JP2011246389A - Condensed-ring pyrazole derivative having ttk inhibiting action - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an inhibitor for effectively inhibiting TTK (tyrosine threonine kinase) protein kinase, and consequently to provide an effective medicine.SOLUTION: There are provided a new series of compounds which inhibit the action of TTK kinase and have specific characteristics particularly useful for preparing the medicines for treating the above disease, and also the related medicine compositions, TTK inhibitors and the like. The compound is useful for diseases for which the inhibition of TTK kinase action is considered to be effective.

Description

  The present invention relates to a condensed pyrazole derivative having an inhibitory / suppressing action on TTK (TTK protein kinase) activity. In another aspect, the present invention relates to a medicament comprising this fused ring pyrazole 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, changes in localization within 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, see Non-Patent Document 4), CHK2 (for example, see 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 describes a method for measuring TTK activity using a partial peptide of p38MAPK as a substrate as a screening method for TTK activity.

International Publication No. 01/94629 Pamphlet JP 2007-104911 A

Mills et al., J. Biol. Chem. (1992) 267, 16000-16006 Lindberg et al., Oncogene (1993) 8,351-359 Liu et al., Mol. Biol. Cell. (2003) 14, 1638-51 Friedman et al., J. Biol. Chem. (2001) 276, 17958-17967 Wei et al., J. Biol. Chem. (2005) 280, 7748-7757 Jelluma et al., Cell (2008) 25,233-246

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

  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 succeeded in discovering a new series of compounds with specific properties that inhibit the action of TTK kinases and make them particularly useful in formulating pharmaceuticals to treat 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.

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

  (1) Formula (I):

(Where
X is -C (-R ') = or -N =
Y is -C (-R ") = or -N =
R ′ and R ″ are each independently hydrogen, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino or substituted Or unsubstituted acyl,

The group represented by

Wherein R ^1A is hydrogen or substituted or unsubstituted alkyl;
R ^1B is hydrogen or substituted or unsubstituted alkyl).
R ² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted carbamoyl,
Formula: —OR ^c , where R ^c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Or a group represented by the formula: —NR ^d R ^e , wherein R ^d and R ^e are each independently hydrogen, substituted or unsubstituted acyl, substituted or Unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or R ^d and R ^e are (It may be combined with the adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing heterocycle.) A group represented,
R ⁴ is substituted or unsubstituted carbamoyl, cyano, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A compound that is heterocyclyl, amino substituted with a substituted or unsubstituted heteroaryl, or amino substituted with a substituted or unsubstituted heterocyclyl, provided that
(I) X is -C (-H) =, Y is -C (-H) =,
R ³ is substituted alkyl, formula: —NR ^d R ^e, where R ^d is hydrogen;
R ^e is hydrogen or substituted acyl. ) Or cyano,
A compound wherein R ⁴ is fluorine,
(Ii) a compound wherein R ⁴ is cyano and R ³ is substituted or unsubstituted alkyloxy or unsubstituted phenyl;
(Iii) a compound wherein R ⁴ is chloro or substituted or unsubstituted phenyl and R ³ is substituted or unsubstituted alkyloxy; and (iv) a compound shown below:

and

Or a pharmaceutically acceptable salt thereof or a solvate thereof.

  (2)

A group represented by

(Wherein R ^1A is a hydrogen atom),
R ² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, formula: —OR ^c , wherein R ^c is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero A group represented by the formula: —NR ^d R ^e , wherein R ^d and R ^e are each independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted Substituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or R ^d and R ^e together with the adjacent nitrogen atom And may form a substituted or unsubstituted nitrogen-containing heterocycle.)
R ⁴ is substituted or unsubstituted carbamoyl, cyano, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, amino substituted with substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl The compound according to item (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is substituted amino.

  (3)

A group represented by

(Wherein, R ^1B is a hydrogen atom),
R ² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, formula: —OR ^c , wherein R ^c is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero A group represented by the formula: —NR ^d R ^e , wherein R ^d and R ^e are each independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted Substituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or R ^d and R ^e together with the adjacent nitrogen atom And may form a substituted or unsubstituted nitrogen-containing heterocycle.)
R ⁴ is substituted or unsubstituted carbamoyl, cyano, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, amino substituted with substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl The compound according to item (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is substituted amino.

(4) R ² is substituted or unsubstituted aryl,
R ³ is a group represented by the formula: —OR ^c (wherein R ^c is substituted or unsubstituted alkyl or substituted or unsubstituted aryl), or a formula: —NR ^d R ^e (where R is ^d is hydrogen, R ^e is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and
The compound according to any one of items (1) to (3), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ⁴ is substituted or unsubstituted carbamoyl, or substituted or unsubstituted heteroaryl. object.

(5) R ³ is a group represented by the formula: -OR ^c (wherein R ^c is as defined in item (4)) or a formula: -NR ^d R ^e (wherein R ^d and R ^e are the items (4 )) And a group represented by
The compound according to any one of items (1) to (4), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ⁴ is substituted or unsubstituted heteroaryl.

(6) The compound according to any one of items (1) to (5), wherein R ³ is a group represented by the formula: -OR ^c (wherein R ^c is as defined in item (4)), The pharmaceutically acceptable salt or solvate thereof.

(7) In any one of items (1) to (6), R ³ is a group represented by the formula: -NR ^d R ^e (wherein R ^d and R ^e are as defined in item (4)) Or a pharmaceutically acceptable salt or solvate thereof.

  (8) A pharmaceutical composition comprising the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (9) The pharmaceutical composition according to item (8), which is a TTK inhibitor.

  (10) A TTK inhibitor comprising the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (11) An anticancer agent comprising the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (12) A therapeutic agent for immune system diseases comprising the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (13) An immunosuppressant comprising the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (14) An autoimmune disease therapeutic agent comprising the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (15) A method, system, apparatus, kit or the like for producing the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (16) Method, system, apparatus, kit, etc. for preparing a pharmaceutical composition containing the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof .

  (17) A method, system, apparatus, kit or the like using the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (18) The pharmaceutical composition according to item (8), which is a medicament for treating or preventing a disease, disorder or condition associated with TTK.

  (19) The pharmaceutical composition according to any one of items (8), (9), and (18) for treating and / or preventing cancer.

  (20) A method for preventing or treating cancer, comprising administering the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  (21) Use of the compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a therapeutic and / or prophylactic agent for cancer. .

  (22) The compound according to any one of items (1) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof for the treatment and / or prevention of cancer.

  Accordingly, these and other advantages of the 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.

  The present invention will be described below with reference to 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”, etc. in the case of English) also include the plural concept thereof unless otherwise specified. 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 will be described 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.

  Abbreviations used in this specification, particularly in the examples, are listed in Table 1 below.

  Table 1

  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, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Preferred is 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.

  In the present specification, “alkenyl” includes linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds in 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, and bridged cyclic hydrocarbon. Group, spiro hydrocarbon group and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.

  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 the present specification, the “spirohydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings 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. Is 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” means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like. Preferably, phenyl or naphthyl (1-naphthyl, 2-naphthyl) is used.

  In the present specification, the “heteroaryl” includes monocyclic aromatic heterocyclic groups and condensed aromatic heterocyclic groups. The monocyclic aromatic heterocyclic group is an optionally substituted group derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring. A group which may have a bond at the position. The condensed aromatic heterocyclic group has 1 to 4 5-8 aromatic rings which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring. It includes a group which may have a bond at any substitutable position which is fused with a member aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.

  In the present specification, examples of the “heteroaryl” include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-furyl). Pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg, 1,2,4) -Triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (Example: 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (Example: 3-isoxazolyl, 4-isoxazolyl, 5 Isoxazolyl), thiazolyl (eg: 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg: 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg: 2-pyridyl, 3-pyridyl) 4-pyridyl), pyridazinyl (eg: 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg: 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanil (eg: 3-furazanyl), pyrazinyl (eg: 2 -Pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), benzofuryl (eg 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl , 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl) Benzothienyl (eg 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b ] Thienyl), benzimidazolyl (eg, 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzoxazolyl, benzothiazolyl, quinoxalyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6- Quinoxalinyl), cinnolinyl (eg: 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg: 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6- Quinazolinyl, 7-quinazolinyl , 8-quinazolinyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg, 1-phthalazinyl, 5-phthalazinyl) 6-phthalazinyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (eg, 2-pteridinyl, 4 -Pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (eg 1-acridinyl) In-drill, 2-in-drill, 3-in-drill, 4 Indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazinyl (eg 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (eg 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl) and the like.

  In the present specification, “heterocycle” may contain 1 to 4 oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring, and has a bond at any substitutable position. Including non-aromatic heterocyclic groups which may be Further, such a non-aromatic heterocyclic group may be further bridged with an alkyl chain having 1 to 4 carbon atoms, and a cycloalkane (preferably a 5- to 6-membered ring) or a benzene ring is condensed. Good. If it is non-aromatic, it may be saturated or unsaturated. The ring is preferably a 5- to 8-membered ring, but a non-aromatic heterocyclic ring may be further condensed. For example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, pyrrolidinone, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4- Imidazolidinyl, imidazolidinone, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidinone, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, Examples include 2-piperazinyl, piperazinone, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, tetrahydrofuranyl 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. Preferably, C1-C6 alkoxy is mentioned. More preferably, C1-C4 alkoxy is mentioned. In particular, when a carbon number is specified, it means “alkoxy” having a carbon number within the range.

  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 Includes substituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclecarbonyl.

In the present specification, “R ^a and R ^b together with adjacent nitrogen atoms form a substituted or unsubstituted nitrogen-containing heterocycle” and “R ^d and R ^e together with adjacent nitrogen atoms”. Examples of the heterocyclic ring in “Forming a substituted or unsubstituted nitrogen-containing heterocycle” include the following rings.

