), isoindolyl (eg, 2-isoindolyl), indolyl (eg, 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (eg, 3-indazolyl), purinyl (eg, For example, 8-purinyl), quinolidinyl (eg, 2-quinolidinyl), isoquinolyl (eg, 3-isoquinolyl), quinolyl (eg, 2-quinolyl, 5-quinolyl), phthalazinyl (eg, 1-phthalazinyl), naphthyridinyl (Eg, 2-naphthyridinyl), quinazolinyl (eg, 2-quinazolinyl), cinnolinyl (eg, 3-cinnolinyl), pteridinyl (eg, 2-pteridinyl), carbazolyl (eg, 2-carbazolyl, 4-carbazolyl), phenant Lydinyl (eg 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (eg 1-acrinidyl, 2-acrinidyl), dibenzofuranyl (eg 1-dibenzofuranyl, 2-dibenzofuranyl) ), Benzimidazolyl (eg, 2-benzimidazolyl), benzoisoxazolyl (eg, 3-benzoisoxazolyl), benzoxazolyl (eg, 2-benzoxazolyl), benzooxadiazolyl (eg, 4-Benzoxadiazolyl), benzoiso Thiazolyl (eg 3-benzoisothiazolyl), benzothiazolyl (eg 2-benzothiazolyl), benzofuryl (eg 3-benzofuryl), benzothienyl (eg 2-benzothienyl), dibenzothienyl (eg 2-dibenzothienyl) ), Benzodioxolyl (for example, 1,3-benzodioxolyl) and the like.

In the present specification, “heterocyclyl” may contain 1 to 4 oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring, and has a bond at any substitutable position. Non-aromatic heterocycles which may be optionally included. Further, such a non-aromatic heterocyclic ring may be further bridged with an alkyl chain having 1 to 4 carbon atoms, such as a non-aromatic heterocyclic ring (including a 5- to 6-membered ring) or an aromatic hydrocarbon ring ( For example, a benzene ring) may be condensed. If it is non-aromatic, it may be saturated or unsaturated. For example, a 5- to 8-membered ring. For example, pyrrolinyl (eg, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), pyrrolidinone, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), imidazolidinyl (eg 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl), imidazolidinone, pyrazolinyl (eg 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl), pyrazolidinyl (eg 1-pyrazolidinyl) , 3-pyrazolidinyl, 4-pyrazolidinyl), piperidinone, piperidino, piperidinyl (eg 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (eg 1-pipedinyl) Jiniru, 2-piperazinyl), piperazinone, morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl), morpholino, tetrahydropyranyl, tetrahydrofuranyl, and the like.

In the present specification, “saturated heterocyclyl” is a ring having no unsaturated bond (double bond) in the above-mentioned “heterocyclyl”, and has a bond at any substitutable position. The non-aromatic heterocyclic ring which may have is included. Further, such a non-aromatic heterocyclic ring may be further bridged with an alkyl chain having 1 to 4 carbon atoms, such as a non-aromatic heterocyclic ring (including 5- to 6-membered ring) or a non-aromatic hydrocarbon ring. May be condensed. For example, a 5- to 8-membered ring. For example, pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), pyrrolidinone, imidazolidinyl (eg, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl), imidazolidinone, pyrazolidinyl (eg, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl), piperidinone, piperidino, piperidinyl (eg 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (eg 1-piperazinyl, 2-piperazinyl), piperazinone, morpholinyl (eg 2 -Morpholinyl, 3-morpholinyl), morpholino, tetrahydropyranyl, tetrahydrofuranyl and the like.

In the present specification, the “aromatic heterocycle” is an arbitrarily selected aromatic 5- to 8-membered ring containing at least one oxygen atom, sulfur atom and / or nitrogen atom in the ring, or 2 Includes rings fused at least. Monocyclic aromatic heterocycles include rings derived from 5- to 8-membered aromatic hydrocarbon rings that may contain from 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. . The monocyclic aromatic heterocycle may have a bond at any substitutable position. The condensed aromatic heterocyclic ring is a 5- to 8-membered aromatic hydrocarbon ring which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring. Includes a ring fused to an 8-membered aromatic hydrocarbon ring or other 5- to 8-membered aromatic heterocycle. The fused aromatic heterocyclic ring may have a bond at any substitutable position. For example, a 5- to 6-membered aromatic heterocyclic ring can be mentioned. Examples of the aromatic heterocycle include pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, isothiazole ring, isoxazole ring, oxazole ring, thiazole ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, tetrazole Ring, oxadiazole ring, thiadiazole ring, indolizine ring, isoindole ring, indole ring, indazole ring, purine ring, quinolidine ring, isoquinoline ring, quinoline ring, phthalazine ring, naphthyridine ring, quinazoline ring, cinnoline ring , Pteridine ring, carbazole ring, phenanthridine ring, acridine ring, dibenzofuran ring, benzimidazole ring, benzisoxazole ring, benzoxazole ring, benzoxazole ring, benzoisothiazole ring, benzothiazole ring, benzoph Down ring, benzothiophene ring, dibenzothiophene ring, such benzodioxole ring. Examples thereof include a thiophene ring, a pyridine ring, a furan ring, a thiazole ring, an oxazole ring, and a pyrimidine ring.

In the present specification, the “non-aromatic heterocycle” is a non-aromatic 5- to 8-membered ring containing at least one oxygen atom, sulfur atom and / or nitrogen atom in the ring, Includes two or more condensed rings. For example, pyrroline ring, pyrrolidine ring, pyrrolidinone ring, imidazoline ring, imidazolidine ring, pyrazoline ring, pyrazolidine ring, piperidinone ring, piperidine ring, piperazine ring, piperazinone ring, morpholine ring, tetrahydropyran ring, tetrahydrofuran ring, dihydropyran ring, And dihydrofuran ring. Examples thereof include a dihydropyran ring, a tetrahydropyran ring, a dihydrofuran ring, and a tetrahydrofuran ring.

As used herein, “acyl” refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted Including substituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl.

In the present specification, “fused pyrazole”, “fused pyrimidine”, and “fused pyridine” mean that pyrazole, pyrimidine, and pyridine are the above “cycloalkyl”, the above “aryl”, the above “heterocyclyl”, or Includes fused rings fused at all possible positions with the “heteroaryl”. Examples of the condensed pyrazole include 4,6-dihydro-1H-thieno [3,4-c] pyrazole. Examples of the condensed pyrimidine include 6,7,8,9-tetrahydro-5H-pyrimido [4,5-d] azepine. Examples of the condensed pyridine include pyrido [3,2-b] pyrazine, 1,8-naphthyridine, quinoline and the like.

In the present specification, “alkoxy” means, for example, methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, Examples include 2-pentyloxy, 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, n-octyloxy and the like. An example is C1-C6 alkoxy. Another example is C1-C4 alkoxy. In particular, when a carbon number is specified, it means “alkoxy” having a carbon number within the range.

In the present specification, “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl” ”,“ Substituted or unsubstituted aryl ”,“ substituted or unsubstituted heteroaryl ”,“ substituted or unsubstituted heterocyclyl ”,“ substituted or unsubstituted saturated heterocyclyl ”“ substituted or unsubstituted alkoxy ” , "Substituted or unsubstituted acyl", "substituted or unsubstituted alkoxycarbonyl", "substituted or unsubstituted piperidine", "substituted or unsubstituted thiophene", "substituted or unsubstituted tetrahydropyran", "substituted Or “unsubstituted fused pyrimidine”, “substituted or unsubstituted fused pyridine” "Substituted or unsubstituted tetrahydrofuran", "Substituted or unsubstituted aromatic hydrocarbon ring", "Substituted or unsubstituted non-aromatic hydrocarbon ring", "Substituted or unsubstituted aromatic heterocycle", "Substituted Or “unsubstituted non-aromatic heterocycle”, “substituted or unsubstituted pyrazolyl”, “substituted or unsubstituted imidazolyl”, “substituted or unsubstituted oxazolyl”, “substituted or unsubstituted oxadiazolyl”, “substituted or “Unsubstituted pyrazole”, “substituted or unsubstituted pyridine”, “substituted or unsubstituted piperidinyl”, “substituted or unsubstituted cyclopropyl”, “substituted sulfinyl”, “substituted or unsubstituted morpholinyl”, or “ Examples of the substituent in the “substituted sulfonyl” include hydroxy, carboxy, halogen, halo. Emissions alkyl _{_{_{_{(eg: CF 3, CH 2 CF 3}}}} , CH 2 CCl 3), nitro, nitroso, cyano, alkyl (e.g. methyl, ethyl, isopropyl, tert- butyl), alkenyl (e.g. vinyl), alkynyl ( Example: ethynyl), cycloalkyl (eg, cyclohexyl, cyclopropyl, adamantyl), cycloalkylalkyl (eg, cyclohexylmethyl, adamantylmethyl), cycloalkenyl (eg, cyclopropenyl), aryl (eg, phenyl, naphthyl), aryl Alkyl (eg benzyl, phenethyl), heteroaryl (eg: pyrazolyl, pyridyl, furyl), heteroarylalkyl (eg: pyridylmethyl), heterocyclyl (eg: piperidyl, tetrahydropyranyl), heterocyclylalkyl (eg : Morpho Rumechiru), alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy), halogenated alkoxy (e.g. _OCF 3), alkenyloxy (e.g. vinyloxy, allyloxy), aryloxy (e.g. phenyloxy), alkyloxycarbonyl (eg : Methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), arylalkyloxy (eg, benzyloxy), unsubstituted amino, substituted amino [eg: alkylamino (eg: methylamino, ethylamino, dimethylamino), acylamino (eg, : Acetylamino, benzoylamino), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino], alkylaminoalkyl (eg, diethylaminomethyl), sulfamoyl, oxo, carbamo It is selected from the group consisting of a Le. It may be substituted with 1 to 4 such substituents.

In the present specification, the substituents of “substituted or unsubstituted amino”, “substituted amino” and “substituted or unsubstituted carbamoyl” include alkyl, alkenyl, aryl, heteroaryl, alkylcarbonyl, arylcarbonyl, heteroaryl. Carbonyl, heterocyclylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, sulfamoyl, carbamoyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, alkyl Sulfinyl, cycloalkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, hydro Shi, mercapto, sulfino, sulfo, and amino and the like.

In the present specification, the alkyl part of “substituted or unsubstituted alkoxy” and “halogenated alkyl” means the above “alkyl”.

In the present specification, the alkoxy moiety of “substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkoxycarbonyl”, and “halogenated alkoxy” means the above “alkoxy”.

Pharmacologically acceptable salts of the compound of the present invention include the following salts.

Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt Aliphatic amine salts such as triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; aralkylamine salts such as N, N-dibenzylethylenediamine salt and venetamine salt; pyridine salt, picoline salt, quinoline salt, Heterocyclic aromatic amine salts such as isoquinoline salt; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium Quaternary ammonium salts such as um salt, methyl trioctyl ammonium salt and tetrabutyl ammonium salt; and basic amino acid salts such as arginine salt and lysine salt.

Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.

In the present specification, the solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate. Examples of the hydrate include monohydrate, dihydrate and the like.

Furthermore, one or more hydrogen, carbon or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon or other atoms. The compound of formula (I) includes all radiolabels of the compound of formula (I). Such “radiolabeled”, “radiolabeled” and the like of the compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. . It is also useful as a pharmaceutical product.

Examples of isotopes that can be incorporated into the compound of formula (I) of the present invention include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, and ³⁵ S, respectively. , ¹⁸ F, and ³⁶ Cl include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. The radiolabeled compound of the present invention can be prepared by methods well known in the art. For example, a tritium labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method involves reacting a compound of formula (I) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. May be. For suitable methods for preparing other tritium labeled compounds, reference may be made to the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ¹⁴ C-labeled compounds can be prepared by using raw materials having ¹⁴ C carbon.

(Preferred pyridine and pyrimidine derivative compounds of the present invention)
In the compound, pharmaceutically acceptable salt or solvate or prodrug thereof (ester, amide, etc.) included in the pharmaceutical composition having TTK inhibitory activity, the above substituents are described herein. Any substituent can be used, and for example, any preferable substituent exemplified in the means for solving the problem can be used.

When considering the pyridine and pyrimidine derivatives of the present invention, the following factors can be considered.

Preferred embodiments of the present invention are exemplified as (A1) to (A12), (B1) to (B6), (C1) to (C13), and (D1) to (D6) below. Unless otherwise specified, each symbol has the same meaning as described above.

(A1)
Formula (I):

In
X includes ═C (R ⁴ ) — or ═N—.

For example, X includes ═C (R ⁴ ) —.

For example, X may be = CH-.

For example, X may be = N-.

A includes a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (however, a substituted or unsubstituted pyrazole or condensed pyrazole (for example, 4,6-dihydro-1H-thieno [3 , 4-c] pyrazole.), Substituted or unsubstituted non-aromatic hydrocarbon rings or substituted or unsubstituted non-aromatic heterocycles.

For example, A includes a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyrazole or fused pyrazole and substituted or unsubstituted thiophene), Examples thereof include a substituted or unsubstituted non-aromatic hydrocarbon ring or a substituted or unsubstituted non-aromatic heterocyclic ring.

For example, A includes a substituted or unsubstituted aromatic hydrocarbon ring.

For example, in A, formula (III):

As the group represented by
Formula (IV):

The group shown by these is mentioned.

Examples of R ¹ include hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR ^1A R ^{1A ′} , or a group represented by the formula: —OR ^1B .

For example, R ¹ includes a group represented by the formula: —NR ^1A R ^{1A ′} or a group represented by the formula: —OR ^1B .

For example, R ¹ includes a group represented by the formula: —NHR ^{1A ′} or a group represented by the formula: —OR ^1B .

For example, R ¹ includes a group represented by the formula: —NHR ^{1A ′} .

For example, R ¹ includes a group represented by the formula: —OR ^1B .

Here, R ^1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cyclo Examples include alkyl or substituted or unsubstituted saturated heterocyclyl.

Here, R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl Or a substituted or unsubstituted saturated heterocyclyl is mentioned.

Here, R ^1B represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl Or a substituted or unsubstituted saturated heterocyclyl is mentioned.

For example, R ¹ includes a group represented by the formula: —NHR ^{1A ′} , where R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated heterocyclyl. Is mentioned.

For example, R ¹ includes a group represented by the formula: —OR ^1B , and R ^1B includes a substituted or unsubstituted cycloalkyl.

R ² is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Heterocyclyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino, halogen, carboxy or hydrogen.

For example, R ² includes cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Examples include substituted heterocyclyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.

For example, R ² includes cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Examples include substituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.

For example, ^{R 2,} include cyano.

Or R ¹ and R ² together with adjacent carbon atoms,
Formula (II):

In group may be formed as shown.

Where
R ^{1A ″} and R ^{2A ″} each independently represent substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, Substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.