(Here, R includes, for example, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, halogen, hydroxy, nitro, cyano, and carboxy).

In the present specification, “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted aryl”, “substituted or unsubstituted cycloalkyl” , "Substituted or unsubstituted cycloalkenyl", "substituted or unsubstituted heteroaryl", "substituted or unsubstituted heterocycle", "substituted or unsubstituted alkoxy", "substituted or unsubstituted acyl" or " Examples of the substituent in the heterocyclic ring in “R ^a and R ^b together with the adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing heterocycle” include, for example, hydroxy, carboxy, halogen, alkyl halide ( _{example: CF 3, CH 2 CF 3} , CH 2 CCl 3), nitro, nitroso, cyano, alkyl ( : Methyl, ethyl, isopropyl, tert-butyl), alkenyl (eg, vinyl), alkynyl (eg: ethynyl), cycloalkyl (eg: cyclopropyl, adamantyl), cycloalkylalkyl (eg: cyclohexylmethyl, adamantylmethyl), Cycloalkenyl (eg: cyclopropenyl), aryl (eg: phenyl, naphthyl), arylalkyl (eg: benzyl, phenethyl), heteroaryl (eg: pyridyl, furyl), heteroarylalkyl (eg: pyridylmethyl), heterocycle (Eg, piperidyl), heterocycle alkyl (eg: morpholylmethyl), alkoxy (eg: methoxy, ethoxy, propoxy, butoxy), halogenated alkoxy (eg: OCF ₃ ), alkenyloxy (eg: vinyloxy, allyloxy) Xy), aryloxy (eg phenyloxy), alkyloxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), arylalkyloxy (eg benzyloxy), amino [alkylamino (eg methylamino, Ethylamino, dimethylamino), acylamino (eg acetylamino, benzoylamino), arylalkylamino (eg benzylamino, tritylamino), hydroxyamino], alkylaminoalkyl (eg diethylaminomethyl), sulfamoyl, oxo, etc. Selected from the group consisting of It may be substituted with 1 to 4 such substituents.

  In the present specification, the substituents of “substituted or unsubstituted amino” and “substituted or unsubstituted carbamoyl” include alkyl, alkenyl, aryl, heteroaryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl , Alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycleoxycarbonyl, carbamoyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclesulfonyl, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, hetero Arylsulfinyl, heterocycle sulfinyl, mercapto, sulfino, sulfo, hydroxy, amino And the like.

  In the present specification, “substituted or unsubstituted alkylcarbonyl” and “halogenated alkyl”, alkylsulfonyl, and the alkyl moiety of alkyloxycarbonyl mean the above “alkyl”.

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

  In the present specification, the alkenyl part of “substituted or unsubstituted alkenylcarbonyl” means the above “alkenyl”.

  In the present specification, the cycloalkyl part of “substituted or unsubstituted cycloalkylcarbonyl” means the above “cycloalkyl”.

  In the present specification, the cycloalkenyl moiety of “substituted or unsubstituted cycloalkenylcarbonyl” means the above “cycloalkenyl”.

  In the present specification, the aryl part of “substituted or unsubstituted arylcarbonyl” means the above “aryl”.

  In the present specification, the heteroaryl part of “substituted or unsubstituted heteroarylcarbonyl” means the above “heteroaryl”.

  In the present specification, the heterocycle part of “substituted or unsubstituted heterocyclecarbonyl” means the above “heterocycle”.

  Examples of the pharmaceutically acceptable salt 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 , Triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt and other aliphatic amine salts; N, N-dibenzylethylenediamine, venetamine salt and other aralkylamine salts; pyridine salt, picoline salt, quinoline salt, isoquinoline Heterocyclic aromatic amine salts such as salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyl Examples include quaternary ammonium salts such as trioctylammonium salt and tetrabutylammonium salt; 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, bicarbonate, 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.

  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.

(Preferred condensed ring pyrazole derivative compound 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 preferred substituent can be used, for example, any preferred substituent exemplified in the means for solving the problem.

  When considering the fused pyrazole derivative of the present invention, the following factors can be considered.

  In preferable embodiment of this invention, it illustrates to (A1)-(A2) below. Each symbol has the same meaning as described above.

(A1)
The definition of each substituent is synonymous with the said item (1) unless there is particular notice.

  Formula (I):

In
X includes -C (-R ') = or -N =.

  Y includes -C (-R ") = or -N =.

  R ′ and R ″ each independently represent hydrogen, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino Or substituted or unsubstituted acyl.

The group represented by

Wherein R ^1A is hydrogen or substituted or unsubstituted alkyl;
R ^1B is hydrogen or a substituted or unsubstituted alkyl).

R ² includes substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted carbamoyl,
Formula: —OR ^c , where R ^c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Or a group represented by the formula: —NR ^d R ^e , wherein R ^d and R ^e are each independently hydrogen, substituted or unsubstituted acyl, substituted or Unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or R ^d and R ^e are (It may be combined with the adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing heterocycle.) They include groups represented.

R ⁴ includes substituted or unsubstituted carbamoyl, cyano, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Substituted heterocyclyl, amino substituted with substituted or unsubstituted heteroaryl, or amino substituted with substituted or unsubstituted heterocyclyl.

However,
(I) X is -C (-H) =, Y is -C (-H) =,
R ³ is substituted alkyl, formula: —NR ^d R ^e, where R ^d is hydrogen;
R ^e is hydrogen or substituted acyl. ) Or a cyano compound wherein R ⁴ is fluorine,
(Ii) a compound wherein R ⁴ is cyano and R ³ is substituted or unsubstituted alkyloxy, or phenyl;
(Iii) compounds wherein R ⁴ is chloro or phenyl and R ³ is substituted or unsubstituted alkyloxy, and (iv) compounds shown below:

and

Is excluded.

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

In general formula (I):
R ^1A includes hydrogen.

R ² includes substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

For example, R ² includes substituted or unsubstituted aryl.

R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, formula: —OR ^c (wherein R ^c is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Or a group represented by the formula: —NR ^d R ^e , wherein R ^d and R ^e are each independently hydrogen, substituted or unsubstituted acyl, substituted Or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or R ^d and R ^e are adjacent nitrogen atoms Taken together may form a substituted or unsubstituted nitrogen-containing heterocycle).

For example, as R ³ , a group represented by the formula: —OR ^c (wherein R ^c is substituted or unsubstituted alkyl or substituted or unsubstituted aryl), or a formula: —NR ^d R ^e ( Wherein R ^d is hydrogen, R ^e is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl.) Can be mentioned.

For example, as R ³ , a group represented by the formula: —OR ^c (wherein R ^c is as defined in item (3)) or a formula: —NR ^d R ^e (wherein R ^d and R ^e are the items ( And a group represented by the same meaning as 3).

For example, R ³ includes a group represented by the formula: —OR ^c (wherein R ^c is as defined in item (3)).

For example, R ³ includes a group represented by the formula: —NR ^d R ^e (wherein R ^d and R ^e are as defined in item (3)).

R ⁴ is substituted or unsubstituted carbamoyl, cyano, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, amino substituted with substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl. And amino substituted with.

For example, R ⁴ includes substituted or unsubstituted carbamoyl, substituted or unsubstituted heteroaryl.

For example, R ⁴ includes substituted or unsubstituted heteroaryl.

  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 the present specification, “prodrug” and “prodrug compound” have a group that can be chemically or metabolically decomposed, and are pharmaceuticals by hydrolysis, solvolysis, or decomposition under physiological conditions. It is a derivative of the compound of the present invention which shows activity. 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). You can refer to it. 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, prodrugs are compounds 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, is 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 ester, for example 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 Pharmaceutically acceptable esters, and pharmaceutically acceptable esters of substituted or unsubstituted heterocyclic groups. In one embodiment, the prodrug has 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 comprising 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)
The general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.

  Below, the manufacturing method of the compound of this invention is 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 compound is a commercially available compound, Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5, Yakugaku Zasshi 1986, 106 (11), 995-1001, Bioorg. Med. Chem. Lett. 2005, 15, 5095-5099, Tetrahedron Lett. 2002, 43, 2695-2697, Tetrahedron Lett. 2000, 41, 4363, others described in this specification, and others cited in this specification Those described in the literature as well as 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 herein as “prodrugs”. 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.

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

  The present invention also relates to systems, devices, and kits for producing the compounds 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)
Typical general synthetic methods of the compounds of the present invention described in Examples are shown in General synthetic methods 1 to 12. The compounds described in the examples were synthesized generally according to these, but are not particularly limited to these methods. Reaction solvents, bases, palladium catalysts, and phosphine ligands that can be used in the production of the compounds are described below. In General Synthesis Methods 1 to 12, preferred ones among them have been presented, but are not particularly limited thereto.
(1) Reaction solvent: DMF, NMP, DMA, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons ( Examples, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water, and mixed solvents thereof.
(2) Base: metal hydride (eg, sodium hydride), metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonate (eg, sodium carbonate) Potassium carbonate, calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal sodium, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
(3) Palladium catalyst: Pd (PPh ₃ ) ₄ , PdCl ₂ , Pd ₂ (dba) ₃ , Pd (dba) ₂ , Pd (OAc) ₂ , PdCl ₂ (dppf), PdCl ₂ (PPh ₃ ) _{2 and the} like.
(4) Phosphine ligands: PPh ₃ , BINAP, Xantphos, S-Phos, X-Phos, DPPF, t-Bu ₃ P, tris o-tolylphosphine, and the like.