For example, R ^{1A ″} and R ^{2A ″} each independently include substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.

R ^a and R ^b each independently include hydrogen or substituted or unsubstituted alkyl.

N is an integer from 0 to 3.

For example, n is an integer from 0 to 2.

R ³ includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen.

For example, R ³ includes hydrogen.

For example, R ³ includes substituted or unsubstituted alkyl.

R ⁴ includes hydrogen or halogen.

For example, R ⁴ includes hydrogen.

R ^5A and R ^5B are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or Examples thereof include unsubstituted carbamoyl, a group represented by the formula: —SO ₂ —R ′, a group represented by the formula: —SO—R ′, or a group represented by the formula: —SR ′.

For example, R ^5A includes substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl.

For example, R ^5A includes substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl.

For example, R ^5B includes hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

Here, R ′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Substituted heterocyclyl is mentioned.

Provided that (i) X is = C (R ⁴ )-and A is substituted or unsubstituted piperidine, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted fused pyrimidine (for example, 6,7,8,9-tetrahydro-5H-pyrimido [4,5-d] azepine), substituted or unsubstituted fused pyridine (eg, pyrido [3,2-b] pyrazine, 1,8-naphthyridine, Quinoline) or substituted or unsubstituted tetrahydrofuran, R ² is cyano.

However, (ii) when X is ═C (R ⁴ ) —, A is a substituted or unsubstituted aromatic hydrocarbon ring, and R ² is nitro, R ¹ is represented by the formula: —NR ^1A R It is not a group represented by ^{1A ′} (where R ^{1A ′} is phenylethyl) and a group represented by the formula: —OR ^1B (where R ^1B is methyl).

However, (iii) when X is ═C (R ⁴ ) — and A is a substituted or unsubstituted non-aromatic hydrocarbon ring, R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (Wherein R ^{1A ′} is substituted or unsubstituted alkyl) and is not a group represented by the formula: —OR ^1B (where R ^1B is substituted or unsubstituted alkyl).

Where (iv) X is ═C (R ⁴ ) —, A is a substituted or unsubstituted aromatic hydrocarbon ring, R ² is cyano, and R ¹ is represented by the formula: —NR ^1A R ^{1A ′} In which R ^{1A ′} is substituted or unsubstituted alkyl, or a group represented by the formula: —OR ^1B (where R ^1B is methyl or ethyl), R ³ is hydrogen is there.

However, (v) when X is ═C (R ⁴ ) — and A is a non-aromatic heterocyclic ring, R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (where R ^{1A '} Is not substituted or unsubstituted alkyl).

However, (vi) when X is ═C (R ⁴ ) —, the number of hydrogens in R ¹ , R ³ and R ⁴ is 2 or less.

However, (vii) when X is = N-, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine). R ² is cyano, R ³ is hydrogen, R ¹ is a group represented by the formula: —NR ^1A R ^{1A ′} (wherein R ^{1A ′} is a substituted or unsubstituted alkyl, substituted or non-substituted Substituted piperidinyl and substituted or unsubstituted cyclopropyl) and a group of formula: —OR ^1B where R ^1B is a substituted or unsubstituted alkyl.

However, (viii) when X is = N-, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine). R ² is cyano, R ³ is hydrogen, and R ^5A is not substituted sulfinyl, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted morpholinyl and substituted sulfonyl.

However, the following compounds:

except for.

The following embodiment may also be one embodiment.

(A2)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X includes ═C (R ⁴ ) — (where R ⁴ has the same meaning as the above item (1A) or (1B)).

As R ¹ and R ² , R ¹ and R ² together with adjacent carbon atoms,
Formula (II):

Is formed.

Where
R ^{1A ″} and R ^{2A ″} each independently include substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.

N is an integer from 0 to 2.

A includes a substituted or unsubstituted aromatic hydrocarbon ring.

R ³ includes hydrogen.

(A3)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is a substituted or unsubstituted aromatic hydrocarbon ring,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl;
R ² is cyano,
R ³ is hydrogen;
R ^5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(A4)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl;
R ² is cyano,
R ³ is hydrogen;
R ^5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(A5)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl;
R ² is cyano,
R ³ is hydrogen;
R ^5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(A6)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(A7)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is a substituted or unsubstituted heteroaryl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(A8)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(A9)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(A10)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl;
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(A11)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is substituted or unsubstituted alkoxy.

(A12)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted benzene,
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is alkoxy substituted with cyano or unsubstituted alkoxy.

In (A1) to (A12), A is an unsubstituted (excluding R ^5A and R ^5B ) aromatic hydrocarbon ring, an unsubstituted (except R ^5A and R ^5B ) aromatic heterocyclic ring, or unsubstituted non-aromatic hydrocarbon ring (excluding ^{R 5A} and ^{R 5B),} a non-aromatic heterocycle unsubstituted ^(except for ^{R 5A} and ^{R 5B),} benzene include unsubstituted ^(except for ^{R 5A} and ^{R 5B)} It is done.

(B1)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted pyridine;
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is a substituted or unsubstituted heteroaryl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(B2)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted pyridine;
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(B3)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted pyridine;
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(B4)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted pyridine;
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(B5)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted pyridine;
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is substituted or unsubstituted alkoxy.

(B6)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I):
X is = CH-
A is substituted or unsubstituted pyridine;
R ¹ is a group represented by the formula: —NHR ^{1A ′} ;
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ² is cyano,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is alkoxy substituted with cyano or unsubstituted alkoxy.

In (B1) to (B6), examples of A include unsubstituted pyridine (excluding R ^5A and R ^5B ).

(C1)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

General formula (I '):

Where
R ^{1A ′} is substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl;
R ³ is hydrogen or substituted or unsubstituted alkyl;
R ^5A is a substituted or unsubstituted heteroaryl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C2)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is hydrogen or substituted or unsubstituted alkyl;
R ^5A is a substituted or unsubstituted heteroaryl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C3)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is hydrogen;
R ^5A is a substituted or unsubstituted heteroaryl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C4)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is hydrogen;
R ^5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C5)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C6)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C7)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is substituted or unsubstituted alkoxy.

(C8)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is hydrogen;
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is alkoxy substituted with cyano or unsubstituted alkoxy.

(C9)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is substituted or unsubstituted alkyl,
R ^5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C10)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is substituted or unsubstituted alkyl,
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C11)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is substituted or unsubstituted alkyl,
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.

(C12)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is substituted or unsubstituted alkyl,
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is substituted or unsubstituted alkoxy.

(C13)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ′):
R ^{1A ′} is a substituted or unsubstituted cycloalkyl,
R ³ is substituted or unsubstituted alkyl,
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is alkoxy substituted with cyano or unsubstituted alkoxy.

(D1)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

General formula (I ″):

Where
R ^5A is a substituted or unsubstituted heteroaryl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl;
R ^a and R ^b are each independently hydrogen,
n is an integer from 0 to 3,
R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.

(D2)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ″):
R ^5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl;
R ^a and R ^b are each independently hydrogen,
n is an integer from 0 to 3,
R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.

(D3)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ″):
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl;
R ^a and R ^b are each independently hydrogen,
n is an integer from 0 to 3,
R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.

(D4)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ″):
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl;
R ^a and R ^b are each independently hydrogen,
n is an integer from 0 to 3,
R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.

(D5)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ″):
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is substituted or unsubstituted alkoxy;
R ^a and R ^b are each independently hydrogen,
n is an integer from 0 to 3,
R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.

(D6)
The definition of each substituent is synonymous with the said item (1A) or (1B) unless there is particular notice.

In general formula (I ″):
R ^5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
R ^5B is alkoxy substituted with cyano or unsubstituted alkoxy;
R ^a and R ^b are each independently hydrogen,
n is an integer from 0 to 3,
R ^{1A ″} and R ^{2A ″} are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.

In another embodiment, the present invention provides a medicament comprising a compound according to any of the above, a pharmaceutically acceptable salt or solvate thereof, or a prodrug (eg, ester, amide) thereof. A composition is provided.

In this specification, “prodrug” and “prodrug compound” have a group that can be chemically or metabolically decomposed, and are pharmaceutically active by hydrolysis, solvolysis, or decomposition under physiological conditions. Is a derivative of the compound of the present invention. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, reference can be made to the following documents (a) to (f). Prodrugs of compounds of formula (I) are prepared by modifying functional groups present in compounds of formula (I) by a modification method such that the parent compound is released upon cleavage in vivo. For example, a prodrug is a compound of formula (I) wherein the hydroxy, sulfhydryl or amino group in the compound of formula (I) is linked to a group that regenerates the free hydroxy, amino, or sulfhydryl group, respectively, when cleaved in vivo. ). Examples of prodrugs include, but are not limited to, esters of hydroxy functional groups (eg, acetate, formate, and benzoate derivatives), carbamates (eg, N, N-dimethylaminocarbonyl) in compounds of formula (I) Etc.
(A) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods
in Enzymology, Vol. 42.p.309-396, edited by K. Widder, et al. (Academic Press, 1985);
(B) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen;
(C) H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);
(D) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
(E) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and (f) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An example of one prodrug group is an in vivo cleavable ester group of a pharmaceutically acceptable ester that is cleaved in the human or animal body to yield the parent acid. For example, a prodrug group, together with the carboxy group to which it is attached, can be combined with a C _1-6 alkyl ester or C _1-6 cycloalkyl ester, such as methyl, ethyl, propyl, isopropyl, n-butyl or Esters of cyclopentyl; C _1-6 alkoxymethyl esters, such as methoxymethyl esters; C _1-6 alkanoyloxymethyl esters, such as pivaloyloxymethyl esters; phthalidyl esters; C _3-8 cycloalkoxycarbonyloxy C _{1 -6} alkyl esters such as 1-cyclohexylcarbonyloxyethyl ester; 1,3-dioxolan-2-ylmethyl ester such as 5-methyl-1,3-dioxolan-2-ylmethyl ester; C _1-6 alkoxy Carbonyloxyethyl esters such as 1- Methoxycarbonyloxyethyl ester; aminocarbonylmethyl ester and its mono- or di-N- (C _1-6 alkyl) variants, such as N, N-dimethylaminocarbonylmethyl ester and N-ethylaminocarbonylmethyl ester Forms pharmaceutically acceptable esters and pharmaceutically acceptable esters of substituted or unsubstituted heterocyclic groups. In one embodiment, the prodrug is an ester with a C _1-4 alkyl group such as isopropyl or cyclopentyl, or an ester selected from an optionally substituted heterocyclic group such as N-methyltetrahydropyridyl. Can be mentioned.

The pharmaceutical composition of the present invention containing any of the specific compounds listed above is also characterized by being a TTK inhibitor. Accordingly, any pharmaceutical composition that exhibits a medicinal effect by being administered to a patient in need of inhibition of TTK is provided.

In another embodiment, the present invention provides a medicament for the treatment or prevention of cancer or immune disease comprising any of the specific compounds listed above.

(Production method)
A general method for producing the compound of the present invention is illustrated below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.

Hereinafter, the method for producing the compound of the present invention will be described.

The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.

The raw material compounds are commercially available compounds, those described in Patent Documents 4 to 60 and Non-Patent Documents 7 to 20, and those described in this specification as well as other references cited in this specification. In addition to those described in (1), other known compounds can be used.

Some of the compounds of the present invention may have tautomers, positional isomers and optical isomers, but the present invention includes all possible isomers and mixtures thereof, including these. To do.

When obtaining a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended and an acid or base is added to form a salt by a conventional method.

In addition, the compounds of the present invention and pharmaceutically acceptable salts thereof may exist in the form of adducts (hydrates or solvates) with water or various solvents, and these adducts are also included in the present invention. Is included.

These derivatives are converted and activated in the body, and are also referred to as “prodrugs” in the present specification. Examples of prodrugs are understood to include, for example, the above salts and solvates, as well as esters (eg, alkyl esters), amides, and the like.

Examples of the compound of the present invention are variously listed in the Examples, and those skilled in the art can produce and use compounds not exemplified in the present invention with reference to these.

The present invention also relates to a system, apparatus and kit for producing the compound of the present invention. It is understood that the constituent requirements of such a system, apparatus, and kit can use those known in the art and can be appropriately designed by those skilled in the art.

(General synthesis method)
A typical method for producing the compound of the present invention is shown in the following scheme. The compounds of the present invention can be produced by the schemes shown below or the methods shown in the examples, but the production methods of the compounds of the present invention are not limited thereto.

In General Synthesis Methods 1 to 11, preferred ones among them have been presented, but are not particularly limited thereto.

(General synthesis method 1: When R ¹ is amino or alkoxy)
Scheme 1

(In the formula, each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.). Here, “Tf” represents a trifluoromethanesulfonyl group.)
The compound represented by the formula (1-3) and the formula (1-4) can be produced from the compound represented by the formula (1-1) in two steps.

As the compounds represented by formula (1-1) and formula (1-5), known compounds may be used, or compounds derived from known compounds by a conventional method may be used. The compound represented by the formula (1-5) can also be produced by the method shown in Scheme 7.

The compound represented by the formula (1-2) can be produced by reacting the compound represented by the formula (1-1) with the compound represented by the formula (1-5). In other words, in the presence of an organic base such as DIEA, NMP, DMF, ether solvents (eg, THF, dioxane, etc.), and alcohol solvents (eg, ethanol, propanol, etc.) should be performed at a temperature of 80 ° C. or higher. Thus, the corresponding compound represented by the formula (1-2) can be produced. In addition, this reaction involves palladium catalysts (eg Pd (OAc) ₂ , Pd ₂ (dba) ₃ etc.), phosphine-based ligands (eg BINAP, Xantphos etc.) and bases (eg cesium carbonate, potassium carbonate etc.) ) In the presence of a solvent such as dioxane and toluene.

The compound represented by the formula (1-3) can be produced by reacting the compound represented by the formula (1-2) with the compound represented by the formula (NHR ^1A R ^{1A ′} ). That is, it corresponds to the formula (1-2) by carrying out a compound represented by the formula (NHR ^1A R ^{1A ′} ) of 2 equivalents or more in a solvent such as NMP and DMF at a temperature of 100 ° C. or higher. A compound represented by the formula (1-3) can be produced. When the reaction proceeds slowly or does not proceed, the temperature can be raised to about 250 ° C. using a microwave reaction apparatus.

The compound represented by the formula (1-4) can be produced by reacting the compound represented by the formula (1-2) and the formula (R ^1B OH). In other words, for the formula (1-2), the compound represented by the formula (R ^1B OH) is carried out in the presence of sodium hydride in a solvent such as NMP and DMF at a temperature of 80 ° C. or higher. A compound represented by the formula (1-4) can be produced. When the reaction proceeds slowly or does not proceed, the temperature can be raised to about 250 ° C. using a microwave reaction apparatus.