  (General synthesis method 1)

(In the formula, each symbol is as defined above, and X ^A and X ^B are halogens (eg, iodine, bromine, chlorine, fluorine, etc.) or elimination of OMs group, OTs group, OTf group, ONs group, etc.) P ⁰ represents a protecting group (for example, Boc group, benzyl group, benzyloxycarbonyl group, SEM group, etc.) As the compound represented by the formula (A1), a known compound may be used. A compound derived from a compound by a conventional method may be used).

  This is a method of synthesizing Formula (A8), which is a compound of the present invention, from Compounds represented by Formula (A1) by Methods A-1 to A-7. Methods A-1 to A-7 are described in detail below.

  Method (A-1)

(In the formula, each symbol is as defined above, and X ^A represents a leaving group such as halogen (for example, iodine, bromine, chlorine and fluorine) or OMs group, OTs group, OTf group, ONs group, etc.) As the compound represented by the formula (A1), a known compound may be used, or a compound derived from a known compound by a conventional method may be used.

In this step, the compound represented by the formula (A1) is reacted with various nucleophiles to introduce the substituent R ³ to produce the compound represented by the formula (A2). Examples of the nucleophilic agent include metal alkoxides, amine derivatives, metal enolates, and the like. In this case, the metal alkoxide is prepared from a commercially available compound when it is available, and when it is not available, it is prepared from the corresponding alcohol and metal sodium, or sodium hydride or hydroxylated against the corresponding alcohol. It can be prepared and reacted in the system using a base such as potassium. The reaction solvent described in (1) can be used as the reaction solvent, and DMF, NMP, DMA, THF, or dioxane is preferable. However, the reaction solvent is not particularly limited as long as it does not react under the present conditions. The reaction temperature is not particularly limited, but when the reactivity is low, it can be prepared by appropriately heating. Even when an amine derivative is used as a nucleophile, it can be carried out in the same reaction solvent and reaction temperature as those of the metal alkoxide. In that case, it is desirable to use 2 or more equivalents of an amine derivative with respect to the compound represented by formula (A1), or to carry out in the presence of an equivalent amount of a base. As the base, organic amines such as triethylamine and diisopropylethylamine and metal carbonates such as potassium carbonate are desirable.

Examples of the compound represented by the formula (A1) include organic boronic acid (Suzuki reaction), organic tin (Still reaction), alkene derivative (Heck reaction) alkyne derivative (Sonogashira reaction), amine derivative (Buchwald reaction), and organic R ³ can also be introduced using a coupling reaction such as zinc (Negishi reaction). At that time, a reagent such as the above-described organic boronic acid can be reacted under a reaction solvent, a palladium catalyst, a phosphine ligand, and a base. The base described in (2) can also be used as the base, but preferably a metal base (eg, sodium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium fluoride, cesium fluoride, potassium acetate, sodium acetate, etc. ), Metal alkoxides (sodium-t-butoxide, potassium-t-butoxide, etc.), organic amines (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) can be used, but they may not be used. There is also. Any coupling reaction is known in the literature and can be followed. As the solvent, a solvent similar to the above nucleophilic substitution reaction can be used, but preferably ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), aromatic hydrocarbons (eg, , Toluene, benzene, etc.), and alcohols. The reaction temperature can be from room temperature to about the boiling point of the solvent, but may be appropriately selected depending on the progress of the reaction. When the progress of the reaction is slow, the temperature may be further increased using a microwave reactor.

  Method (A-2)

(In the formula, each symbol is as defined above, and the compound represented by the formula (A2) may be a known compound, or a compound derived from a known compound by a conventional method).

In this step, the compound represented by the formula (A2) is reduced to a compound represented by the formula (A3) by reducing the nitro group using various reducing agents. As the reducing agent, palladium carbon or platinum oxide (PtO ₂ ) is preferably used as a catalyst, and it is preferably carried out in a hydrogen atmosphere. However, when R ³ and R ⁴ contain a functional group susceptible to hydrogenation reaction such as halogen. Is preferably carried out by a method of adding an acid such as ammonium chloride, hydrochloric acid or acetic acid in the presence of Fe, a method of allowing hydrazine to act in the presence of FeCl ₃ or activated carbon, a method using SnCl ₂ or the like. In this case, examples of the reaction solvent include those described in (1), and an organic solvent such as methanol, ethanol, ethyl acetate, toluene, DMF, NMP, or DMA, and in some cases, a mixed solvent of these and water are used. It is preferable. The reaction temperature is preferably a temperature from room temperature to the boiling point of the solvent used, but is not particularly limited and may be appropriately selected depending on the progress of the reaction. All of the above reactions are known, and basically may be synthesized according to known literature.

  Method (A-3)

(In the formula, each symbol is as defined above, and the compound represented by the formula (A3) may be a known compound or a compound derived from a known compound by a conventional method).

  This is a step of converting an o-toluidine derivative represented by the formula (A3) or a 2-methyl-3-aminopyridine derivative into an indazole or a pyrazolo [4,3-b] pyridine derivative. In this case, the formula (A3) may be protected with an amide group or the like, and is preferably carried out using acetic acid or acetic anhydride as a reaction solvent in the presence of nitrite or nitrite. As the nitrite, sodium or potassium salt can be used, and as the nitrite, isoamyl nitrite, t-butyl nitrite or the like can be used. The reaction temperature is not particularly limited, but the reaction can be performed at a low temperature of about 0 ° C. to about the boiling point of the reaction solvent. In this case, it may be selected appropriately depending on the progress of the reaction.

  Method (A-4)

(In the formula, each symbol has the same meaning as described above, and X ^B represents halogen (for example, iodine, bromine, chlorine, fluorine, etc.) The compound represented by the formula (A4) may be a known compound. Well, a compound derived from a known compound by a conventional method may be used).

In this step, the compound represented by the formula (A4) is halogenated and converted to the compound represented by the formula (A5). X ^{B in the} formula (A5) represents a halogen. In this case, iodine or bromine is preferable as the halogen, and iodine is particularly preferable. There are many known methods for halogenation and can be carried out according to these methods. In particular, iodine is used as a reaction solvent in the presence of an inorganic salt such as sodium hydroxide, potassium hydroxide, or sodium hydrogen carbonate. It is preferable to use DMF, NMP, DMA, dichloromethane or the like. The reaction temperature is preferably room temperature, but can be raised to about the boiling point, and may be appropriately selected depending on the progress of the reaction.

  Method (A-5)

(Wherein each symbol has the same meaning as described above, and X ^B represents halogen (for example, iodine, bromine, chlorine, fluorine, etc.), P ⁰ represents a protecting group, a compound represented by formula (A5)) May be a known compound, or a compound derived from a known compound by a conventional method).

In this step, a protecting group (P ⁰ in the formula) is introduced into the 1-position nitrogen of the indazole or pyrazolo [4,3-b] pyridine ring of the compound represented by the formula (A5). The protecting group is not particularly limited as long as it is not deprotected in the cross-coupling reaction of the method (A-6) described below, but a carbamate functional group such as a Boc group or a benzyloxycarbonyl (Cbz) group, A methoxymethyl group (MOM) group, a 2- (trimethylsilyl) ethoxymethyl (SEM) group, a 2-tetrahydropyranyl (THP) group, or the like can be used. The above protecting group can be introduced according to a known method. For example, in the case of the Boc group, di-t-butyl dicarbonate is used, an organic base such as triethylamine, or sodium hydroxide, sodium bicarbonate, sodium carbonate, etc. In the presence of an inorganic base, the reaction may be carried out using DMF, NMP, DMA, dichloromethane, or a mixed solvent thereof with water as the reaction solvent. In some cases, the reaction proceeds by adding a catalytic amount of DMAP. Promoted. The reaction temperature is preferably about 0 ° C. to room temperature, but may be appropriately selected depending on the progress of the reaction. In this method, depending on the protecting group, a compound in which not only the 1-position of the indazole ring but also the 2-position is protected may be obtained, but the method (A-6) described below is carried out using a mixture thereof. be able to.

In addition, a compound in which R ¹ is substituted or unsubstituted alkyl can be synthesized by reacting the compound represented by the formula (A5) with an alkyl halide. The reaction conditions may be the same as in the step of introducing the protecting group.

  Method (A-6)

(In the formula, each symbol has the same meaning as described above, and X ^B represents halogen (for example, iodine, bromine, chlorine and fluorine). P ⁰ represents a protecting group (for example, Boc group, benzyl group, benzyloxy) A compound represented by formula (A6) may be a known compound, or a compound derived from a known compound by a conventional method).

In this step, a compound represented by the formula (A6) and a reagent having a substituent R ² are subjected to a cross-coupling reaction to be converted into a compound represented by the formula (A7). The cross coupling reaction can be performed according to the method (A-1). At this time, it is preferable to use a Suzuki coupling reaction using an organic boronic acid reagent in the presence of a palladium catalyst shown in (3), optionally a phosphine ligand shown in (4), and a base shown in (2). . The organic boronic acid was synthesized using a commercially available compound when available, and was synthesized according to a known method in the case of a known compound. It can also be synthesized by the method shown in General Synthesis Method 2 (compounds represented by Formulas (B2), (B4), (B7), and (B10)).

  Method (A-7)

(In the formula, each symbol has the same meaning as described above, and P ⁰ represents a protecting group (for example, Boc group, benzyl group, benzyloxycarbonyl group, etc.) The compound represented by formula (A7) is a known compound. Or a compound derived from a known compound by a conventional method may be used).

  In this step, the protecting group of the compound represented by the formula (A7) is deprotected and converted to the compound represented by the formula (A8). Although deprotection can be carried out according to a conventional method, for example, in the case of a Boc group, it is preferable to use dichloromethane as a reaction solvent and allow trifluoroacetic acid of about 50% volume of the reaction solvent to act, but it is limited to this method. It is not a thing. Other protecting groups may be deprotected according to known methods.