(General synthesis method 2: When R ¹ is an alkyl group)
Scheme 2

(Wherein each symbol has the same meaning as the above item (1A) or (1B), X represents a leaving group (halogen, OTf, etc.), where “Tf” represents a trifluoromethanesulfonyl group. (The compound represented by (2-3) means the corresponding boronic acid or boronic ester.)
The compound represented by the formula (2-2) can be produced from the compound represented by the formula (1-1) in two steps.

The compound represented by the formula (1-2) is synonymous with the compound shown in Scheme 1, and can be produced by the method shown in Scheme 1, but a known compound may be used or from a known compound A compound derived by a conventional method may be used.

The compound represented by the formula (2-1) can be produced by a Suzuki coupling reaction between the compound represented by the formula (1-2) and the formula (2-3). That is, in the presence of a palladium catalyst (eg, Pd (PPh ₃ ) ₄ , Pd ₂ (dba) ₃ ) and a base (eg, sodium carbonate, potassium carbonate), NMP, DMF, an ether solvent (eg, THF, dioxane) Etc.) and an alcohol solvent (eg, ethanol, propanol, etc.) at a temperature of 50 ° C. or higher, the corresponding compound represented by the formula (2-1) can be produced. This reaction is not limited to these conditions, and a known method can be applied.

The compound represented by the formula (2-2) can be produced by a hydrogenation reaction to an olefin. In other words, in the presence of palladium carbon, NMP, DMF, ethyl acetate, ether solvents (eg, THF, dioxane, etc.), alcohol solvents (eg, ethanol, propanol, etc.), or a mixed solvent thereof in a hydrogen atmosphere. By doing so, the corresponding compound represented by the formula (2-2) can be produced. This reaction is not limited to these conditions, and a known method can be applied.

(General synthesis method 3: when R ¹ is an alkyl group)
Scheme 3

(In the formula, each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.). Here, “Tf” represents a trifluoromethanesulfonyl group.)
The compound represented by the formula (3-1) can be produced from the compound represented by the formula (1-2).

The compound represented by the formula (3-1) can be produced by Negishi coupling reaction between the compound represented by the formula (1-2) and the compound represented by the formula (R ¹ -ZnX: X = halogen). That is, the corresponding compound represented by the formula (3-1) can be produced by carrying out in the presence of a palladium catalyst (eg, Pd (PPh ₃ ) ₄ ) in a THF solvent at a temperature of 50 ° C. or higher. This reaction is not limited to these conditions, and a known method can be applied.

(General synthesis method 4: R ² = NO ₂ or substituted or unsubstituted acyl)
Scheme 4

(In the formula, each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.). Here, “Tf” represents a trifluoromethanesulfonyl group.)
The compound represented by the formula (4-5) and the formula (4-5) can be produced from the compound represented by the formula (4-1) in two steps.

As the compound represented by the formula (4-1), a known compound may be used, or a compound derived from a known compound by a conventional method may be used.

The compound represented by the formula (4-2) can be produced by reacting the compound represented by the formula (4-1) with the compound represented by the formula (NHR ^1A R ^{1A ′} ). That is, when the compound represented by the formula (NHR ^1A R ^{1A ′} ) of 2 equivalents or more with respect to the formula (4-1) is carried out in a solvent such as NMP and DMF at room temperature, the corresponding formula (4- The compound shown in 2) can be produced. When the reaction proceeds slowly or does not proceed, the temperature can be raised to about 100 ° C.

The compound represented by the formula (4-3) can be produced by reacting the compound represented by the formula (4-1) and the formula (R ^1B OH). In other words, for the formula (4-1), the compound represented by the formula (R ^1B OH) is carried out in the presence of sodium hydride in a solvent such as NMP and DMF at a temperature of 80 ° C. or higher. A compound represented by the formula (4-3) can be produced. When the reaction proceeds slowly or does not proceed, the temperature can be raised to about 100 ° C.

The compound represented by formula (4-4) or formula (4-5) is obtained by reacting the compound represented by formula (4-2) or formula (4-3) with the compound represented by formula (1-5). Can be manufactured. That is, in the presence of a palladium catalyst (eg, Pd (OAc) ₂ , Pd ₂ (dba) _3, etc.), a phosphine-based ligand (eg, BINAP, Xantphos, etc.), and a base (eg, cesium carbonate, potassium carbonate), A compound represented by the formula (4-4) or the formula (4-5) can be produced by carrying out the reaction at a temperature of 80 ° C. or higher in a solvent such as dioxane and toluene.

(General synthesis method 5: when R ² is substituted or unsubstituted aryl, heteroaryl, alkenyl, or alkynyl)
Scheme 5

(In the formula, each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.). Here, “Tf” represents a trifluoromethanesulfonyl group.)
The compound represented by formula (5-4) can be produced from the compound represented by formula (5-1) in three steps.

X ¹ shown in Scheme 5 is a halogen atom or an OTf group, preferably a fluorine or chlorine atom. X ² is a halogen atom or an OTf group, preferably a bromine or iodine atom. X is as defined above. As the compound represented by the formula (5-1) or the formula (R ² -X), a known compound may be used, or a compound derived from a known compound by a conventional method may be used. The compound represented by the formula (R ¹ -H) is synonymous with the compound represented by the formula (NHR ^1A R ^{1A ′} ) or the formula (R ^1B OH) described above.

The compound represented by the formula (5-2) can be produced by reacting the compound represented by the formula (5-1) and the formula (R ¹ -H). This reaction can be carried out under the same conditions as in the production method of formula (1-3) or formula (1-4).

The compound represented by the formula (5-3) can be produced by a Suzuki coupling reaction between the compound represented by the formula (5-2) and the compound represented by the formula (R ² -X). That is, in the presence of a palladium catalyst (eg, Pd (PPh ₃ ) ₄ , Pd ₂ (dba) ₃ ) and a base (eg, sodium carbonate, potassium carbonate), NMP, DMF, an ether solvent (eg, THF, dioxane) Etc.) and an alcohol solvent (eg, ethanol, propanol, etc.) at a temperature of 50 ° C. or higher, the corresponding compound represented by the formula (5-3) can be produced. This reaction is not limited to these conditions, and a known method can be applied.

The compound represented by the formula (5-4) can be produced by reacting with the compound represented by the formula (1-5). This reaction can be carried out under the same conditions as in the production method of formula (1-2).

(General synthesis method 6: In the case of pyrimidine derivatives)
Scheme 6

(Wherein each symbol has the same meaning as in the above item (1A) or (1B), R represents a lower (eg, C1-C6) alkyl group, and X represents a leaving group (halogen, OTf, etc.). Here, “Tf” represents a trifluoromethanesulfonyl group.)
The compound represented by formula (6-6) can be produced from the compounds represented by formula (6-1) and formula (6-2) in four steps.

As the compound represented by the formula (6-1) or the formula (6-2), a known compound may be used, or a compound derived from a known compound by a conventional method may be used. The compounds represented by the formula (1-5) and the formula (R ¹ -H) are synonymous with the compounds described above.

The compound represented by the formula (6-3) can be produced by reacting the compound represented by the formula (6-1) or a salt thereof with the compound represented by the formula (6-2). That is, in the presence of a base (eg, potassium hydroxide aqueous solution) in an ether solvent (eg, THF, dioxane, etc.) or an alcohol solvent (eg, ethanol, etc.) at 0 ° C. to room temperature, A corresponding compound represented by the formula (6-3) can be produced.

The compound represented by the formula (6-4) can be produced by reacting the compound represented by the formula (6-3) with the compound represented by the formula (1-5). In other words, in the presence of acetic acid, the reaction is carried out at a temperature of 80 ° C. or higher in an ether solvent (eg, dioxane, diglyme, etc.) and an alcohol solvent (eg, t-butanol, ethanol, propanol, etc.). A compound represented by the formula (6-4) can be produced.

The compound represented by the formula (6-5) can be produced by heating and refluxing the formula (6-4) in phosphorus oxychloride.

The compound represented by the formula (6-6) can be produced by reacting the compound represented by the formula (6-5) with the compound represented by the formula (R ¹ -H). This reaction can be carried out under the same conditions as in the production method of formula (1-3) or formula (1-4).

(General synthesis method 7: In the case of condensed pyridine derivatives)
Scheme 7

(In the formula, each symbol has the same meaning as the above item (1A) or (1B), R represents a phenyl group, lower (eg, C1-C6) alkyl, and X represents a leaving group (halogen, OTf, etc.). Here, “Tf” represents a trifluoromethanesulfonyl group.)
The compound represented by the formula (7-5) can be produced from the compound represented by the formula (7-1) in four steps.

As the compound represented by the formula (7-1) or the formula (R ^{2A ″} -X), a known compound may be used, or a compound derived from a known compound by a conventional method may be used. -5) and the compound represented by the formula (R ¹ -H) are synonymous with the compounds described above.

The compound represented by the formula (7-2) can be produced by reacting the compound represented by the formula (7-1) with the compound represented by the formula (NH ₂ R ^{1A ″} ). The compound represented by the formula (7-2) is produced by carrying out the compound represented by the formula (NH ₂ R ^{1A ″} ) of 2 equivalents or more in a solvent such as NMP and DMF at a temperature of 150 ° C. or higher. can do. If the reaction proceeds slowly or does not proceed, the temperature can be raised to about 250 ° C. using a microwave reaction apparatus.

The compound represented by the formula (7-3) can be produced by reacting the compound represented by the formula (7-2) and the formula (ClC (= O) OR) or the formula (XC (= O) X). The compound represented by the formula (ClC (═O) OR) is preferably phenyl chloroformate, and the compound represented by the formula (XC (═O) X) is preferably carbonyldiimidazole or triphosgene. This reaction is carried out in the presence of a base (eg, sodium bicarbonate water, triethylamine, etc.) in a solvent such as ethyl acetate, THF, or acetonitrile at a temperature of about room temperature to about 100 ° C. to give the corresponding formula (7-3). The compounds shown can be prepared. The base may not be used depending on the reactant used.

The compound represented by the formula (7-4) can be produced by reacting the compound represented by the formula (7-3) with the compound represented by the formula (R ^{2A ″} -X). That is, in the presence of sodium hydride, DMF, NMP, Alternatively, the corresponding compound represented by the formula (7-4) can be produced by carrying out the reaction at room temperature in an ether solvent (eg, dioxane, diglyme, etc.).

The compound represented by the formula (7-5) can be produced by reacting with the compound represented by the formula (1-5). This reaction can be carried out under the same conditions as in the production method of formula (1-2).

(General Synthesis Method 8: Introduction of Substituents R ^5A and R ^{5B in} A)
Scheme 8

(In the formula, each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.), where “Tf” represents a trifluoromethanesulfonyl group. (The compound represented by ^5A- B (OR) ₂ means a corresponding boronic acid or boronic ester.)
Although the production method in the case where A of the compound represented by the formula (1-5) is a benzene ring is described in Scheme 8, it is not limited to the method described above.

The compound represented by the formula (8-5) can be produced from the compound represented by the formula (8-1) in four steps.

As the compound represented by the formula (8-1), R ^5A -B (OR) ₂ (boronic acid or boronic ester) or the formula (R ^{5B ′} -X), a known compound may be used. A compound derived from a compound by a conventional method may be used. PG described above represents a hydroxyl-protecting group, and examples thereof include ether-based protecting groups such as a methyl group and a methoxymethyl (MOM) group, and Si-based protecting groups such as a t-butyldimethylsilyl (TBS) group. However, it is not limited to these.

The compound represented by the formula (8-2) can be produced by deprotecting the formula (8-1) by a conventional method.

The compound represented by the formula (8-3) can be produced by reacting the compound represented by the formula (7-3) with the compound represented by the formula (R ^{5B ′} -X). That is, in the presence of a base (eg, potassium carbonate, sodium hydride, etc.) in DMF, NMP, or an ether solvent (eg, THF, dioxane, diglyme, etc.) at room temperature, the corresponding formula (8 -3) can be produced.

The compound represented by the formula (8-4) can be produced by a Suzuki coupling reaction between the compound represented by the formula (8-3) and the compound represented by the formula (R ^5A -B (OR) ₂ ). That is, in the presence of a palladium catalyst (eg, Pd (PPh ₃ ) ₄ , Pd ₂ (dba) ₃ ) and a base (eg, sodium carbonate, potassium carbonate), NMP, DMF, an ether solvent (eg, THF, dioxane) Etc.) and an alcohol solvent (eg, ethanol, propanol, etc.) at a temperature of 50 ° C. or higher, the corresponding compound represented by the formula (5-3) can be produced. This reaction is not limited to these conditions, and a known method can be applied.

The compound represented by the formula (8-5) can be produced by a reduction reaction of a nitro group. This reaction can be carried out by a known method. For example, in the presence of palladium carbon, NMP, DMF, ethyl acetate, an ether solvent (eg, THF, dioxane, etc.), an alcohol solvent (eg, ethanol, propanol, etc.), or By carrying out under a hydrogen atmosphere in these mixed solvents, the corresponding compound represented by the formula (2-2) can be produced. This reaction is not limited to these conditions, and a known method can be applied.

(General Synthesis Method 9: Introduction of Substituent R ^{5A in} A)
Scheme 9

(In the formula, each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.), where “Tf” represents a trifluoromethanesulfonyl group. Can include hydrogen or any suitable substituents such as alkyl, aryl, alkenyl, acyl, amino, alkoxy, sulfamoyl, carbamoyl, etc. Also, two R together form a ring. May be.)
The compound represented by the formula (9-3) can be produced from the compound represented by the formula (9-1) in two steps.

As the compound represented by the formula (9-1) and R ^5A -B (OR) ₂ (boronic acid or boronic acid ester), a known compound may be used, and it is derived from a known compound by a conventional method. A compound may be used.

The compound represented by the formula (9-2) can be produced by reacting with a compound represented by the formula (R ^5A -B (OR) ₂ ). This reaction can be carried out under the same conditions as in the production method of formula (8-4).

The compound represented by the formula (9-3) can be produced by a reduction reaction of a nitro group. This reaction can be carried out under the same conditions as in the production method of formula (8-5).

(General synthesis method 10: when R ² is substituted or unsubstituted acyl, carbamoyl or carboxy)
Scheme 10

(In the formula, each symbol has the same meaning as the above item (1A) or (1B), and Alk represents lower (for example, C1-C6) alkyl. R ^{2 ′} is suitably used as a substituent such as hydrogen or alkyl. And two R ^{2 ′s} may be combined to form a ring.)
The compound represented by formula (10-3) can be produced from the compound represented by formula (10-1) in two steps.

The compound represented by the formula (10-2) can be produced by hydrolyzing the compound represented by the formula (10-1). The reaction solvent is ether solvent such as dioxane, THF and DME, alcohol solvent such as ethanol and methanol, solvent such as DMF, DMA, DMSO and NMP and water are mixed and water is used as the base. Lithium hydroxide or the like can be used. The reaction temperature is preferably room temperature, but may be further increased when the reaction proceeds slowly.

The compound represented by the formula (10-3) can be synthesized by condensing the compound represented by the formula (10-2) with a compound represented by the formula NH (R ^{2 ′} ) ₂ . As the reaction solvent, DMF, NMP, DMA, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile and the like can be used. Examples of the condensing agent include DCC (dicyclohexylcarbodiimide), BOP (benzotriazol-1-yloxy-trisdimethylaminophosphate), PyBOP (hexafluorophosphate (benzotriazol-1-yloxy) tripyrrolidinophosphonium), PyBrop (hexafluoro). Bromotrispyrrolidinophosphonium phosphate), HATU, DPPA, WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), DMT-MM (4- (4,6-dimethoxy-1,3, 5-triazin-2-yl) -4-methylmorpholinium chloride) and the like can be used. These reagents can be used in combination with, for example, HOSu (1-hydroxysuccinimide), HOBt (1-hydroxybenzotriazole), HOAt (1-hydroxy-7-azabenzotriazole) and the like. In some cases, it is preferably carried out in the presence of an organic amine such as triethylamine or DIEA. The reaction temperature and reaction time are not particularly limited, but the reaction is usually carried out at room temperature, and when the reaction proceeds slowly, the reaction may be promoted by heating.

(General synthesis method 11: when R ² is substituted or unsubstituted amino)
Scheme 11

(In the formula, each symbol has the same meaning as the item (1A) or (1B), and examples of R ^{2 ″} include hydrogen, alkyl, and the like, which are appropriate as substituents.)
The compound represented by the formula (11-3) can be produced from the compound represented by the formula (11-1) in two steps.

The compound represented by the formula (11-2) can be produced by reducing the compound represented by the formula (11-1). As the reaction solvent, an ether solvent such as dioxane, THF and DME, an alcohol solvent such as ethanol and methanol, a solvent such as DMF, DMA, DMSO and NMP and water are mixed and used. As the reducing agent, for example, hydrogen and palladium carbon can be used. The reaction temperature is preferably room temperature, but if the reaction proceeds slowly, the temperature may be further increased.

The compound represented by the formula (11-3) is obtained by converting the compound represented by the formula (11-2) into a carboxylic acid represented by the formula R ^{2 ″} C (═O) OH or a corresponding acid chloride, and an acid anhydride. It can synthesize | combine by making it react. When carboxylic acid is used, it can be carried out under the same conditions as in the production method of formula (10-3). Moreover, what is necessary is just to implement according to a conventional method about reaction with an acid chloride and an acid anhydride.

The production of the present invention can be carried out by appropriately modifying, combining, or adding known techniques to the above preferred embodiments.

The compound of the present invention can be protected using a protecting group. For example, typically, halogen (I, Br, Cl, F, etc.), lower (here, typically, C1-C6 is shown, but not limited thereto) alkoxy, lower alkylthio, lower alkylsulfonyloxy, aryl Represents sulfonyloxy and the like. ), An appropriate substituent can be protected by a method known in the art. Examples of such protecting groups include protection described in Protective Groups in Organic Synthesis, TWGreen, John Wiley & Sons Inc. (1981), such as ethoxycarbonyl, t-butoxycarbonyl, acetyl, and benzyl. You can raise a group. Methods for introducing and removing protecting groups are those commonly used in organic synthetic chemistry [for example, see Protective Groups in Organic Synthesis, written by TWGreene, John Wiley & Sons Inc. (1981)], or the like. It can obtain according to. In addition to the above production method, the functional group contained in each substituent can be converted by a known method [for example, Comprehensive Organic Transformations, RCLarock (1989), etc.], and the compound of the present invention. Some of these can lead to further novel derivatives as synthetic intermediates. The intermediates and target compounds in the above production methods are isolated and purified by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do. In addition, the intermediate can be subjected to the next reaction without any particular purification.

(TTK protein kinase)
“TTK protein kinase” is an enzyme described and defined in Patent Document 3, for example, an amino acid sequence registered as Genbank NM — 003318, or a deletion or addition of one or several amino acids in the amino acid sequence. And a polypeptide containing an amino acid sequence which is inserted or substituted and has kinase activity. Here, as a preferable amino acid sequence, any of those listed in Patent Document 3 can be adopted. Here, “activity of TTK protein kinase” and “TTK activity” mean phosphorylation of threonine and / or serine and / or tyrosine. For example, in p38 MAPK (see Patent Document 3), phosphorylation of the 180th threonine and / or the 182nd tyrosine is mentioned. TTK activity can be measured using the measurement method used in the screening method of Patent Document 3. Whether or not the polypeptide has kinase activity is determined by, for example, contacting the polypeptide, a substrate for measuring TTK activity, and a phosphate group donor, measuring TTK activity, and TTK activity of wild-type TTK protein kinase under the same conditions. Can be examined by comparing with. A known substrate for measuring TTK activity and a phosphate donor can be used. Further, the novel substrate for measuring TTK activity described in the present invention may be used. About TTK activity, what is described in a nonpatent literature 1 can be considered. And the measurement of TTK activity can mention what was described in patent document 3, for example. The TTK protein kinase only needs to be a polypeptide having TTK protein kinase activity, that is, one or several amino acids are deleted or added in the amino acid sequence described in Patent Document 3 known as a kinase activity domain. Any polypeptide that contains an amino acid sequence that may be inserted or substituted and that has kinase activity may be used. The total length of the polypeptide, addition of a modifying group, alteration of amino acid residues, and the like are appropriately selected as necessary, and are not limited to the sequences described herein. Therefore, in this specification, even when simply referred to as “TTK”, it is understood that it is used synonymously with this “TTK protein kinase” unless otherwise noted. TTK has the following alias names, which can be referred to.
TTK → TTK protein kinase (TTK PROTEIN KINASE)
hMPS1 → human monopolar spindle 1 (human MONOPOLARSPINDLE 1)
PYT → Phosphotyrosine-picked threonine kinase (PHOSPHOTYROSINE-PICKED THREONINE KINASE)
MPS1L1 → Monopolar spindle 1-like 1 (MONOPOLARSPINDLE 1-LIKE 1)
ESK → ESK, mouse ESK (= EC STY Kinase) homolog (ESK; MOUSE HOMOLOG OF ESK (= EC STY Kinase)).

The compound obtained by the screening method of the present invention or a salt thereof can exert a therapeutic or preventive action against a disease that develops in association with an increase in TTK activity. For example, according to the screening method of the present invention, a candidate compound for a therapeutic or prophylactic agent effective for cancer, immune disease, etc. that develops due to an increase in TTK activity can be screened.

Examples of the “cancer” include various malignant neoplasms such as solid cancer, hemangioma, hemangioendothelioma, sarcoma, Kaposi sarcoma and hematopoietic tumor, and include colon cancer and liver cancer, and further metastasis of these cancers. Is also included. The present invention has succeeded in the discovery of a novel series of compounds having specific properties that inhibit the action of TTK kinases and make them particularly useful in formulating pharmaceuticals for treating the above diseases. In particular, the compounds are particularly useful in the treatment of proliferative diseases such as cancers where TTK kinase, which develops as either a solid tumor or a hematological tumor, is known to be active, in particular colorectal cancer, It is useful in diseases such as breast cancer, lung cancer, prostate cancer, pancreatic cancer or bladder cancer and kidney cancer as well as leukemia and lymphoma.

Examples of “immune diseases” include atopy, asthma, rheumatism, collagen disease, allergies and the like.

In addition, the compound of the present invention or a salt thereof provides a pharmaceutical composition for use in the treatment or prevention of diseases related to TTK protein kinase, for example, cancer or immune disease involving TTK protein kinase.

The above-mentioned pharmaceutical composition is characterized by containing the compound of the present invention or a salt thereof as an active ingredient. Therefore, the pharmaceutical composition exhibits an excellent effect of being able to act on the disease that develops in connection with TTK protein kinase through suppression of the activity of the enzyme. For example, the pharmaceutical composition of the present invention has an excellent effect that it can act on cancers, immune diseases, etc., particularly cancers, immune diseases, etc. that develop in relation to TTK activity, through suppression of the enzyme activity. Demonstrate. When the pharmaceutical composition is used for the treatment or prevention of cancer, conventional cancer therapy, for example, radiation therapy, chemotherapy, in particular, prior to or prior to the application of a DNA degrading agent for presensitizing tumor cells. But you can use it.

The content of the compound or a salt thereof in the pharmaceutical composition can be adjusted as appropriate depending on the disease to be treated, the age, weight, etc. of the patient, and may be a therapeutically effective amount. In the case of a compound, for example, 0.0001 to 1000 mg, preferably 0.001 to 100 mg. In the case of a polypeptide or a derivative thereof, for example, 0.0001 to 1000 mg, preferably 0.001 to 100 mg, a nucleic acid or a derivative thereof. In this case, for example, it is desirable to be 0.00001 to 100 mg, preferably 0.0001 to 10 mg.

The pharmaceutical composition may further contain various auxiliaries that can stably hold the compound or a salt thereof. Specifically, pharmaceutically acceptable auxiliaries, excipients, binders, and stabilizers that exhibit the property of inhibiting the active ingredient from degrading before reaching the site where the active ingredient is to be delivered. Agents, buffers, solubilizers, isotonic agents and the like.

The dosage form of the pharmaceutical composition is appropriately selected according to the type of active ingredient; individual, organ, local site, tissue to be administered; age, weight, etc. of the individual to be administered. Examples of the administration form include subcutaneous injection, intramuscular injection, intravenous injection, and local administration.

In addition, the dosage of the above pharmaceutical composition is also appropriately selected according to the type of active ingredient; individual, organ, local site, tissue to be administered; age, weight, etc. of the individual to be administered. The administration is not particularly limited, but when the active ingredient is a low molecular compound or a high molecular compound, the amount of the active ingredient is, for example, 0.0001 to 1000 mg / kg body weight, preferably 0.001 to 100 mg. / Kg body weight, in the case of a polypeptide or a derivative thereof, for example, 0.0001 to 1000 mg / kg body weight, preferably 0.001 to 100 mg / kg body weight, in the case of a nucleic acid or a derivative thereof, for example, 0.00001 to 100 mg / kg Administration may be performed a plurality of times per day, for example, 1 to 3 times, so as to obtain a single dose of kg body weight, preferably 0.0001 to 10 mg / kg body weight.

(Medicine)
The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. In addition, these pharmaceutical preparations are used for animals and humans.

The administration route is preferably the most effective one for treatment, and can be oral or parenteral such as rectal, buccal, subcutaneous, intramuscular, intravenous and the like.

Administration forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, and injections. Liquid preparations such as emulsions and syrups suitable for oral administration include water, sugars such as sucrose, sorbit, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil And preservatives such as p-hydroxybenzoates, and flavors such as strawberry flavor and peppermint. In addition, capsules, tablets, powders, granules, etc. are excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl It can be produced using a binder such as alcohol, hydroxypropylcellulose, gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin.

Formulations suitable for parenteral administration preferably comprise sterile aqueous preparations containing the active compound that is isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of salt water and a glucose solution.

Topical formulations are prepared by dissolving or suspending the active compound in one or more media such as mineral oil, petroleum, polyhydric alcohol and the like or other bases used in topical pharmaceutical formulations.

Preparations for enteral administration are prepared using conventional carriers such as cacao butter, hydrogenated fat, hydrogenated fatty carboxylic acid and the like and provided as suppositories.

In the present invention, glycols, oils, flavors, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surface active agents exemplified in oral preparations are used in parenteral preparations. One or more auxiliary components selected from agents, plasticizers and the like can also be added.

The effective dose and frequency of administration of the compound of the present invention or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc. The daily dose is 0.01 to 1000 mg / person, preferably 5 to 500 mg / person, and the administration frequency is preferably once a day or divided.

The compound of the present invention preferably has the inhibitory activity of the test substance on the basis of the fluorescence value when the TTK IC _{50 in} the case of screening for a compound having a TTK kinase activity inhibitory action using the p38MAPK peptide is no test substance. Is 1 μM or less, preferably 0.1 μM or less, more preferably 0.01 μM or less, or in the case of screening for cancer cell growth inhibitory compounds (A549 assay), in the range of 10 nM to 10 μM Preferably a compound having an IC ₅₀ value of less than 10 μM, more preferably less than 1 μM.

For more information on formulation, see Comprehensive Medicinal Chemistry (Corwin Hansch; Cairman of Editorial Board), Pergamon Press, Volume 5, Chapter 25.2.

The present invention also relates to a system, device, and kit for producing the pharmaceutical composition of the present invention. It is understood that the constituent requirements of such a system, apparatus, and kit can use those known in the art and can be appropriately designed by those skilled in the art.

The present invention also relates to a system, apparatus, and kit using the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof. It is understood that the constituent requirements of such a system, apparatus, and kit can use those known in the art and can be appropriately designed by those skilled in the art.

The compound of the present invention is a compound having utility as a medicine. Here, as usefulness as a medicine, it is a compound with high metabolic stability, low induction of drug metabolizing enzymes, small inhibition of drug metabolizing enzymes that metabolize other drugs, and high oral absorbability A point, a point with a small clearance, or a point with a sufficiently long half-life for exhibiting a medicinal effect is included.

References such as scientific literature, patents, and patent applications cited in this specification are incorporated herein by reference in their entirety to the same extent as if they were specifically described.

Hereinafter, the present invention will be described in more detail by way of examples. However, the technical scope of the present invention is not limited by these examples.

The equipment described below was used for the equipment used and the measurement conditions.

LC / MS analysis used a Waters system (ZQ2000 mass detector; 1525 HPLC pump; 2996 photodiode array detector; 2777 autosampler). For the analysis, a reverse phase C18 column (Waters, X-Bridge C18, 4.6 × 50 mm, 5 μM) was used, and water / acetonitrile (0.1% formic acid) was used as an elution solvent. Elution conditions were 10-100% acetonitrile (3 minutes linear gradient) and 100% acetonitrile (1 minute) at a flow rate of 3 mL / min. The described LC / MS t _R indicates the retention time (minute) of the target compound in LC / MS analysis, and UV at 254 nm was used for peak detection.

Reverse phase preparative liquid chromatography was performed using a Waters system (ZQ 2000 mass detector; 2525 HPLC pump; 2996 photodiode array detector; 2777 autosampler). A reverse phase C18 column (Waters, X-Bridge, 19 × 50 mm, 5 μM) was used, and water / acetonitrile (0.1% formic acid) was used as an elution solvent. Elution conditions were 10-100% acetonitrile (5 minutes linear gradient) and 100% acetonitrile (2 minutes) at a flow rate of 25 mL / min.

Silica gel chromatography used a system of Yamazen (YFLC-Wprep2XY), Moritex (Purif-α2), or Isco (Combi Flash Companion). The column was a Yamazen Hi-Flash column (S to 5 L), and the elution solvent was hexane / ethyl acetate or chloroform / methanol.