(General synthesis method 2)
Method (B-1)

(In the formula, each symbol is as defined above, and X ₁ represents a leaving group such as a halogen (for example, iodine, bromine, chlorine and fluorine) or an OMs group, an OTs group, an OTf group, an ONs group, etc.) Represents N, O, and S. Examples of R ^B1 , R ^B2, and R ^B3 include any suitable substituents such as alkyl, aryl, alkenyl, acyl, amino, alkoxy, carbamoyl, sulfamoyl, and the like. These substituents are exemplified herein).

In this method, the formulas (B2) and (B4) are synthesized using the formulas (B1) and (B3) as starting materials. As the compounds represented by the formulas (B1) and (B3), a known compound may be used, or a compound derived from a known compound by a conventional method may be used. X ₁ represents halogen or a leaving group. As the halogen, iodine and bromine are preferable, and as the leaving group, an OTf group (trifluoromethanesulfonic acid ester) is preferable. Conversion to the corresponding organic boronic acid or organic boronic acid ester involves lithiation of the halide represented by the formula (B1) or (B3) with alkyllithium such as n-butyllithium, By acting, it can be converted to a compound represented by the formula (B2) or (B4). The reaction solvent is not particularly limited as long as it does not react with alkyllithium such as THF and dioxane. The temperature of the lithiation reaction is preferably from a low temperature of about -78 ° C to about 0 ° C, and may be raised to room temperature after the addition of the borate ester. The boric acid ester is preferably a methyl ester or an isopropyl ester, and can be converted to an organic boronic acid after the reaction by adding water or a dilute hydrochloric acid aqueous solution. In addition, the compounds represented by the formulas (B2) and (B4) are compounds represented by the formula (B1) or (B3), the palladium catalyst used in the method (A-1) of the general synthesis method 1, a base, and a reaction solvent. And in the presence of bis (pinacolato) diborane, the reaction can be carried out at room temperature to the boiling point of the solvent.

Hereinafter, a method for introducing a substituent into R ^B2 will be exemplified.

  Method (B-2)

(In the formula, each symbol is as defined above, and X ₁ represents a leaving group such as halogen (for example, iodine, bromine, chlorine and fluorine) or OMs group, OTs group, OTf group, ONs group, etc.). Represents any suitable leaving group such as halogen, alkoxy, etc. R ^B1 , R ^B3 , R ^B4 , and R ^B5 include alkyl, aryl, alkenyl, acyl, amino, alkoxy, etc. Any suitable substituent can be mentioned, and these substituents are exemplified in the present specification, and the compounds represented by the formula (B5) and the formula (HN-R ^B4 R ^B5 ) are publicly known. A compound may be used, and a compound derived from a known compound by a conventional method may be used).

In this method, the compound represented by the formula (B5) is reacted with the compound represented by the formula (HN-R ^B4 R ^B5 ) in the presence of a base and a condensing agent to synthesize the compound represented by the formula (B6).

  As the reaction solvent, the reaction solvent described in (1) can be used, among which DMF, NMP, DMA, THF, or dioxane is preferable, but is not particularly limited as long as it does not react under the present conditions.

  As the base, the base described in (2) can be used. Preferably, for example, a metal hydride (eg, sodium hydride), a metal hydroxide (eg, sodium hydroxide, potassium hydroxide, hydroxide) Lithium, barium hydroxide, etc.), metal carbonates (eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.). The base is not necessarily used, but can be used as necessary.

  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 (diphenyl phosphate azide), 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.

  Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, etc.), N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide as the reaction solvent, and organic amines (eg, triethylamine, diisopropylethylamine) as the base DBU, 2,6-lutidine, etc.), HATU or PyBOP (hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium) may be used as a condensing agent. 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.

  In addition, the compound represented by the formula (B6) can be converted into the corresponding organic boronic acid or organic boronic acid ester represented by the formula (B7) by the reaction of the method described in the method (B-1).

  Method (B-3)

Wherein each symbol is as defined above, and X ₁ and X ₂ represent a leaving group such as halogen (eg iodine, bromine, chlorine and fluorine) or OMs group, OTs group, OTf group, ONs group, etc. Examples of R ^B1 , R ^B3 , R ^B4 , and R ^B6 include any suitable substituents such as alkyl, aryl, alkenyl, acyl, amino, alkoxy, sulfamoyl, carbamoyl, and the like. Substituents are exemplified in this specification, and the compound represented by the formula (B8) may be a known compound or a compound derived from a known compound by a conventional method).

In this method, the compound represented by the formula (B8) is reacted with the formula (R ^B6 -X ₂ ) to synthesize the compound represented by the formula (B9). X ₂ is preferably a halogen group or an OTf group. The reaction may be carried out in the solvent described in (1), preferably alcohols such as NMP, DMA, DMSO, dioxane, toluene, and ethanol. The reaction temperature may be from 50 ° C. to the temperature at which the solvent used is refluxed. When the reaction rate is slow, the temperature may be raised to about 250 ° C. using a microwave reactor. As the base, the base described in (2) can be used, but it may not be used.

  In addition, the compound represented by the formula (B9) can be converted to the corresponding organic boronic acid or organic boronic acid ester represented by the formula (B10) by the reaction of the method described in the method (B-1).

(General synthesis method 3)
In the compound represented by the formula (A1), when R ⁴ is ^Xc , a substituent can be introduced at the 6-position of the indazole ring by the following method.

(In the formula, each symbol is as defined above, and X ^A and X ^c are halogen (eg, iodine, bromine, chlorine, fluorine, etc.) or elimination of OMs group, OTs group, OTf group, ONs group, etc. P ⁰ represents a protecting group (for example, a Boc group, a benzyl group, a benzyloxycarbonyl group, etc.) The compound represented by the formula (C1) may be a known compound, which is usually a known compound. Compounds derived by the method may be used).

Method (C)
This is a method of synthesizing a compound represented by the formula (C3) by reacting various nucleophiles with the compound represented by the formula (C2) to introduce a substituent R ⁴ . Alternatively, for example, an organic boronic acid (Suzuki reaction), an organic tin (Still reaction), an alkene derivative (Heck reaction), an alkyne derivative (Sonogashira reaction), an amine derivative (Buchwald reaction) with respect to the compound represented by the formula (C2) And R ⁴ can also be introduced using a coupling reaction such as organic zinc (Negishi reaction). Any of them can be carried out under the same conditions as in General Synthesis Method 1 (A-1). The compound represented by the formula (C2) is synthesized using the methods (A-1) to (A-6) described in General Synthesis Method 1 with respect to the compound represented by the formula (C1).

  Furthermore, the compound of the present invention represented by the formula (C4) can be synthesized from the compound represented by the formula (C3) by the reaction of the method described in the method (A-7).

(General synthesis method 4-1)
In the compound represented by the formula (A1), when R ³ is O—P ¹ , a substituent can be introduced into the 5-position of the indazole ring by the following method.

(Wherein each symbol is defined as above, also, ^{X c} is a halogen (e.g., indicating iodine, bromine, chlorine and fluorine) or OMs group, OTs group, OTf group, a leaving group such as ONs group P ⁰ and P ^{1 each} represent a protecting group (for example, Boc group, benzyl group, benzyloxycarbonyl group, etc.) The compound represented by the formula (D1) may be a known compound, and may be a known compound. Compounds derived by the method may be used).

  From the compound represented by the formula (D2), the method (D-1), the method (D-2) and the method (A-7) are used to formula (D5) and the method (D- This is a method for synthesizing the formula (D8) using 1), method (D-3), method (D-4) and method (A-7). The compound represented by the formula (D2) can be synthesized by using the methods (A-1) to (A-6) and the method (C) described above. The methods (D-1) to (D-4) are described in detail below.

  Method (D-1)

Wherein each symbol is as defined above, and P ⁰ and P ^{1 each} represent a protecting group (for example, Boc group, benzyl group, benzyloxycarbonyl group, etc.) The compounds represented by formula (D2) are known. A compound may be used, and a compound derived from a known compound by a conventional method may be used).

In this step, the protecting group P ¹ of the compound represented by the formula (D2) is deprotected and converted to a compound represented by the formula (D3). The deprotection can be carried out according to a conventional method, but is carried out under the condition that only the hydroxy protecting group P ¹ is deprotected and the amino protecting group P ⁰ is not deprotected. For example, when P ⁰ is protected with a Boc group and P ¹ is protected with a benzyl group, only the benzyl group can be selectively deprotected by using a hydrogenation reaction using palladium carbon. However, the present invention is not limited to this method. . Other protecting groups may be deprotected according to known methods.

  Method (D-2)

(In the formula, each symbol has the same meaning as described above, and R ^D1 can include any suitable alkyl substituent. These substituents are exemplified herein.)

  In this step, the compound represented by the formula (D3) is reacted with an alkylating reagent in the presence of a base to convert it to a compound represented by the formula (D4). Examples of the alkylating reagent include benzyl bromide. As the base, the base described in (2) can be used. Preferably, for example, a metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonate ( Examples thereof include sodium carbonate, calcium carbonate, cesium carbonate and the like. The base is not necessarily used, but can be used as necessary. As the reaction solvent, the reaction solvent described in (1) can be used, among which DMF, NMP, DMA, THF, or dioxane is preferable, but is not particularly limited as long as it does not react under the present conditions. The reaction temperature is not particularly limited, but when the reactivity is low, it can be prepared by appropriately heating.

  Furthermore, the compound of the present invention represented by the formula (D5) can be synthesized from the compound represented by the formula (D4) under the same conditions as in the method described in the method (A-7).

  Method (D-3) and Method (D-4)

(In the formula, each symbol is as defined above, and P ⁰ represents a protecting group (for example, Boc group, benzyl group, benzyloxycarbonyl group, etc.) X ₃ represents a halogen group (for example, iodine, bromine, chlorine). And a leaving group such as an Ms group, Ts group, Tf group, Ns group, etc. The compound represented by the formula (X ₃ -P ² ) may be a known compound, and may be a known compound. A compound derived by a conventional method may be used).

In this step, the compound represented by the formula (D3) is reacted with X ₃ -P ² to be converted into a compound represented by the formula (D6). Examples of the X ₃ group of the compound represented by the formula (D6) obtained by this reaction include a leaving group such as an Ms group, a Ts group, a Tf group, an Ns group, and the like (where “Ms” is A methanesulfonyl group, “Ts” represents a para-toluenesulfonyl group, “Tf” represents a trifluoromethanesulfonyl group, and “Ns” represents an orthonitrobenzenesulfonyl group.) Preferably, the P ² group is converted to a Tf group. The reaction can be carried out using trifluoromethanesulfonic anhydride in the presence of a base such as triethylamine, DIEA, pyridine, sodium hydride, LHMDS and the like using a solvent such as dichloromethane, THF, dioxane and the like. Since these methods are known in the literature, they can be carried out according to them.

  Furthermore, a compound represented by the formula (D7) can be synthesized by performing a cross-coupling reaction on the compound represented by the formula (D6). The cross coupling reaction is performed using the same conditions as in method (A-1).

  With the compound represented by the formula (D7), the compound of the present invention represented by the formula (D8) can be synthesized under the same conditions as in the method described in the method (A-7).

(General synthesis method 4-2)
In the compound represented by the formula (D8), when R ³ is a substituted or unsubstituted alkenyl (formula (D8 ′)), the compound (D9) having a substituted or unsubstituted alkyl at R ³ is obtained by the following method. Can be converted.

  Method (D-5)

(In the formula, each symbol has the same meaning as described above, and R ^{3 ′} may include any suitable substituent such as alkyl, aryl, alkenyl, acyl, amino, alkoxy, sulfamoyl, carbamoyl, etc.)
In this step, the compound represented by the formula (D8 ′) is converted to the compound represented by the formula (D9) by hydrogenation using a catalyst. As the catalyst, palladium carbon or the like can be used, but this reaction is a method known to those skilled in the art and is not limited to the above.

(General synthesis method 5)
The compound (E4) of the present invention when Y is nitrogen can be synthesized by the following method.

(In the formula, each symbol has the same meaning as described above, and X ^B represents a leaving group such as halogen (for example, iodine, bromine, chlorine and fluorine) or OMs group, OTs group, OTf group, ONs group, etc.) P ⁰ represents a protecting group (for example, Boc group, benzyl group, benzyloxycarbonyl group, etc.) R ^E1 can include any suitable substituents such as alkyl, aryl, acyl and the like. These substituents are exemplified in the present specification.As the compound represented by the formula (E1), a known compound may be used, or a compound derived from a known compound by a conventional method may be used).

  In this method, a compound represented by formula (E3) is synthesized from a compound represented by formula (E1) using methods (E-1) and (E-2). Furthermore, the compound represented by the formula (E3) can synthesize the formula (E4) which is the compound of the present invention by using the methods (A-2) to (A-7). The methods (E-1) and (E-2) are described in detail below.

  Method (E-1)

(In the formula, each symbol has the same meaning as described above. The compound represented by the formula (E1) may be a known compound or a compound derived from a known compound by a conventional method).

  In this method, the compound represented by the formula (E2) is synthesized by nitration of the formula (E1). For example, the reaction can be carried out in a sulfuric acid solvent in the presence of nitric acid, potassium nitrate, or sodium nitrate. Although reaction temperature is not specifically limited, Preferably, it can implement at low temperature of about 0 degreeC to room temperature. In this case, the temperature may be appropriately selected depending on the progress of the reaction.

  Method (E-2)

(In the formula, each symbol is as defined above. As R ^E1 , any suitable alkyl substituent can be exemplified. These substituents are exemplified in the present specification. X ₄ is halogen. Or a leaving group such as an OMs group, an OTs group, an OTf group, an ONs group, etc. The compound represented by X ₄ -R ^E1 and the formula (E2) is A known compound may be used, and a compound derived from a known compound by a conventional method may be used).

In this method, the compound represented by the formula (E2) is reacted with X ₄ -R ^E1 in the presence of a base to synthesize the compound represented by the formula (E3). As the base, the base described in (2) can be used. Preferably, for example, a metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonate ( Examples include sodium carbonate, calcium carbonate, cesium carbonate, etc.), metal hydrides (sodium hydride, etc.) and the like. As the reaction solvent, the reaction solvent described in (1) can be used, among which DMF, NMP, DMA, THF, or dioxane is preferable, but is not particularly limited as long as it does not react under the present conditions. The reaction temperature is not particularly limited, but when the reactivity is low, it can be prepared by appropriately heating.

  (General synthesis method 6)

(In the formula, each symbol has the same meaning as described above, and R ^F1 can include any appropriate one, such as substituted or unsubstituted alkyl, heterocycle, cycloalkyl, aryl, and heteroaryl.)
The compounds represented by the formula (F12) and the formula (F15) can be synthesized from the compound represented by the formula (F1) according to the method shown above. The method (F-1) and the method (F-2) are described in detail below.

  Method (F-1)

Method (F-1) is a method of synthesizing a compound represented by formula (F3) from a compound represented by formula (F2) by cyclization using hydrazine or a hydrate thereof. For example, the reaction can be carried out in the presence of hydrazine or a hydrate thereof in DMF, NMP, acetonitrile, THF, dioxane, and an alcohol solvent. The reaction temperature is not particularly limited, but can be raised to about 150 ° C. when the reaction proceeds slowly.

  Method (F-2)

Method (F-2) is a method of synthesizing a corresponding compound represented by the formula (F11) from a compound represented by the formula (F10) by reductive alkylation reaction in the presence of an aldehyde or a ketone. For example, the reaction can be carried out in DMF, NMP, acetonitrile, THF, dioxane, and dichloromethane solvents in the presence of an aldehyde or ketone and sodium cyanoborohydride or sodium triacetoxyborohydride. The reaction temperature is not particularly limited, but can be raised to about 80 ° C. when the reaction proceeds slowly.

  (General synthesis method 7)

(In the formula, each symbol has the same meaning as described above, and R ^G1 can include any appropriate ones such as substituted or unsubstituted alkyl, heterocycle, cycloalkyl, aryl, and heteroaryl.)
The compound represented by the formula (G14) can be synthesized from the compound represented by the formula (G1) according to the method shown above. The method (G-1) and the method (G-2) are described in detail below.

  Method (G-1)

Method (G-1) is a method of synthesizing a compound represented by formula (G2) from a compound represented by formula (G1) by a halogenation reaction. The halogenation reaction may be synthesized according to known literatures.

In the presence of a halogenating reagent represented by The reaction temperature is preferably about 0 ° C. to room temperature.

  Method (G-2)

Method (G-2) is a method of synthesizing a compound represented by formula (G2) from a compound represented by formula (G3) via a diazo compound. This reaction may be synthesized according to known literatures. For example, the reaction can be carried out by adding a diazo compound corresponding to an aqueous sulfuric acid solution after diazotization using nitrite or nitrite. The reaction temperature is preferably about 0 to 5 ° C. in the diazotization reaction, and may be raised to a reflux temperature after addition to the sulfuric acid aqueous solution.

  (General synthesis method 8)

(In the formula, each symbol has the same meaning as described above.)
The compound represented by the formula (H3) can be synthesized from the compound represented by the formula (G13) according to the method shown above. The method (H-1) will be described in detail below.

  Method (H-1)

In the method (H-1), after deprotecting the substituent represented by R ^G1 from the compound represented by the formula (G13), the compound represented by the formula (H1) is substituted with a Tf (trifluoromethanesulfonyl) group. It is a method of synthesis. For R ^G1, for example, it can be used a benzyl group _{^{(R G1 = -CH 2 Ph)}} , deprotection at that time, but a palladium on carbon can be carried out by reacting as a catalyst under a hydrogen ^{atmosphere, R G1} And the deprotection thereof are not limited to this method, and can be carried out according to the method of arable land. Next, the compound represented by the formula (H1) can be synthesized by carrying out according to the method (D-3).

  (General synthesis method 9)

(In the formula, each symbol has the same meaning as described above, and R ^I1 can include any appropriate ones such as substituted or unsubstituted alkyl, heterocycle, cycloalkyl, aryl, and heteroaryl.)
The compound represented by the formula (I11) can be synthesized from the compound represented by the formula (G2) according to the method shown above.

  (General synthesis method 10)

Wherein each symbol is as defined above, alk represents lower alkyl, and R ^J1 and R ^J2 are each an appropriate group such as substituted or unsubstituted alkyl, heterocycle, cycloalkyl, aryl, and heteroaryl. Any can be mentioned.)
The compound represented by the formula (J3) can be synthesized from the compound represented by the formula (C2) according to the method shown above.

  Details are described below.

Method (J-1)
The compound represented by the formula (J1) can be synthesized by carbonylating the compound represented by the formula (C2) using carbon monoxide. The carbonylation reaction using carbon monoxide may be synthesized according to known literature. For example, it is carried out in a DMF-alcohol solvent in the presence of a palladium catalyst such as PdCl ₂ (PPh ₃ ) ₂ and a base such as triethylamine. it can.

Method (J-2)
The compound represented by the formula (J2) can be synthesized by hydrolyzing the compound represented by the formula (J1). The reaction solvent is an ether solvent such as dioxane, THF, or DME, an alcohol solvent such as ethanol or methanol, a solvent such as DMF, DMA, DMSO, or NMP, and water, and the base is sodium hydroxide. 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.