1H NMR spectrum was measured using Varian Gemini-300 (300 MHz) or Bruker AV-400 (400 MHz). Chemical shifts are described as δ values (ppm) using TMS (tetramethylsilane) as an internal standard. In the analysis results, s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad were used as abbreviations.

The microwave reactor used was Biotage initiator 8 or initiator 60.

(Evaluation methods)
Screening of compounds with T38 kinase activity inhibitory activity using p38 MAPK peptide 1.0 μL of test substance (solvent: 10% (v / v) DMSO), 5 μL of TTK solution (composition: 4 μg / ml TTK, 25 mM Tris-HCl, pH 7.5, 5 mM β-glycerophosphate, 2 mM DTT, 0.1 mM Na ₃ VO ₄ , 5 mM MgCl ₂ , 0.1% (w / v) BSA), substrate solution 5 μL (composition: 60 μM p38 MAPK peptide, 60 μM ATP, 25 mM Tris) -HCl, pH 7.5, 5 mM β-glycerophosphate, 2 mM DTT, 0.1 mM Na ₃ VO ₄ , 5 mM MgCl ₂ , 0.1% (w / v) BSA) in polypropylene 384-well microtiter plate (Corning) Mix and place in a constant temperature humidifier. After standing overnight at a temperature of 25 ° C and a humidity of 95%, the reaction stop solution (composition: 25 mM Tris-HCl, pH 7.5, 100 mM EDTA, 0.01% (v / v) TritonX-100, 0.1% (w / v ) BSA) 50 μL was added and mixed.

Remove 1.7 μL from this, mix with 60 μL of reaction stop solution in 384-well polypropylene microtiter plate (Corning), transfer 40 μL to 384-well black NeutrAvidin plate (Pierce), seal, and seal at room temperature for 30 minutes Incubated. The plate was washed 3 times with 100 μL of TTBS (composition: 10 mM Tris, 40 mM Tris-HCl, 150 mM NaCl ₂ , 0.05% (v / v) Tween 20), and then the primary antibody solution (Anti-phosphop38 antibody-28B10 (Cell Signaling) , # 9216)) was added and incubated at room temperature for 1 hour. Similarly, after washing 3 times with 100 μL of TTBS, 40 μL of secondary antibody solution (Eu-N1 labeled Anti-mouse IgG (Perkin Elmer, # AD0124)) was added and incubated at room temperature for 30 minutes. The plate was washed 5 times with 100 μL of TTBS, 40 μL of enhancement solution (Perkin Elmer) was added and incubated at room temperature for 5 minutes, and the fluorescence value at 615 nm was measured with ARVO (Perkin Elmer). Based on the fluorescence value in the absence of the test substance, the inhibitory activity of the test substance was calculated, and a compound showing a TTK kinase activity inhibitory action was obtained as a candidate compound of a TTK activity inhibitor.

Screening for cancer cell growth inhibitory compounds Cell suspension (RERF-LC-AI) adjusted to an appropriate concentration by D-MEM (Nacalai Tesque) with 10% FBS (High clone) , A549: 1 × 10 ⁴ / ml, MRC5: 3 × 10 ⁴ / ml and 1 × 10 ⁵ / ml) at 100 μL / well to a 96-well plate (hereinafter referred to as well plate), and CO at 37 ° C. for 1 day Cultured in ₂ incubators. 2 μL of 10 mM compound (100% DMSO solution) that showed TTK kinase activity inhibitory action in a 96-well assay block was added to 998 μL of the culture solution to prepare a 20 μM solution, and 10 concentrations were prepared in a 2-fold dilution series. Next, 100 μL / well of the above compound dilution was added to each well of the well plate in which the cells were prepared to give 200 μL / well. Thereafter, the cells were further cultured in a 37 ° C. CO ₂ incubator for 3 days. 10 μL each of WST-8 kit (Kishida Chemical) solution for cell number measurement was added to each well of the well plate, and a color reaction was performed for 1 to 4 hours in a CO ₂ incubator. A compound that shows growth inhibitory activity in cancer cells after measuring the absorbance at 450 nm (reference wavelength 620 nm) with a microplate reader and calculating the inhibitory activity of the test substance based on the absorbance value without the test substance Selected.

Example 1
Example 1-1
Methyl-2- (cyclohexylamino) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinate

Step 1: Methyl-6-chloro-2- (cyclohexylamino) nicotinate Methyl-6-chloro-2- (cyclohexylamino) nicotinate (5.65 g, 27.4 mmol) in NMP (20 mL) was added to cyclohexylamine (5.71 g , 6.59 mL, 57.6 mmol) and stirred at room temperature for 5 hours. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered, concentrated under reduced pressure, and the residue was solidified with dichloromethane / ether to give the title compound (4.03 g, 15.0 mmol, 55%) as a colorless solid.
1H-NMR (400 MHz, DMSO-d6) δ 1.27-1.38 (m, 5H), 1.53 (brs, 1H), 1.64 (brs, 2H), 1.90 (brs, 2H), 3.80 (s, 3H), 3.91 (s, 1H), 6.61 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H).
MS (ESI) m / z = 269 (M + H) ⁺ .
LC / MS t _R = 2.85 min.

Step 2: Methyl 2- (cyclohexylamino) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinate Methyl 6-chloro-2- (cyclohexylamino) nicotinate ( 213 mg, 0.793 mmol), 3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) aniline (177 mg, 0.872 mmol), Xantphos (68.8 mg, 0.119 mmol), and cesium carbonate (387 mg) , 1.19 mmol) in dioxane (2.0 mL) was added Pd (OAc) ₂ (17.8 mg, 0.079 mmol) and stirred for 8 hours under reflux. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The obtained residue was purified by reverse phase HPLC (acetonitrile / water / 0.3% formic acid: 10-100% acetonitrile) to give the title compound (344 mg, 0.789 mmol, 100%) as a brown solid.
1H-NMR (400 MHz, DMSO-d6) δ 1.23-1.42 (m, 5H), 1.54-1.60 (m, 1H), 1.68 (br s, 2H), 1.96 (br s, 2H), 3.16 (d, J = 5.1 Hz, 1H), 3.72 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 4.03-4.10 (m, 1H), 6.02 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.82 (s, 1H), 8.02 (s, 1H ), 8.21 (d, J = 7.1 Hz, 1H), 9.39 (s, 1H).
MS (ESI) m / z = 436 (M + H) ⁺ .
LC / MS t _R = 2.48 min.

Example 1-2
2- (Cyclohexylamino) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinic acid

Add 2N to a solution of methyl 2- (cyclohexylamino) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinate (144 mg, 0.332 mmol) in DMSO (3.0 mL). An aqueous sodium hydroxide solution (633 μL) was added and the mixture was stirred at 80 ° C. for 3 hours. A 2N aqueous hydrochloric acid solution was added, and then ethyl acetate was added for separation. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered, and the reaction solution was concentrated to give the title compound (344 mg, 0.789 mmol, 100%) as a brown solid.
1H-NMR (400 MHz, DMSO-d6) δ 1.28-1.41 (m, 5H), 1.58 (br s, 1H), 1.68 (br s, 2H), 1.97 (br s, 2H), 3.84 (s, 3H ), 3.87 (s, 3H), 4.02 (s, 1H), 6.00 (d, J = 8.3 Hz, 1H), 7.28 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.54 (d , J = 7.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 8.01 (s, 1H), 8.35 (d, J = 7.1 Hz, 1H), 9.31 (s , 1H), 12.02 (s, 1H).
MS (ESI) m / z = 422 (M + H) ⁺ .
LC / MS t _R = 1.92 min.

Example 1-3
2- (Cyclohexylamino) -N-cyclopropyl-6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinamide

2- (cyclohexylamino) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinic acid (54.4 mg, 0.129 mmol), DIEA (41.7 mg, 56 μL, 0.323 mmol) and cyclopropylamine (14.7 mg, 0.258 mmol) in DMF (0.5 mL) were added HATU (98 mg, 0.258 mol) and stirred for 5 hours. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated aqueous sodium bicarbonate, 0.1 mol / L hydrochloric acid, and saturated brine, and magnesium sulfate. Dried. The organic phase was filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (acetonitrile / water / 0.3% formic acid: 10-100% acetonitrile) to give the title compound (19.9 mg, 0.043 mmol, 34%) Was obtained as a white solid.
1H-NMR (400 MHz, DMSO-d6) δ 0.50 (br s, 2H), 0.63 (br s, 2H), 1.23-1.41 (m, 6H), 1.57 (br s, 1H), 1.68 (br s, 2H), 1.94 (br s, 2H), 2.72 (br s, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 3.99 (br s, 1H), 7.26 (s, 1H), 7.41 ( d, J = 8.6 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.92 (s, 1H), 7.99 ( s, 1H), 9.05 (d, J = 7.6 Hz, 1H), 9.11 (s, 1H).
MS (ESI) m / z = 461 (M + H) ⁺ .
LC / MS t _R = 2.02 min.

Example 1-8
N- (Cyanomethyl) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -2- (tetrahydro-2H-pyran-4-ylamino) nicotinamide

The title compound was synthesized according to the method of Example 1-3.
1H-NMR (400 MHz, DMSO-d6) δ 1.47 (m, 2H), 2.00 (m, 2H), 3.49 (t, 2H, J = 11.1 Hz), 3.86 (s, 3H), 3.87 (m, 2H ), 3.88 (s, 3H), 4.18 (s, 1H), 4.22 (d, 2H, J = 4.0 Hz), 6.02 (d, 1H, J = 8.1 Hz), 7.18 (s, 1H), 7.48 (d , 1H, J = 8.6 Hz), 7.57 (d, 1H, J = 8.6 Hz), 7.76 (d, 1H, J = 8.1 Hz), 7.84 (s, 1H), 8.03 (s, 1H), 8.64 (s , 1H), 8.90 (d, 1H, J = 6.6 Hz), 9.29 (s, 1H).
MS (ESI) m / z = 462 (M + H) ⁺ .
LC / MS t _R = 1.54 min.

Example 1-9
N- (2- (cyclohexyloxy) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyridin-3-yl) acetamide

Step 1: 6- (Cyclohexyloxy) -N- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -5-nitropyridin-2-amine cyclohexanol (778 mg, 7.77 mmol), and 2,6-Dichloro-3-nitropyridine (1.0 g, 5.18 mmol) was added to an NMP solution (7 mL) of 60% sodium hydride (249 mg, 6.22 mol), and the mixture was stirred at room temperature for 1 hour. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel chromatography (hexane: ethyl acetate = 95: 5) to give 6-chloro-2- (cyclohexyloxy) -3-nitropyridine. (956 mg, 1.86 mmol, 72%) was obtained as a colorless oil.

6-chloro-2- (cyclohexyloxy) -3-nitropyridine (444 mg, 0.865 mmol), 4- (1-methyl-1H-pyrazol-4-yl) aniline (360 mg, 2.08 mmol), Xantphos (200 Pd (OAc) ₂ (38.8 mg, 0.173 mmol) was added to a dioxane (4.0 mL) solution of mg, 0.346 mmol) and potassium carbonate (359 mg, 2.59 mmol), and the mixture was stirred for 3 hours under reflux. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 30% ethyl acetate) to give the title compound (206 mg, 0.523 mmol, 30%) as a red-brown solid.
1H-NMR (400 MHz, DMSO-d6) δ 1.38-1.49 (m, 3H), 1.62 (br s, 4H), 1.79 (br s, 2H), 1.99 (br s, 3H), 3.86 (s, 3H ), 5.17 (br s, 1H), 6.45 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.83 (s, 1H), 8.11 (s, 1H), 8.25 (d, J = 9.1 Hz, 1H).

Step 2: 6- (Cyclohexyl) -N ^2- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyridine-2,5-diamine 6- (Cyclohexyloxy) -N- (4- ( 1-methyl-1H-pyrazol-4-yl) phenyl) -5-nitropyridin-2-amine (25 mg, 0.073 mmol) in THF: methanol = 1: 1 (8 mL) was added to 10% palladium on carbon ( 26 mg) was added, and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the obtained residue was solidified and washed with hexane to give the title compound (111 mg, 0.305 mmol, 88%) as a black solid.
MS (ESI) m / z = 364 (M + H) ⁺ .
LC / MS t _R = 1.35 min.

Step 3: N- (2- (cyclohexyloxy) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyridin-3-yl) acetamide 6- (cyclohexyl) -N ^2- (4- (1-Methyl-1H-pyrazol-4-yl) phenyl) pyridine-2,5-diamine (35 mg, 0.096 mmol) and triethylamine (48.7 mg, 67 μL, 0.481 mmol) in THF (2.0 mL ) Acetic anhydride (19.7 mg, 18 μL, 0.193 mol) was added to the solution and stirred at room temperature for 1 hour. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 80% ethyl acetate) to give the title compound (8.3 mg, 0.020 mmol, 23%) as beige. Obtained as a colored solid.
1H-NMR (400 MHz, DMSO-d6) δ 1.30 (m, 1H), 1.41-1.62 (m, 5H), 1.80 (m, 2H), 2.03 (s, 3H), 2.03 (m, 2H), 3.85 (s, 3H), 4.96 (m, 1H), 6.33 (d, 1H, J = 8.1 Hz), 7.42 (d, 2H, J = 7.6 Hz), 7.60 (d, 2H, J = 7.6 Hz), 7.76 (s, 1H), 7.80 (d, 1H, J = 8.1 Hz), 8.02 (s, 1H), 8.86 (s, 1H), 8.95 (s, 1H).
MS (ESI) m / z = 406 (M + H) ⁺ .
LC / MS t _R = 1.87 min.

Example 1-10
2- (Cyclohexyloxy) -N-cyclopropyl-6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinamide

Step 1: 2,6-Dichloro-N-cyclopropylnicotinamide Implemented in the same manner as in Example 1-3 to obtain the title compound (265 mg, 1.15 mmol, 73%) as a white solid.
1H-NMR (400 MHz, DMSO-d6) δ 0.51 (s, 2H), 0.70 (d, J = 6.3 Hz, 2H), 2.80 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 8.65 (s, 1H).

Step 2: 6-chloro-2- (cyclohexyloxy) -N-cyclopropylnicotinamide 2 in NMP solution (2 mL) of cyclohexanol (195 mg, 1.95 mmol) and sodium hydride (51.9 mg, 1.30 mmol) , 6-Dichloro-N-cyclopropylnicotinamide (150 mg, 0.649 mmol) 60% was added and stirred at room temperature for 3 hours. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 40-50% ethyl acetate gradient) to give 6-chloro-2- (cyclohexyloxy)- N-cyclopropylnicotinamide (184 mg, 0.623 mmol, 96%) was obtained as a colorless oil.
MS (ESI) m / z = 295 (M + H) ⁺ .
LC / MS t _R = 2.39 min.

Step 3: 2- (cyclohexyloxy) -N-cyclopropyl-6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinamide Example 1-1, Step 2 The title compound (51.1 mg, 0.111 mmol, 60%) was obtained as a beige amorphous substance.
1H-NMR (400 MHz, DMSO-d6) δ 0.48 (m, 2H), 0.75 (m, 2H), 1.47 (br, 4H), 1.65 (m, 4H), 1.98 (m, 2H), 2.85 (m , 1H), 3.86 (s, 3H), 3.88 (s, 3H), 5.26 (m, 1H), 6.48 (d, 1H, J = 8.6 Hz), 7.22 (s, 1H), 7.38 (d, 2H, J = 8.6 Hz), 7.49 (d, 1H, J = 8.6 Hz), 7.83 (s, 1H), 7.87 (m, 1H), 8.03 (s, 1H), 8.06 (d, 1H, J = 8.6 Hz) , 9.51 (s, 1H).
MS (ESI) m / z = 462 (M + H) ⁺ .
LC / MS t _R = 2.13 min.

Example 1-11
6- (4-Carbamoylphenylamino) -2- (cyclohexyloxy) -N-cyclopropylnicotinamide

The title compound was synthesized according to the method of Example 1-10.
MS (ESI) m / z = 395 (M + H) ⁺ .
LC / MS t _R = 1.68 min.

Example 1-12
2- (Cyclohexylamino) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -4-methylnicotinamide

The title compound was synthesized according to the method of Example 1-1.
MS (ESI) m / z = 435 (M + H) ⁺ .
LC / MS t _R = 1.86 min.

Example 1-13
2- (Cyclohexyloxy) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -4-methylnicotinamide

The title compound was synthesized according to the method of Example 1-10.
1H-NMR (400 MHz, DMSO-d6) δ 1.36 (m, 3H), 1.54 (m, 3H), 1.74 (m, 2H), 1.91 (m, 2H), 2.20 (s, 3H), 3.85 (s , 3H), 3.86 (s, 3H), 5.06 (m, 1H), 6.22 (s, 1H), 7.27 (s, 2H), 7.30 (d, 1H, J = 8.6 Hz), 7.37 (s, 1H) , 7.44 (d, 1H, J = 8.6 Hz), 7.81 (s, 1H), 8.00 (s, 1H), 9.06 (s, 1H).
MS (ESI) m / z = 435 (M + H) ⁺ .
LC / MS t _R = 1.86 min.

Example 1-14
1- (2- (cyclohexylamino) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyridin-3-yl) ethanone

The title compound was synthesized according to the method of Example 1-1.
MS (ESI) m / z = 420 (M + H) ⁺ .
LC / MS t _R = 2.24 min.

Example 1-15
2- (5- (6- (cyclohexylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-ylamino) -2- (1-methyl-1H-pyrazol-4-yl) Phenoxy) acetonitrile

Step 1-1: 2-Bromo-5-nitrophenol 1-Bromo-2-methoxy-4-nitrobenzene (5.0 g, 21.6 mmol) in dichloromethane (50 mL) was added to BBr ₃ (1 M DCM solution, 32.3 mL). ) Was added at 0 ° C. and stirred overnight. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 10% ethyl acetate) to give the title compound (3.16 g, 14.5 mmol, 67%). Obtained as a white solid.
1H-NMR (300 MHz, CDCl ₃ ) δ 7.57 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 11.35 (s, 1H).

Step 1-2: 2- (2-Bromo-5-nitrophenoxy) acetonitrile 2-Bromo-5-nitrophenol (5.64 g, 25.9 mmol), and potassium carbonate (10.7 g, 78.0 mmol) in acetonitrile (100 mL) Bromoacetonitrile (3.72 g, 2.16 mL, 31.0 mmol) was added to the solution, followed by stirring overnight at room temperature. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and then concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 10-50% ethyl acetate gradient) to give the title compound (6.69 g, 26.0 mmol, 100 %) As an orange solid.
1H-NMR (300 MHz, DMSO-d6) δ 5.49 (s, 2H), 7.89 (dd, J = 8.6, 2.4 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H).

Step 1-3: 2- (2- (1-Methyl-1H-pyrazol-4-yl) -5-nitrophenoxy) acetonitrile 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazole (6.50 g, 31.2 mmol), 2- (2-bromo-5-nitrophenoxy) acetonitrile (6.69 g, 26.0 mmol), and PdCl ₂ (dppf) To a solution of CH ₂ Cl ₂ (2.13 g, 2.61 mmol) in THF (80 mL) was added 2M aqueous sodium carbonate solution (26 mL), and the mixture was stirred for 8 hours under reflux with heating. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered, concentrated under reduced pressure, and solidified with ethyl acetate to give the title compound (4.39 g, 17.0 mmol, 65%) as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 5.49 (s, 2H), 7.96-7.97 (m, 2H), 8.04 (d, J = 1.3 Hz, 1H), 8.09 (s , 1H), 8.36 (s, 1H).

Step 1-4: 2- (5-Amino-2- (1-methyl-1H-pyrazol-4-yl) phenoxy) acetonitrile Performed in the same manner as in Example 1-9 and Step 2, and the residue was medium pressure The title compound (1.27 g, 5.54 mmol, 33%) was obtained by purification by silica gel chromatography (chloroform / ethyl acetate; 20-100% ethyl acetate gradient).
1H-NMR (300 MHz, DMSO-d6) δ 3.82 (s, 3H), 5.08 (s, 2H), 5.24 (s, 2H), 6.29 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.66 (s, 1H), 7.84 (s, 1H).

Step 2-1: 6-chloro-N-cyclohexyl-3-iodopyridin-2-amine 2,6-dichloro-3-iodopyridine (6.85 g, 25.0 mmol) in NMP (100 mL) was added to cyclohexylamine ( 5.45 g, 6.29 mL, 55.0 mmol) was added, followed by stirring at 100 ° C. for 8 hours. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 10-90% ethyl acetate gradient) to give the title compound (4.65 g, 13.8 mmol, 55 %).
1H-NMR (300 MHz, DMSO-d6) δ 1.20-1.36 (m, 6H), 1.57-1.61 (m, 1H), 1.68-1.72 (m, 2H), 1.83-1.86 (m, 2H), 3.75- 3.76 (m, 1H), 5.56 (d, J = 7.8 Hz, 1H), 6.38-6.41 (m, 1H), 7.88 (d, J = 7.8 Hz, 1H).

Step 2-2: 6-chloro-N-cyclohexyl-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine Performed in the same manner as in Step 1-3, and the title compound (3.14 g , 10.8 mmol, 78%) was obtained as a red oil.
1H-NMR (300 MHz, DMSO-d6) δ 1.14-1.35 (m, 5H), 1.60-1.67 (m, 3H), 1.86-1.89 (m, 2H), 3.88 (s, 3H), 5.46 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.64 (s, 1H), 7.95 (s, 1H).

Step 2-3: 2- (5- (6- (cyclohexylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-ylamino) -2- (1-methyl-1H-pyrazole -4-yl) phenoxy) acetonitrile The title compound (71.9 mg, 0.149 mmol, 43%) was obtained in the same manner as in Example 1-1, Step 2.
1H-NMR (300 MHz, DMSO-d6) δ 1.28-1.35 (m, 5H), 1.68-1.71 (m, 3H), 1.99-2.02 (m, 2H), 3.86-3.87 (m, 7H), 4.99 ( d, J = 7.6 Hz, 1H), 5.12 (s, 2H), 6.09 (d, J = 8.1 Hz, 1H), 7.22-7.23 (m, 2H), 7.44 (d, J = 8.6 Hz, 1H), 7.56 (s, 1H), 7.72 (dd, J = 8.6, 1.8 Hz, 1H), 7.79 (s, 1H), 7.83 (s, 1H), 8.00 (s, 1H), 8.89 (s, 1H).
MS (ESI) m / z = 483 (M + H) ⁺ .
LC / MS t _R = 1.78 min.

Example 1-16
2- (5- (6- (cyclohexylamino) -5- (oxazol-5-yl) pyridin-2-ylamino) -2- (1-methyl-1H-pyrazol-4-yl) phenoxy) acetonitrile

Step 1: 5- (2,6-dichloropyridin-3-yl) oxazole 2,6-dichloronicotinaldehyde (4.90 g, 27.8 mmol) and TosMIC (6.52 g, 33.4 mmol) in methanol (60 mL) solution After adding potassium carbonate (5.00 g, 36.2 mmol), the mixture was stirred for 2 hours with heating under reflux. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 30% ethyl acetate) to give the title compound (3.74 g, 17.4 mmol, 63%). Obtained.
1H-NMR (300 MHz, DMSO-d6) δ 7.73 (d, J = 8.2 Hz, 1H), 7.94 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.67 (s, 1H).

Step 2: 6-Chloro-N-cyclohexyl-3- (oxazol-5-yl) pyridin-2-amine 5- (2,6-dichloropyridin-3-yl) oxazole (430 mg, 2.0 mmol) NMP ( 2.0 mL) solution was added with cyclohexylamine (436 mg, 0.503 mL, 4.40 mmol), and then stirred at 150 ° C. for 10 hours under microwave irradiation. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 10% ethyl acetate) to give the title compound (126 mg, 0.454 mmol, 18%). Obtained.
1H-NMR (300 MHz, DMSO-d6) δ 1.15-1.41 (m, 6H), 1.58-1.72 (m, 3H), 1.89-1.92 (m, 2H), 3.87-3.88 (m, 1H), 6.03 ( d, J = 7.7 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 8.47 (s, 1H).

Step 3: 2- (5- (6- (Cyclohexylamino) -5- (oxazol-5-yl) pyridin-2-ylamino) -2- (1-methyl-1H-pyrazol-4-yl) phenoxy) acetonitrile Example 1-1 was carried out in the same manner as in step 2, and the title compound (95 mg, 0.202 mmol, 45%) was obtained.
1H-NMR (300 MHz, DMSO-d6) δ 1.34-1.42 (m, 5H), 1.66-1.70 (m, 3H), 2.00-2.03 (m, 2H), 3.86 (s, 3H), 3.94-3.97 ( m, 1H), 5.14 (s, 2H), 5.58 (d, J = 7.6 Hz, 1H), 6.16 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 7.30 ( s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.77 (dd, J = 8.5, 1.6 Hz, 1H), 7.81 (s, 1H), 8.02 (s, 1H), 8.35 (s, 1H), 9.18 (s, 1H).
MS (ESI) m / z = 470 (M + H) ⁺ .
LC / MS t _R = 2.00 min.

Examples 1-24
6- (3- (Cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -2- (cyclohexylamino) nicotinonitrile

Step 1: 6- (4-Bromo-3-methoxyphenylamino) -2-chloronicotinonitrile 2,6-dichloronicotinonitrile (9.15 g, 52.9 mmol) and DIEA (10.3 g, 13.9 mL, 79 mmol) 4-Bromo-3-methoxyaniline (12.8 g, 63.5 mmol) was added to an NMP (130 mL) solution, and the mixture was stirred at 100 ° C. for 10 hours. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and then concentrated under reduced pressure. A methanol / chloroform / hexane solution (40 mL / 60 mL / 480 mL) was added to the resulting residue to solidify, and the title compound (11.5 g, 34.1 mmol) was collected by filtration. , 64%) as a white solid.
1H-NMR (300 MHz, DMSO-d6) δ 3.85 (s, 3H), 6.87 (d, J = 8.7 Hz, 1H), 7.14 (dd, J = 8.7, 2.4 Hz, 1H), 7.51-7.52 (m , 2H), 8.00 (d, J = 8.7 Hz, 1H), 10.24 (s, 1H).

Step 2: 6- (4-Bromo-3-methoxyphenylamino) -2- (cyclohexylamino) nicotinonitrile 6- (4-Bromo-3-methoxyphenylamino) -2-chloronicotinonitrile (9.03 g, To a solution of 26.7 mmol) in NMP (90 mL) was added cyclohexylamine (15.3 mL, 15.3 mmol), followed by stirring at 150 ° C. for 5 hours. The reaction solution was returned to room temperature, poured into ice water, and the obtained solid was collected by filtration to give the title compound (9.74 g, 24.3 mmol, 91%) as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 1.21-1.33 (br m, 5H), 1.63-1.73 (m, 3H), 1.87-1.90 (m, 2H), 3.84 (s, 4H), 6.04 (d , J = 8.4 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.48-7.55 (m , 2H), 9.50 (s, 1H).

Step 3: 6- (4-Bromo-3-hydroxyphenylamino) -2- (cyclohexylamino) nicotinonitrile Example 1-15 was carried out in the same manner as in Step 1-1, and the title compound (9.93 g, 25.6 mmol, 100%) as a brown solid.
1H-NMR (300 MHz, DMSO-d6) δ 1.14-1.40 (m, 7H), 1.64-1.69 (m, 3H), 1.90 (br s, 2H), 3.84 (s, 1H), 6.02 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.8 , 2.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H),
9.36 (s, 1H), 10.02 (s, 1H).

Step 4: 6- (4-Bromo-3- (cyanomethoxy) phenylamino) -2- (cyclohexylamino) nicotinonitrile Example 1-15 was carried out in the same manner as in Step 1-2, and the title compound (7.10 g, 16.7 mmol, 70%) was obtained as a pale green solid.
1H-NMR (300 MHz, DMSO-d6) δ 1.13-1.43 (m, 6H), 1.64-1.74 (m, 3H), 1.91 (br s, 2H), 3.85 (br s, 1H), 5.20 (s, 2H), 6.07 (d, J = 8.6 Hz, 1H), 6.44 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H) , 7.56 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 8.8, 2.3 Hz, 1H), 9.63 (s, 1H).

Process 5:
Example 1-15 The method was carried out in the same manner as in Step 1-3 to obtain the title compound (1.89 g, 4.42 mmol, 45%) as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 1.20 (m, 1H), 1.37 (m, 4H), 1.66 (m, 1H), 1.76 (m, 2H), 1.93 (m, 2H), 3.87 (s , 3H), 3.87 (m, 1H), 5.16 (s, 2H), 6.08 (d, 1H, J = 8.6 Hz), 6.37 (d, 1H, J = 7.1 Hz), 7.24 (s, 1H), 7.52 (d, 1H, J = 8.6 Hz), 7.54 (d, 1H, J = 8.6 Hz), 7.72 (d, 1H, J = 8.6 Hz), 7.84 (s, 1H), 8.06 (s, 1H), 9.54 (s, 1H).
MS (ESI) m / z = 428 (M + H) ⁺ .
LC / MS t _R = 2.11 min.