Method (J-3)
The compound represented by the formula (J3) can be synthesized by condensing the compound represented by the formula (J2) with an amine compound represented by the formula HNR ^J1 R ^J2 . As the reaction solvent, DMF, NMP, DMA, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile and the like can be used. Examples of condensing agents include DCC (dicyclohexylcarbodiimide), BOP (benzotriazol-1-yloxy-trisdimethylaminophosphate), PyBOP (hexafluorophosphate (benzotriazol-1-yloxy) tripyrrolidinophosphonium), PyBrop (hexafluoro). Bromotrispyrrolidinophosphonium phosphate), HATU, DPPA (diphenyl phosphate azide), 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 preferable to carry 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)
The compound (K10) of the present invention in which X is —C (—R ′) ═ and R ′ is a substituted or unsubstituted amino group can be synthesized by the following method.

(In the formula, each symbol is as defined above, and X ^A represents a leaving group such as halogen (for example, iodine, bromine, chlorine and fluorine) or OMs group, OTs group, OTf group, ONs group, etc.) X ^B and X ^D each represent a halogen (eg, iodine, bromine, chlorine, fluorine, etc.) P ⁰ and P ¹ are protecting groups (eg, Boc group, benzyl group, benzyloxycarbonyl group, SEM group, etc.) As the compound represented by the formula (K1), 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 (K10) can be synthesized from the compound represented by the formula (K1) according to the method shown above. The method (K-1), method (K-2), method (K-3) and method (K-4) will be described in detail below.

Method (K-1)
The compound represented by the formula (K3) can be synthesized by halogenating the compound represented by the formula (K2). The halogenation reaction may be synthesized according to known literature. For example, it can be carried out by reacting with bromine in a methanol solvent in the presence of acetic acid.

Method (K-2)
The compound represented by the formula (K5) is obtained by alkylating the 2-position nitrogen of the indazole or pyrazolo [4,3-b] pyridine ring of the compound represented by the formula (K4) according to the method (A-5). Can be synthesized. For example, it can be carried out at a reaction temperature of about 0 ° C. to room temperature in the presence of an alkylating reagent such as methyl iodide, benzyl bromide, and p-methoxybenzyl bromide in a reaction solvent such as DMF and NMP.

Method (K-3)
The compound represented by the formula (K6) is obtained by coupling the compound represented by the formula (K5) with an amine compound (H ₂ NR ^K1 ) according to the method (A-1), and further protecting group according to the method (A-5). It can be synthesized by introducing (P ¹ ).

Method (K-4)
The compound represented by the formula (K10) can be synthesized by deprotecting the protecting group P ⁰ or P ¹ from the compound represented by the formula (K9) according to the method (A-7).

(General synthesis method 12)
The compound (L6) of the present invention when X is —C (—R ′) ═ and R ′ is a substituted or unsubstituted amino group can be synthesized by the following method.

(In the formula, each symbol is as defined above, and X ^A represents a leaving group such as halogen (for example, iodine, bromine, chlorine and fluorine) or OMs group, OTs group, OTf group, ONs group, etc.) X ^B and X ^D each represent a halogen (eg, iodine, bromine, chlorine, fluorine, etc.) P ⁰ and P ¹ are protecting groups (eg, Boc group, benzyl group, benzyloxycarbonyl group, SEM group, etc.) As the compound represented by the formula (K1), 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 (L6) can be synthesized from the compound represented by the formula (K4) according to the method shown above. The method (L-1) will be described in detail below.

Method (L-1)
The compound represented by the formula (L1) is obtained by reacting the compound represented by the formula (K4) with an alkylating reagent in the presence of a base, and R ^{1 is} bonded to the nitrogen at the 2-position of the indazole or pyrazolo [4,3-b] pyridine ring. ^'This is the process of introducing groups. Examples of the alkylating reagent include methyl iodide, benzyl bromide, and p-methoxybenzyl bromide. As the base, the base described in (2) can be used, and preferably, for example, cesium carbonate is used. The reaction temperature is preferably about 0 ° C. to room temperature.

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

The compounds of the present invention can be protected using protecting groups. 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 protecting groups described in Protective Groups in Organic Synthesis, TWGreen, John Wiley & Sons Inc. (1981), such as ethoxycarbonyl, t-butoxycarbonyl, acetyl, and benzyl. Can give. Methods for introducing and removing protecting groups are those commonly used in organic synthetic chemistry [for example, see Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons Inc. (1981)], etc. It can be obtained similarly. In addition to the above production method, the functional group contained in each substituent can also be converted by a known method [for example, Comprehensive Organic Transformations, RC Larock (1989), etc.]. Some can lead to further derivatives as synthetic intermediates. The intermediates and target compounds in each of the above production methods are isolated and purified by purification methods commonly used in synthetic organic 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 2, 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 that is inserted or substituted and has kinase activity. Here, as a preferable amino acid sequence, any of those listed in Patent Document 2 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 2), phosphorylation of the 180th threonine and / or the 182th tyrosine is mentioned. TTK activity can be measured using the measurement method used in the screening method of Patent Document 2. 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 2, 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 2 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 modifying groups, 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 above-mentioned “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 the “immune disease” include atopy, asthma, rheumatism, collagen disease, allergy 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, immune disease and the like involving TTK protein kinase.

The pharmaceutical composition has one feature in that it contains 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. To 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, 0.00001 to 100 mg, preferably 0.0001 to 10 mg is desirable.

  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.

  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. Although it does not specifically limit as administration, When an active ingredient is a low molecular compound or a high molecular compound, as an amount of the said active ingredient, it is 0.0001-1000 mg / kg body weight, Preferably, it is 0.001-100 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, for example, 1 to 3 times per day 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 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, injections and the like. Liquid preparations such as emulsions and syrups suitable for oral administration are 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, hydroxypropyl cellulose, gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin.

  Formulations suitable for parenteral administration preferably comprise a sterile aqueous formulation 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, polyalcohol and the like or other bases used in topical pharmaceutical formulations.

  A preparation for enteral administration is prepared using a normal carrier such as cacao butter, hydrogenated fat, hydrogenated fatty carboxylic acid and the like, and is provided as a suppository.

  In the present invention, glycols, oils, flavors, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants exemplified in oral preparations are also 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 based on the fluorescence value when the TTK IC50 in the case of screening for a compound having a TTK kinase activity inhibitory action using the p38MAPK peptide is absent. 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), within the range of 10 nM to 10 μM, Preferably, the compound has an IC50 value of less than 10 μM, more preferably less than 5 μM, and even more preferably less than 1 μM.

  For further information regarding formulation, reference can be made to Chapter 25.2 of Volume 5, Pergamon Press 1990, Comprehensive Medicinal Chemistry (Corwin Hansch; Cairman of Editorial Board).

    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 systems, devices, and kits using the compounds of the present invention, pharmaceutically acceptable salts, or solvates 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 having a sufficiently long half-life for exhibiting a medicinal effect are included.

  References such as scientific literature, patents and patent applications cited herein are hereby incorporated by reference in their entirety to the same extent as if each was specifically described.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, the technical scope of this invention is not limited by this Example.

  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 0-100% 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.

  Reversed 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 0-100% acetonitrile (5 minutes linear gradient) and 100% acetonitrile (2 minutes) at a flow rate of 25 mL / min.

  Silica gel chromatography used systems from Yamazen (YFLC-Wprep2XY), Moritex (Purif-α2), and 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 spectra were measured using Varian Gemini-300 (300 MHz) and 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 and 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) are mixed in a 384-well polypropylene microtiter plate (Corning). And placed 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 polypropylene 384-well 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) Tween20), 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, A549: 1 × 10 ⁴ ) adjusted to an appropriate concentration by D-MEM (Nacalai Tesque) with 10% FBS (High clone) / ml, MRC5: 3 × 10 ⁴ / ml and 1 × 10 ⁵ / ml) was added to a 96-well plate (hereinafter, well plate) at 100 μl / well and cultured in a CO ₂ incubator at 37 ° C. for 1 day. In a 96-well assay block, 2 μl of 10 mM compound (100% DMSO solution) that showed TTK kinase activity inhibitory action 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 compound dilution was added to each well of a well plate prepared with cells to make 200 μl / well. Thereafter, the cells were further cultured for 3 days in a 37 ° C. CO ₂ incubator. 10 μl 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. After measuring the absorbance at 450 nm (reference wavelength 620 nm) with a microplate reader, the inhibitory activity of the test substance is calculated based on the absorbance value in the absence of the test substance, showing the growth inhibitory action in cancer cells Selected compounds.

Example 1
Example 1-1
(E) -N- (3- (5- (2-Cyclopropylvinyl) -6-fluoro-1H-indazol-3-yl) phenyl) acetamide

Step 1: 1-bromo-2-fluoro-5-methyl-4-nitrobenzene Concentrated sulfuric acid (27.6 g, 15 mL) was added to nitric acid (21.2 g, 15 mL, 17.3 mmol) at 0 ° C. To the resulting solution, 2-bromo-1-fluoro-4-methylbenzene (22.61 g, 15 mL, 120 mmol) was added dropwise at the same temperature over 10 minutes, and then stirred at room temperature for 5 hours. The reaction solution was poured into ice water, and the precipitated solid was collected by filtration and washed with water, saturated aqueous sodium bicarbonate, and methanol / water (1/1) solution to give the title compound (21.1 g, 90 mmol, 75%) Was obtained as a solid.
1H-NMR (300 MHz, DMSO-d6) δ 2.49 (d, J = 0.3 Hz, 4H), 7.98 (d, J = 7.1 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H).

Step 2: 4-Bromo-5-fluoro-2-methylaniline
1-Bromo-2-fluoro-5-methyl-4-nitrobenzene (21.1 g, 90 mmol), activated carbon (3.24 g), and iron trichloride hexahydrate (1.46 g, 5.4 mmol) in methanol (50 mL) ) The solution was heated to reflux for 10 minutes, and then hydrazine hydrate (18.0 g, 17.5 mL, 360 mmol) was added dropwise over 30 minutes while heating to reflux. After stirring for 5 hours under heating to reflux, the temperature was returned to room temperature. The reaction solution was filtered through Celite and concentrated, and the residue was purified by medium pressure silica gel chromatography (hexane / chloroform; 60-100% chloroform gradient) to give the title compound (17.7 g, 87.0 mmol, 96%). It was.
1H-NMR (300 MHz, DMSO-d6) δ 2.00 (s, 3H), 5.32 (s, 2H), 6.50 (d, J = 11.4 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H).

Step 3: 5-Bromo-6-fluoro-1H-indazole
To a solution of 4-bromo-5-fluoro-2-methylaniline (17.7 g, 87 mmol) in acetic acid (870 mL), slowly add an aqueous solution (8.7 mL) of sodium nitrite (6.57 g, 95 mmol) to 60 ° C. For 5 hours. The reaction solution was concentrated and diluted by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate. 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (chloroform / ethyl acetate; 0-20% ethyl acetate gradient) to give the title compound (14.9 g, 69.5 mmol, 80%). Obtained as a yellow solid.
1H-NMR (DMSO-d6) δ 7.54 (d, J = 9.2 Hz, 1H), 8.06 (s, 1H), 8.15 (d, J = 6.9 Hz, 1H), 13.29 (s, 1H).

Step 4: 5-bromo-6-fluoro-3-iodo-1H-indazole The title compound (22.2 g, 65.0) was synthesized according to the method of Example 1-262 (Step 5) of Patent Application 2008-285971. mmol, 94%).
1H-NMR (300 MHz, DMSO-d6) δ 7.62 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 6.4 Hz, 1H), 13.73 (s, 1H).

Step 5: tert-Butyl 5-bromo-6-fluoro-3-iodo-1H-indazole-1-carboxylate By synthesizing according to the method of Example 1-262 (Step 6) of Patent Application 2008-285971 The title compound (27.1 g, 61.4 mmol, 94%) was obtained.
1H-NMR (300 MHz, DMSO-d6) δ 1.63 (s, 9H), 7.91 (d, J = 2.0 Hz, 1H), 7.94 (s, 1H).

Step 6: tert-butyl 3- (3-acetamidophenyl) -5-bromo-6-fluoro-1H-indazole-1-carboxylate
tert-butyl 5-bromo-6-fluoro-3-iodo-1H-indazole-1-carboxylate (441 mg, 1.0 mmol), 2M Na ₂ CO ₃ aqueous solution (2.0 mL, 4.0 mmol), and PdCl ₂ (dppf ) · CH ₂ Cl ₂ (82 mg, 0.1 mmol) in THF (4 mL) was added 3-acetamidophenylboronic acid (179 mg, 1.0 mmol), and the mixture was stirred for 3 hours under heating to 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 30-80% ethyl acetate gradient) to give the title compound (354 mg, 0.79 mmol, 79%). Obtained.
1H-NMR (300 MHz, DMSO-d6) δ 1.66 (s, 9H), 2.09 (s, 3H), 7.46-7.49 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.77 (d , J = 8.1 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 8.16 (s, 1H), 8.36 (d, J = 6.4 Hz, 1H), 10.16 (s, 1H).

Step 7: (E) -tert-butyl 3- (3-acetamidophenyl) -5- (2-cyclopropylvinyl) -6-fluoro-1H-indazole-1-carboxylate
tert-butyl 3- (3-acetamidophenyl) -5-bromo-6-fluoro-1H-indazole-1-carboxylate (50 mg, 0.11 mmol), 2M K ₂ CO ₃ aqueous solution (223 μL, 0.45 mmol), And (E) -2- (2-cyclopropylvinyl) boronic acid pinacol ester (65 mg, 69 μL, 0.335 mmol) were added to a THF (2 mL) solution of PdCl ₂ (dtbpf) (3.6 mg, 0.0056 mmol) The mixture was stirred for 3 hours under heating to 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 30-80% ethyl acetate gradient) to give the title compound (49 mg, 0.11 mmol, 100%). Obtained.
1H-NMR (300 MHz, DMSO-d6) δ 0.57-0.60 (m, 2H), 0.82-0.87 (m, 3H), 1.66 (s, 9H), 2.08 (s, 3H), 6.07 (dd, J = 16.0, 9.1 Hz, 1H), 6.66 (d, J = 16.0 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 11.2 Hz, 1H), 8.14 (d, J = 7.1 Hz, 1H), 8.24 (s, 1H), 10.17 (s, 1H).
MS (ESI) m / z = 436 (M + H) ⁺ .
LC / MS t _R = 2.68 min.

Step 8: Title compound
(E) -tert-butyl 3- (3-acetamidophenyl) -5- (2-cyclopropylvinyl) -6-fluoro-1H-indazole-1-carboxylate (49 mg, 0.11 mmol) in dichloromethane: TFA = A 1: 1 solution (2 mL) was added and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, 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 residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 40-100% ethyl acetate gradient) and solidified with hexane / ethyl acetate to give the title compound (37 mg, 0.11 mmol, 100%).
1H-NMR (300 MHz, DMSO-d6) δ 0.56-0.58 (m, 2H), 0.81-0.85 (m, 2H), 1.65-1.66 (m, 1H), 2.09 (s, 3H), 5.96 (dd, J = 15.9, 9.1 Hz, 1H), 6.64 (d, J = 15.9 Hz, 1H), 7.34 (d, J = 11.2 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.63 (t, J = 5.9 Hz, 2H), 8.09 (d, J = 7.4 Hz, 1H), 8.27 (s, 1H), 10.08 (s, 1H), 13.24 (s, 1H).
MS (ESI) m / z = 336 (M + H) ⁺ .
LC / MS t _R = 1.95 min.

Example 1-2
(E) -N- (3- (6-Cyano-5- (2-cyclopropylvinyl) -1H-indazol-3-yl) phenyl) acetamide

Step 1: tert-Butyl 3- (3-acetamidophenyl) -5- (benzyloxy) -6-cyano-1H-indazole-1-carboxylate Synthesize according to the method of Example 1-1 (Step 6) This gave the title compound (77.6 mg, 0.161 mmol, 16%).
1H-NMR (300 MHz, DMSO-d6) δ 1.68 (s, 9H), 2.10 (s, 3H), 5.41 (s, 2H), 7.34-7.56 (m, 6H), 7.62 (d, J = 7.5 Hz , 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.80 (s, 1H), 8.27 (s, 1H), 8.42 (s, 1H), 10.20 (s, 1H).

Step 2: tert-butyl 3- (3-acetamidophenyl) -6-cyano-5-hydroxy-1H-indazole 1-carboxylate
tert-Butyl 3- (3-acetamidophenyl) -5- (benzyloxy) -6-cyano-1H-indazole-1-carboxylate (77 mg, 0.933 mmol) in THF: methanol = 1: 1 (20 mL) To the solution was added 10% palladium carbon (30 mg), and the mixture was stirred overnight under a hydrogen atmosphere. The reaction solution was filtered through celite and concentrated under reduced pressure to give the title compound (55 mg, 0.14 mmol, 88%).
1H-NMR (300 MHz, DMSO-d6) δ 1.66 (s, 9H), 2.07 (s, 3H), 7.35 (s, 1H), 7.35-7.47 (m, 2H), 7.71-7.75 (m, 1H) , 8.13 (s, 1H), 8.18 (s, 1H), 10.17 (s, 1H).
MS (ESI) m / z = 393 (M + H) ⁺ .
LC / MS t _R = 1.91 min.

Step 3: tert-Butyl 3- (3-acetamidophenyl) -6-cyano-5- (trifluoromethylsulfonyloxy) -1H-indazole-1-carboxylate
tert-butyl 3- (3-acetamidophenyl) -6-cyano-5-hydroxy-1H-indazole 1-carboxylate (98 mg, 0.25 mmol) in THF (5 mL) in NaHMDS (1.06 M THF solution; 259 μL, 0.275 mmol) was added at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. Then _{PhNTf 2 (107 mg, 0.30 mmol} ) and after addition at -78 ° C., and stirred for further 1 hour and warmed to room temperature. 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 30-80% ethyl acetate gradient) to give the title compound (111 mg, 0.21 mmol, 85%). Obtained.
1H-NMR (300 MHz, DMSO-d6) δ 1.69 (s, 9H), 2.09 (s, 3H), 7.51-7.57 (m, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.75 (d , J = 7.9 Hz, 1H), 8.25 (s, 1H), 8.47 (s, 1H), 8.74 (s, 1H), 10.19 (s, 1H).

Step 4: Title compound The title compound (33 mg, 0.095 mmol, 45%) was obtained by synthesis according to the method of Example 1-1 (Steps 7 and 8).
1H-NMR (300 MHz, DMSO-d6) δ 0.60-0.63 (m, 2H), 0.86-0.89 (m, 2H), 1.69-1.75 (m, 1H), 2.09 (s, 3H), 6.10 (dd, J = 15.6, 9.3 Hz, 1H), 6.81 (d, J = 15.6 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 8.15 (s, 1H), 8.28 (s, 1H), 8.32 (s, 1H), 10.10 (s, 1H), 13.70 (s, 1H).
MS (ESI) m / z = 343 (M + H) ⁺ .
LC / MS t _R = 1.89 min.