Example 1-79
(E) -3- (4- (5-Cyano-6- (cyclohexylamino) pyridin-2-ylamino) -2- (cyanomethoxy) phenyl) acrylamide

Acrylamide (12.1 mg, 0.171 mmol), 6- (4-Bromo-3- (cyanomethoxy) phenylamino) -2- (cyclohexylamino) nicotinonitrile (48.7 mg, 0.114 mmol), and Pd [P (t- Triethylamine (23.1 mg, 0.228 mmol) was added to a NMP (1.2 mL) solution of Bu) ₃ ] ₂ (5.84 mg, 0.011 mmol), and the mixture was stirred for 8 hours under microwave irradiation. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel chromatography (chloroform / methanol: 5% methanol) to give the title compound (26.6 mg, 0.064 mmol, 56%) as a yellow solid. Got as.
1H-NMR (300 MHz, DMSO-d6) δ 1.14-1.45 (5H, m), 1.63-1.78 (3H, m), 1.92-1.95 (2H, m), 3.88 (1H, br s), 5.19 (2H , s), 6.11 (1H, d, J = 8.5 Hz), 6.49 (1H, d, J = 9.0 Hz), 6.54 (1H, d, J = 15.0 Hz), 7.02 (1H, br s), 7.15 ( 1H, s), 7.48-7.62 (4H, m), 7.86 (1H, d, J = 8.8 Hz), 9.73 (1H, s).
MS (ESI) m / z = 417 (M + H) ⁺ .
LC / MS t _R = 1.78 min.

Example 1-80
N ² -cyclohexyl-N ^6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -3-methylpyridine-2,6-diamine

The title compound was synthesized according to the method of Example 1-24.
MS (ESI) m / z = 392 (M + H) ⁺ .
LC / MS t _R = 1.58 min.

Example 1-81
(E) -3- (6- (3- (Cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -2- (cyclohexylamino) pyridin-3-yl) -N -Cyclopropylacrylamide

Step 1: (E) -methyl 3- (6-chloro-2- (cyclohexylamino) pyridin-3-yl) acrylate acrylamide (12.1 mg, 0.171 mmol), 6- (4-bromo-3- (cyanomethoxy) Phenylamino) -2- (cyclohexylamino) nicotinonitrile (48.7 mg, 0.114 mmol) and Pd [P (t-Bu) ₃ ] ₂ (5.84 mg, 0.011 mmol) in NMP (1.2 mL) solution in triethylamine (1.2 mL) 23.1 mg, 0.228 mmol) was added and stirred for 8 hours under microwave irradiation. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel chromatography (chloroform / methanol: 5% methanol) to give the title compound (26.6 mg, 0.064 mmol, 56%) as a yellow solid. Got as.
1H-NMR (300 MHz, DMSO-d6) δ 1.13-1.31 (m, 5H), 1.65-1.81 (m, 5H), 3.71 (s, 3H), 3.84-3.85 (m, 1H), 6.46-6.54 ( m, 2H), 6.95 (d, J = 7.7
Hz, 1H), 7.80-7.84 (m, 2H).

Step 2: (E) -3- (6-Chloro-2- (cyclohexylamino) pyridin-3-yl) acrylic acid (E) -methyl 3- (6-chloro-2- (cyclohexylamino) pyridine-3- Yl) acrylate (767 mg, 2.60 mmol) in methanol / THF solution (4.0 mL / 4.0 mL) was added 4 mol / L sodium hydroxide aqueous solution (1.95 mL), and the mixture was stirred at room temperature for 4 hours. After acidifying with 2 mol / L hydrochloric acid aqueous solution, ethyl acetate was added and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered, and then the reaction solution was concentrated to obtain the title compound (831 mg).
1H-NMR (300 MHz, DMSO-d6) δ 1.11-1.27 (br m, 5H), 1.56-1.83 (m, 5H), 3.79 (br s, 1H), 6.33 (d, J = 15.6 Hz, 1H) , 6.42 (br s, 1H), 6.50 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 15.6 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H).

Step 3: (E) -3- (6-Chloro-2- (cyclohexylamino) pyridin-3-yl) -N-cyclopropylacrylamide Performed in the same manner as in Example 1-3, and the title compound (428 mg , 1.34 mmol, 52%).
1H-NMR (300 MHz, DMSO-d6) δ 0.43-0.46 (m, 2H), 0.67-0.69 (m, 2H), 1.12-1.35 (m, 5H), 1.65-1.81 (m, 5H), 2.72- 2.76 (m, 1H), 3.82-3.83 (m, 1H), 6.34 (d, J = 15.4 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H ), 7.50-7.54 (m, 2H), 8.13 (d, J = 4.4 Hz, 1H).

Step 4: (E) -3- (6- (3- (cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -2- (cyclohexylamino) pyridin-3-yl ) -N-cyclopropylacrylamide The title compound (11.9 mg, 0.023 mmol, 7%) was obtained in the same manner as in Example 1-1 / Step 2.
1H-NMR (300 MH, DMSO-d6) δ 0.43-0.44 (m, 2H), 0.65-0.67 (m, 2H), 1.20-1.35 (m, 5H), 1.74-1.77 (m, 3H), 1.97- 2.00 (m, 2H), 2.72-2.74 (m, 1H), 3.84-3.88 (m, 4H), 5.12 (s, 2H), 6.07-6.11 (m, 2H), 6.21 (d, J = 7.4 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 7.45 (dd, J = 8.5, 2.8 Hz, 2H), 7.52 (d, J = 15.4 Hz, 1H), 7.76-7.80 (m, 2H), 7.89 (d, J = 4.2 Hz, 1H), 8.02 (s, 1H), 9.15 (s, 1H).
MS (ESI) m / z = 512 (M + H) ⁺ .
LC / MS t _R = 1.82 min.

Example 1-82
4- (Cyclohexylamino) -2- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile

Step 1: 4-hydroxy-2- (methylthio) pyrimidine-5-carbonitrile To a solution of potassium hydroxide (2.33 g, 41.5 mmol) in methanol (15 mL), S-methylisothiourea sulfate (6.80 g, 24.4 mmol) ) Was added at 0 ° C., followed by stirring at room temperature for 1 hour. The reaction solution was filtered to remove insoluble matters. (E) -ethyl 2-cyano-3-ethoxyacrylate (8.27 g, 48.9 mmol) was added to the filtrate at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. The precipitated solid was collected by filtration and washed with methanol and ether cooled at 0 ° C. To the obtained solid was added 0.5 mol / L aqueous sodium hydroxide solution (48.9 mL, 24.3 mmol), and the mixture was stirred at 50 ° C. for 30 min. The reaction solution was filtered to remove insolubles, and then a 2N aqueous hydrochloric acid solution was added to the filtrate cooled to 0 ° C. to adjust the pH to about 1. The precipitated solid was collected by filtration to give the title compound (935 mg, 5.59 mmol, 23%) as a white solid.
1H-NMR (400 MHz, CD3OD) δ 2.62 (s, 3H), 8.37 (s, 1H).

Step 2: 4-hydroxy-2- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile 4-hydroxy-2- (methylthio) pyrimidine-5 -Carbononitrile (56.2 mg, 0.336 mmol) and acetic acid (385 μL, 6.72 mmol) in t-butanol solution (1.7 mL) were mixed with 3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) aniline (89.0 mg, 0.437 mmol) was added, followed by stirring for 3 hours under microwave irradiation. The reaction solution was poured into water and the precipitated solid was collected by filtration to give the title compound (69.1 mg, 0.214 mmol, 64%) as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 3.86 (s, 6H), 7.20 (dd, J = 8.3, 1.2 Hz, 1H), 7.38 (d, J = 1.2 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 8.05 (s, 1H), 8.35 (s, 1H), 10.11 (s, 1H).

Step 3: 4-chloro-2- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile 4-hydroxy-2- (3-methoxy-4 A solution of-(1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile (54.3 mg, 0.168 mmol) in phosphorus oxychloride (1.0 mL) was stirred at 80 ° C. for 2 hours. The solvent was concentrated under reduced pressure, and the obtained residue was solidified with hexane / ethyl acetate to give the title compound (77.6 mg) as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 3.86 (s, 3H), 3.87 (s, 3H), 7.30 (br s, 1H), 7.48 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 8.09 (s, 1H), 8.91 (s, 1H), 10.86 (s, 1H).

Step 4: 4- (Cyclohexylamino) -2- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile 4-chloro-2- (3- Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile (63.6 mg, 0.187 mmol) and DIEA (130 μL, 0.747 mmol) in dioxane (2.0 mL) After adding cyclohexylamine (64 μL, 0.560 mmol), the mixture was stirred at 80 ° C. for 4 hours. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and then concentrated under reduced pressure. Ethyl acetate / hexane was added to the obtained residue to solidify it, and the title compound (50.8 mg, 0.126 mmol, 68%) was obtained as a yellow solid by filtration.
1H-NMR (300MHz, DMSO-d6) δ: 1.10-1.49 (5H, m), 1.62-1.67 (5H, m), 3.86 (6H, s), 3.98-4.09 (1H, m), 7.42-7.45 ( 4H, m), 7.83 (1H, s), 8.03 (1H, s), 8.33 (1H, s), 9.74 (1H, br s).
MS (ESI) m / z = 404 (M + H) ⁺ .
LC / MS t _R = 1.90 min.

Example 1-83
2- (5- (3-Cyclopentyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-ylamino) -2- (1-methyl-1H- Pyrazol-4-yl) phenoxy) acetonitrile

Step 1: 6-Chloro-N ² -cyclopentylpyridine-2,3-diamine 2,6-dichloropyridin-3-amine (1.63 g, 10 mmol) in NMP (10 mL) was added to cyclopentylamine (4.93 mL, 50 mmol) and then stirred at 200 ° C. for 10 hours under microwave irradiation. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and then concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate: 10-30% ethyl acetate gradient) to give the title compound (2.33 g, 11.0 mmol, 100 %).
1H-NMR (300 MHz, DMSO-d6) δ 1.36-1.73 (m, 6H), 1.95-1.99 (m, 3H), 4.12-4.17 (m, 1H), 4.84 (s, 2H), 5.69 (d, J = 6.5 Hz, 1H), 6.30 (d,
J = 7.7 Hz, 1H), 6.64 (d, J = 7.7 Hz, 1H).

Step 2: 5-chloro-3-cyclopentyl-1H-imidazo [4,5-b] pyridin-2 (3H) -one 6-chloro-N ² -cyclopentylpyridine-2,3-diamine (2.33 g, 11.0 mmol ), And sodium hydrogen carbonate (2.77 g, 33.0 mmol) in water / ethyl acetate (10 mL / 25 mL) was added dropwise phenylchloroformate (2.07 mL, 16.5 mmol) at 0 ° C, and 70 ° C for 2 hours. Stir. The reaction solution was returned to room temperature, the organic phase was separated and extracted, and the solvent was concentrated under reduced pressure. The obtained residue was solidified with isopropyl ether to give the title compound (1.54 g, 6.48 mmol, 59%).
1H-NMR (300 MHz, DMSO-d6) δ 1.61-1.63 (m, 2H), 1.90-1.92 (m, 5H), 2.08-2.17 (m, 2H), 4.66-4.77 (m, 1H), 7.04 ( d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 11.27 (s, 1H).

Step 3: 5-chloro-3-cyclopentyl-1-methyl-1H-imidazo [4,5-b] pyridin-2 (3H) -one 5-chloro-3-cyclopentyl-1H-imidazo [4,5-b ] Methyl iodide (0.304 mL, 4.86 mmol) was added to a DMF (5.0 mL) solution of pyridin-2 (3H) -one (770 mg, 3.24 mmol) and 60% sodium hydride (194 mg, 4.86 mmol). The solution was added dropwise at ° C and stirred at room temperature for 1 hour. The reaction solution was returned to room temperature, poured into ice water, and the resulting solid was collected by filtration to give the title compound (602 mg, 2.39 mmol, 74%).
1H-NMR (300 MHz, DMSO-d6) δ 1.60-1.67 (m, 2H), 1.84-1.94 (m, 5H), 2.09-2.14 (m, 2H), 3.33 (s, 3H), 4.70-4.81 ( m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H).

Step 4: 2- (5- (3-Cyclopentyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-ylamino) -2- (1-methyl -1H-pyrazol-4-yl) phenoxy) acetonitrile The title compound (85.9 mg, 0.194 mmol, 49%) was obtained in the same manner as in Example 1-1 / Step 2.
1H-NMR (300 MHz, DMSO-d6) δ 1.64-1.66 (m, 2H), 1.94-1.97 (m, 4H), 2.21-2.28 (m, 2H), 3.29 (s, 3H), 3.86 (s, 3H), 4.83-4.86 (m, 1H), 5.18 (s, 2H), 6.58 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.46-7.48 (m, 2H), 7.80 (s, 1H), 8.00 (s, 1H), 9.04 (s, 1H).
MS (ESI) m / z = 444 (M + H) ⁺ .
LC / MS t _R = 1.70 min.

Example 1-84
2- (5- (3- (cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -3-cyclopentyl-2-oxo-2,3-dihydro-1H-imidazo [ 4,5-b] pyridin-1-yl) acetonitrile

The title compound was synthesized according to the method of Example 1-83.
1H-NMR (300 MHz, DMSO-d6) δ 1.64-1.66 (m, 2H), 1.94-1.99 (m, 4H), 2.20-2.23 (m, 2H), 3.86 (s, 3H), 4.84-4.86 ( m, 1H), 5.08 (s, 2H), 5.19 (s, 2H), 6.63 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.5, 1.9 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 8.00 (s, 1H), 9.16 (s, 1H ).
MS (ESI) m / z = 469 (M + H) ⁺ .
LC / MS t _R = 1.71 min.

Example 1-85
2- (5- (3- (cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -2-oxo-3- (tetrahydro-2H-pyran-4-yl)- 2,3-Dihydro-1H-imidazo [4,5-b] pyridin-1-yl) acetonitrile

The title compound was synthesized according to the method of Example 1-83.
1H-NMR (DMSO-d6) δ 1.67-1.69 (m, 2H), 2.61-2.73 (m, 2H), 3.47 (t, J = 11.5 Hz, 2H), 3.86 (s, 3H), 4.02 (dd, J = 11.6, 3.9 Hz, 2H), 4.45-4.49 (m, 1H), 5.23 (s, 2H), 6.55 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 8.5, 1.9 Hz, 1H ), 7.24 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 0.5 Hz, 1H), 7.98 (s, 1H), 9.02 (s, 1H), 10.76 (s, 1H).
MS (ESI) m / z = 446 (M + H) ⁺ .
LC / MS t _R = 1.28 min.

Example 1-86
4- (6- (3- (cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -2- (cyclohexylamino) pyridin-3-yl) -N-cyclopropylbenzamide

The title compound was synthesized according to the method of Example 1-15.
1H-NMR (DMSO-d6) δ 0.58-0.59 (m, 2H), 0.68-0.71 (m, 2H), 1.22-1.36 (m, 5H), 1.67-1.69 (m, 3H), 1.95-1.99 (m , 2H), 2.86-2.87 (m, 1H), 3.84-3.88 (m, 4H), 5.13 (s, 3H), 6.16 (d, J = 8.1 Hz, 1H), 7.21-7.24 (m, 2H), 7.46 (dd, J = 8.4, 3.1 Hz, 3H), 7.75 (dd, J = 8.5, 1.8 Hz, 1H), 7.80 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 8.01 (s , 1H), 8.43 (d, J = 4.3 Hz, 1H), 9.03 (s, 1H).
MS (ESI) m / z = 562 (M + H) ⁺ .
LC / MS t _R = 1.95 min.

(Example 2) Results of TTK assay and A549 assay Representative results of the TTK assay and A549 assay are shown below.
Table 7

(Example 3) CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test to examine the enhancement of CYP3A4 inhibition of a compound by metabolic reaction. Was debenzylated with the CYP3A4 enzyme, and the reaction that produces a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) was performed as an indicator.

The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), pre- 62.5 pmol / mL during reaction, 6.25 pmol / mL during reaction (diluted 10 times); test drug concentration, 0.625, 1.25, 2.50, 5.00, 10.0, 20.0 μmol / L (6 points).

Add the enzyme and test drug solution to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) with the above pre-reaction composition, and add the substrate and K-Pi buffer to the other 96-well plate. A portion thereof was transferred so as to be diluted by 10/10, and a reaction using NADPH as a coenzyme was started as an index (no pre-reaction). After reaction for a predetermined time, acetonitrile: 0.5 mol / L Tris ( The reaction was stopped by adding (trishydroxyaminomethane) = 4: 1. Also, add NADPH to the remaining pre-reaction solution to start the pre-reaction (with pre-reaction), and after the pre-reaction for a predetermined time, make sure that another plate is diluted 1/10 with the substrate and K-Pi buffer. The reaction was started by moving the part. After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile: 0.5 mol / L Tris (trishydroxyaminomethane)-= 4: 1. The fluorescence value of 7-HFC, which is a metabolite, was measured with a fluorescent plate reader on the plate on which each index reaction was performed (Ex = 420 nm, Em = 535 nm).

The control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the test drug solution was calculated. The IC ₅₀ was calculated by inverse estimation using a logistic model. The case where the difference in IC ₅₀ value was 5 μM or more was designated as (+), and the case where it was 3 μM or less was designated as (−).

Example 4 CYP Inhibition Test 7-ethoxyresorufin O-deethylation as a typical substrate metabolic reaction of human tumor CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), hydroxylation of terfenadine (CYP3A4) The degree to which the amount of each metabolite produced was inhibited by the test compound was evaluated.

The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6) ), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; test drug concentration, 1.0, 5.0, 10, 20 μmol / L ( 4 points).

As a reaction solution in a 96-well plate, each of 5 types of substrates, human liver microsomes, and test drug was added to the above composition in 50 mM Hepes buffer solution, and NADPH, a coenzyme, was added to perform a metabolic reaction as an index. After starting and reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the supernatant was collected using a fluorescent multilabel counter with tolbutamide hydroxide (CYP2C9 metabolite) and mephenytoin 4 ′ hydroxide (CYP2C19 metabolite). Then, dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.

The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the test drug solution was calculated. The IC ₅₀ was calculated by inverse estimation using a logistic model.

(Example 5) FAT test 20 μL of frozen Salmonella typhimurium TA98 strain, TA100 strain was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) for 10 hours at 37 ° C. Incubated before shaking. TA98 strain culture solution was removed by a bacterial solution of 9mL centrifuged (2000 × g, 10 min), Micro F buffer _{_{9mL (K 2 HPO 4: 3.5}} g / L, KH2PO4: 1 g / L, ( NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L) : Micro F buffer solution containing 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL), and TA100 strain was added to 120 mL of Exposure medium to 3.16 mL bacterial solution to prepare a test bacterial solution . Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 μg / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, TA100 strain, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, metabolic activation conditions against TA98 strain 40 μg / mL 2-aminoanthracene DMSO solution and 20 μg / mL 2-aminoanthracene DMSO solution for TA100 strain, respectively, and 588 μL test bacterial solution (498 μL test bacterial solution under metabolic activation conditions) And S9 mix 90 μL) were mixed, and cultured at 37 ° C. for 90 minutes with shaking. 460 μL of bacterial solution exposed to the test substance is added to Indicator Medium (MicroF buffer solution containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL) 2300 50 μL each was mixed in μL, dispensed into 48 microwells / dose of the microplate, and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability due to mutations in the amino acid (histidine) synthase gene turn from purple to yellow due to pH change, count the number of bacteria growth wells that turn yellow in 48 wells per dose. Evaluation was made in comparison with the negative control group.

(Example 6) Solubility test The solubility of the compound was determined under the condition of addition of 1% DMSO. Prepare 10 mM compound solution in DMSO, add 6 μL of the compound solution to pH 6.8 artificial intestinal fluid (250 mL of 0.2 mol / L potassium dihydrogen phosphate reagent, 118 mL of 0.2 mol / L NaOH reagent, and 1000 mL by adding water. Added to 594 μL. After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 2-fold with methanol / water = 1/1, and the concentration in the filtrate was measured by HPLC or LC / MS / MS by the absolute calibration curve method.

(Example 7) Metabolic stability test Using commercially available pooled human liver microsomes, the target compound was reacted for a certain period of time, and the residual ratio was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver. .

Presence of 1 mmol / L NADPH in 0.2 mL buffer (50 mmol / L tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg human liver microsome protein / mL The reaction was allowed to proceed at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The test compound in the centrifugal supernatant was quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction was calculated with the amount of the compound at 0 minute reaction as 100%.

(Example 8) hERG test For the purpose of risk assessment of ECG QT interval prolongation, HEK293 cells expressing human ether-a-go-go related gene (hERG) channel are used to play an important role in ventricular repolarization process We investigated the effect on delayed rectifier K + current (IKr).

Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at -80 mV membrane potential by the whole cell patch clamp method, +50 mV depolarization stimulation was further applied for 2 seconds. IKr induced when 50 mV of repolarization stimulus was applied for 2 seconds was recorded. After the generated current has stabilized, the extracellular fluid (NaCl: 137 mmol / L, KCl: 4 mmol / L, CaCl ₂・ 2H ₂ O: 1.8 mmol) in which the test substance is dissolved at the target concentration (1.0 μM) / L, MgCl ₂ · 6H ₂ O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazineethane-sulfonic acid, 4- (2-hydroxyethyl) -1- Piperazine ethanesulfonic acid): 10 mmol / L, pH- = 7.4) was applied to the cells for 10 minutes at room temperature. The absolute value of the maximum tail current was measured from the obtained IKr using analysis software (DataXpress ver. 1, Molecular Devices Corporation) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the test substance was calculated, and compared with the medium application group (0.1% dimethyl sulfoxide solution), the influence of the test substance on IKr was evaluated.

(Example 9: Formulation example 1 tablet)
A tablet having the following composition is produced by a conventional method.
100 mg of the compound of the present invention
Lactose 60mg
Potato starch 30mg
Polyvinyl alcohol 2mg
Magnesium stearate 1mg
Tar pigment Trace amount.

(Example 10: Formulation example 2 powder)
A powder having the following composition is produced by a conventional method.
150 mg of the compound of the present invention
Lactose 280 mg.

(Example 11: Formulation example 3 syrup)
A syrup having the following composition is produced by a conventional method.
100 mg of the compound of the present invention
Purified white sugar 40 g
40 mg ethyl p-hydroxybenzoate
Propyl p-hydroxybenzoate 10mg
Chocolate flavor 0.1cc
Water is added to make a total amount of 100 cc.

As described above, the present invention has been exemplified using the preferred embodiment of the present invention, but the present invention should not be construed as being limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range based on the description of the present invention and the common general technical knowledge from the description of specific preferred embodiments of the present invention. Patents, patent applications, and references cited herein should be incorporated by reference in their entirety as if the contents themselves were specifically described herein. Understood.

This application is based on Japanese Patent Application No. 2009-183833 filed in Japan, the contents of which are incorporated in full herein.

The present invention provides a medicament for treating a TTK kinase-dependent disease, a compound used therefor, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound of the present invention exhibits an excellent TTK kinase inhibitory action as described in the above Examples.

Claims

Formula (I):

(Where
X is = C (R 4 )-or = N-
A represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyrazole or fused pyrazole), a substituted or unsubstituted non-aromatic hydrocarbon ring. Or a substituted or unsubstituted non-aromatic heterocycle,
R 1 is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B ;
R 1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl or substituted or Unsubstituted saturated heterocyclyl,
R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted saturated heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
R 1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Saturated heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl , Substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino, halogen, carboxy or hydrogen, or
R 1 and R 2 together with the adjacent carbon atom
Formula (II):

(Where
R 1A ″ and R 2A ″ each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl Substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl,
R a and R b are each independently hydrogen or substituted or unsubstituted alkyl;
n is an integer of 0 to 3. ) May be formed,
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
R 4 is hydrogen or halogen;
R 5A and R 5B are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted carbamoyl, a group represented by the formula: —SO 2 —R ′, a group represented by the formula: —SO—R ′, or a group represented by the formula: —SR ′;
R ′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl It is.
However,
(I) X is ═C (R 4 ) —, and A is substituted or unsubstituted piperidine, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted fused pyrimidine, substituted or unsubstituted When substituted condensed pyridine or substituted or unsubstituted tetrahydrofuran, R 2 is cyano;
(Ii) when X is ═C (R 4 ) —, A is a substituted or unsubstituted aromatic hydrocarbon ring and R 2 is nitro, R 1 is of the formula: —NR 1A R 1A ′ A group represented by formula (where R 1A ′ is phenylethyl) and a group represented by the formula: —OR 1B (where R 1B is methyl),
(Iii) When X is ═C (R 4 ) — and A is a substituted or unsubstituted non-aromatic hydrocarbon ring, R 1 is a group represented by the formula: —NR 1A R 1A ′ (here R 1A ′ is substituted or unsubstituted alkyl) and a group represented by the formula: —OR 1B (where R 1B is substituted or unsubstituted alkyl),
(Iv) X is ═C (R 4 ) —, A is a substituted or unsubstituted aromatic hydrocarbon ring, R 2 is cyano, and R 1 is represented by the formula: —NR 1A R 1A ′ R 3 is hydrogen, wherein R 1A ′ is a substituted or unsubstituted alkyl or a group of the formula: —OR 1B (where R 1B is methyl or ethyl),
(V) when X is ═C (R 4 ) — and A is a non-aromatic heterocyclic ring, R 1 is a group represented by the formula: —NR 1A R 1A ′ (where R 1A ′ is Instead of substituted or unsubstituted alkyl)
(Vi) when X is = C (R 4 )-, the number of hydrogens in R 1 , R 3 and R 4 is 2 or less;
(Vii) When X is ═N—, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine). , R 2 is cyano, R 3 is hydrogen, and R 1 is a group represented by the formula: —NR 1A R 1A ′ (where R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted Piperidinyl and substituted or unsubstituted cyclopropyl) and a group represented by the formula: —OR 1B (where R 1B is substituted or unsubstituted alkyl),
(Viii) When X is ═N—, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine). , R 2 is cyano, R 3 is hydrogen and R 5A is not substituted sulfinyl, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted morpholinyl and substituted sulfonyl.
) A compound represented by the following formula (however, the compound shown below:

except for. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
R 1 is a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B (wherein R 1A , R 1A ′ and R 1B are as defined in claim 1),
R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R is a substituted, unsubstituted or carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy object.
The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein A is a substituted or unsubstituted aromatic hydrocarbon ring.
The compound according to claim 1 or 2, its pharmaceutically acceptable salt, or a solvate thereof, wherein X is = C (R 4 )-(wherein R 4 is as defined in claim 1).
The compound, pharmaceutically acceptable salt or solvate thereof according to claim 1 or 2, wherein X is = CH-.
R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, The compound, its pharmaceutically acceptable salt or solvate thereof according to claim 1 or 2, which is substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.
The compound according to claim 1, wherein R 2 is cyano, a pharmaceutically acceptable salt thereof, or a solvate thereof.
The compound according to claim 1, wherein R 3 is hydrogen, a pharmaceutically acceptable salt thereof, or a solvate thereof.
The R 1 is a group represented by the formula: -NHR 1A ' or a group represented by the formula: -OR 1B (wherein R 1A' and R 1B are as defined in claim 1), Compound, its pharmaceutically acceptable salt or solvate thereof.
2. R 1 is a group represented by the formula: —NHR 1A ′ , and R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated heterocyclyl. Or the compound according to 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.
R 1 has the formula: a group represented by -OR 1B, R 1B is a substituted or unsubstituted cycloalkyl, claim 1 or 2 A compound according, salts or solvates are pharmaceutically acceptable .
Formula (III):

A group represented by
Formula (IV):

Or a pharmaceutically acceptable salt thereof or a solvate thereof, according to claim 1, wherein R 5A and R 5B are as defined in claim 1.
The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl.
The compound according to claim 1 or 2, wherein R 5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl, A pharmaceutically acceptable salt or a solvate thereof.
The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl. .
X is = C (R 4 )-(where R 4 is as defined in claim 1);
R 1 and R 2 together with adjacent carbon atoms
Formula (II):

Wherein R 1A ″ and R 2A ″ are each independently substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl,
n is an integer of 0 to 2, and R a and R b are the same as defined in claim 1,
A is a substituted or unsubstituted aromatic hydrocarbon ring,
The compound according to claim 1, wherein R 3 is hydrogen, a pharmaceutically acceptable salt thereof, or a solvate thereof.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, or a solvate thereof.
The pharmaceutical composition according to claim 17, which is a TTK inhibitor.
Formula (I):

(Where
X is = C (R 4 )-
A represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyrazole or fused pyrazole and substituted or unsubstituted thiophene), substituted or unsubstituted A non-aromatic hydrocarbon ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R 1 is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B ;
R 1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl or substituted or Unsubstituted saturated heterocyclyl,
R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A substituted saturated heterocyclyl;
R 1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted Of saturated heterocyclyl
R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl , Substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino, halogen, carboxy or hydrogen, or
R 1 and R 2 together with the adjacent carbon atom
Formula (II):

(Where
R 1A ″ and R 2A ″ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted Or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl,
R a and R b are each independently hydrogen or substituted or unsubstituted alkyl;
n is an integer of 0 to 3. )
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
R 4 is hydrogen or halogen;
R 5A and R 5B are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Carbamoyl, a group represented by the formula: —SO 2 —R ′, a group represented by the formula: —SO—R ′, or a group represented by the formula: —SR ′;
R ′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl The pharmaceutical composition which has TTK inhibitory activity containing the compound which is these, its pharmaceutically acceptable salt, or those solvates.