Example 1-3
3- (5- (Cyclohexyloxy) -6- (1-methyl-1H-pyrazol-4-ylamino) -1H-indazol-3-yl) benzenesulfonamide

Step 1: 1-Bromo-2- (cyclohexyloxy) -4-methyl-5-nitrobenzene
To a solution of 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (3 g, 12.82 mmol) and cyclohexanol (18.9 g, 20.0 mL, 189 mmol) in acetonitrile (107 mL) was added potassium hydroxide (9.35 g, 167 mmol) was added at 0 ° C. The mixture was warmed to room temperature and stirred for 22 hours. The reaction solution was diluted with water and ethyl acetate, and then separated by adding ethyl acetate. 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 residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 0-10% ethyl acetate gradient) to give the title compound (12.5 g, 39.9 mmol, 36%). Obtained.
1H-NMR (300 MHz, DMSO-d6) δ 1.37-1.61 (m, 6H), 1.65-1.75 (m, 2H), 1.84-1.90 (m, 2H), 2.53 (s, 3H), 4.67-4.74 ( m, 1H), 7.26 (s, 1H), 8.25 (s, 1H).

Step 2: 5-Bromo-4- (cyclohexyloxy) -2-methylaniline The title compound (9.61 g, 33.8 mmol, 85%) was synthesized by synthesizing according to the method of Example 1-1 (Step 2). Obtained.
1H-NMR (300 MHz, DMSO-d6) δ 1.23-1.37 (m, 3H), 1.39-1.49 (m, 3H), 1.66-1.74 (m, 2H), 1.78-1.85 (m, 2H), 1.99 ( s, 3H), 4.00-4.06 (m, 1H), 4.67 (s, 2H), 6.74 (s, 1H), 6.78 (s, 1H).

Step 3: 6-Bromo-5- (cyclohexyloxy) -1H-indazole The title compound (7.5 g, 25.4 mmol, 75%) was obtained by synthesis according to the method of Example 1-1 (Step 3). It was.
1H-NMR (300 MHz, DMSO-d6) δ 1.31-1.41 (m, 3H), 1.47-1.60 (m, 3H), 1.69-1.78 (m, 2H), 1.85-1.92 (m, 2H), 4.35- 4.42 (m, 1H), 7.39 (s, 1H), 7.77 (s, 1H), 7.94 (s, 1H), 12.95 (s, 1H).

Step 4: 6-Bromo-5- (cyclohexyloxy) -3-iodo-1H-indazole The title compound (10.7) was synthesized according to the method of Example 1-262 (Step 5) of Patent Application 2008-285971. g, 25.4 mmol, 100%).
1H-NMR (300 MHz, DMSO-d6) δ: 1.35-1.63 (m, 6H), 1.69-1.78 (m, 2H), 1.83-1.91 (m, 2H), 4.48-4.55 (m, 1H), 6.93 (s, 1H), 7.84 (s, 1H), 13.41 (s, 1H).

Step 5: tert-Butyl 6-bromo-5- (cyclohexyloxy) -3-iodo-1H-indazole-1-carboxylate Synthesis according to the method of Example 1-262 (Step 6) of Japanese Patent Application No. 2008-285971 This gave the title compound (13.3 g, 25.5 mmol, 91%).
1H-NMR (300 MHz, DMSO-d6) δ 1.37-1.63 (m, 5H), 1.62 (s, 9H), 1.67-1.77 (m, 2H), 1.84-1.91 (m, 2H), 4.64-4.71 ( m, 1H), 7.07 (s, 1H), 8.26 (s, 1H).

Step 6: tert-Butyl 6-bromo-5- (cyclohexyloxy) -3- (3-sulfamoylphenyl) -1H-indazole-1-carboxylate According to the method of Example 1-1 (Step 6) The title compound (1.24 g, 2.26 mmol, 59%) was obtained by synthesis.
1H-NMR (300 MHz, DMSO-d6) δ 1.36-1.62 (m, 6H), 1.67 (s, 9H), 1.70-1.78 (m, 2H), 1.83-1.91 (m, 2H), 4.64-4.72 ( m, 1H), 7.53 (s, 2H), 7.60 (s, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.95-7.98 (m, 1H), 8.18-8.21 (m, 1H), 8.36 -8.37 (m, 2H).

Step 7: Title compound
tert-Butyl 6-bromo-5- (cyclohexyloxy) -3- (3-sulfamoylphenyl) -1H-indazole-1-carboxylate (83 mg, 0.15 mmol), cesium carbonate (73 mg, 0.23 mmol) 1-methyl-1H-pyrazol-4-amine (73 mg, 0.75 mmol) was added to a dioxane (2 mL) solution of palladium acetate (6.7 mg, 0.030 mmol), and the mixture was stirred at 70 ° C. for 8 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 concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC (acetonitrile / water / 0.3% formic acid: 10-100% acetonitrile). The obtained compound was processed according to the method of Example 1-266 (Step 8) to give the title compound (20 mg, 0.042 mmol, 28%).
1H-NMR (300 MHz, DMSO-d6) δ 1.23-1.44 (m, 3H), 1.52-1.63 (m, 3H), 1.74-1.80 (m, 2H), 1.97-2.04 (m, 2H), 3.84 ( s, 3H), 4.40-4.48 (m, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 7.38 (s, 1H), 7.46 (s, 3H), 7.66 (t, J = 7.8 Hz , 1H), 7.75-7.78 (m, 2H), 8.12 (d, J = 7.8 Hz, 1H), 8.35-8.36 (m, 1H), 12.62 (s, 1H).
MS (ESI) m / z = 467 (M + H) ⁺ .
LC / MS t _R = 1.73 min.

Example 1-4
3- (3-Acetamidophenyl) -5- (cyclohexyloxy) -N-cyclopropyl-1H-indazole 6-carboxamide

Step 1: tert-Butyl 3- (3-acetamidophenyl) -6-bromo-5- (cyclohexyloxy) -1H-indazole-1-carboxylate Synthesize according to the method of Example 1-1 (Step 6) This gave the title compound (1.66 g, 3.15 mmol, 82%).
1H-NMR (300 MHz, DMSO-d6) δ 1.23-1.89 (m, 19H), 2.09 (s, 3H), 4.60-4.67 (m, 1H), 7.46-7.53 (m, 1H), 7.60-7.62 ( m, 3H), 8.35 (s, 2H), 10.17 (s, 1H).

Step 2: 1-tert-butyl 6-methyl 3- (3-acetamidophenyl) -5- (cyclohexyloxy) -1H-indazole-1,6-dicarboxylate
tert-butyl 3- (3-acetamidophenyl) -6-bromo-5- (cyclohexyloxy) -1H-indazole-1-carboxylate (264 mg, 0.50 mmol), and PdCl ₂ (PPh ₃ ) ₂ (49 mg , 0.07 mmol) in DMF: methanol = 5: 1 (6 mL) solution was added triethylamine (304 mg, 416 μL, 3.0 mmol), and the mixture was stirred at 80 ° C. for 8 hours in a carbon monoxide (CO) atmosphere. 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 30-100% ethyl acetate gradient) to give the title compound (136 mg, 0.268 mmol, 54%). Obtained.
1H-NMR (300 MHz, DMSO-d6) δ 1.35-1.87 (m, 19H), 2.09 (s, 3H), 3.86 (s, 3H), 4.57-4.64 (m, 1H), 7.46-7.53 (m, 2H), 7.61-7.64 (m, 4H), 8.37 (s, 2H), 10.18 (s, 1H).

Step 3: 3- (3-acetamidophenyl) -5- (cyclohexyloxy) -1H-indazole-6-carboxylic acid
1-tert-butyl 6-methyl 3- (3-acetamidophenyl) -5- (cyclohexyloxy) -1H-indazole-1,6-dicarboxylate (254 mg, 0.50 mmol) in methanol (2 mL) 4N Aqueous sodium hydroxide solution (2 mL, 8 mmol) was added, and the mixture was stirred at room temperature overnight. A 2N aqueous hydrochloric acid solution was added to the reaction solution, and the precipitated solid was collected by filtration to give the title compound (158 mg, 0.402 mmol, 80%).
1H-NMR (300 MHz, DMSO-d6) δ 1.31-1.89 (m, 9H), 2.08 (s, 3H), 4.40-4.47 (m, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.57-7.62 (m, 2H), 7.77 (s, 1H), 8.36 (s, 1H), 10.08 (s, 1H), 13.30 (s, 1H).

Step 4: Title compound
3- (3-acetamidophenyl) -5- (cyclohexyloxy) -1H-indazole-6-carboxylic acid (70 mg, 0.178 mmol), DIEA (35 mg, 47 μL, 0.267 mmol), and cyclopropylamine (31 mg, 0.534 mmol) in DMF (1 mL) was added HATU (101 mg, 0.267 mol) and stirred at room temperature for 4 hours. The reaction solution was diluted with water, and then separated by adding ethyl acetate. 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 reverse phase HPLC (acetonitrile / water / 0.3% formic acid: 10-100% acetonitrile) to give the title compound (23.2 mg, 0.054 mmol, 30%) Got.
1H-NMR (300 MHz, DMSO-d6) δ 0.50-0.56 (m, 2H), 0.71-0.77 (m, 2H), 1.33-1.58 (m, 6H), 1.68 (br s, 2H), 1.96 (br s, 2H), 2.08 (s, 3H), 2.83-2.91 (m, 1H), 4.48-4.54 (m, 1H), 7.38-7.47 (m, 2H), 7.58-7.62 (m, 2H), 7.84 ( s, 1H), 8.31 (d, J = 4.2 Hz, 1H), 8.41 (s, 1H), 10.06 (s, 1H), 13.27 (s, 1H).

(Example 2)
Example 2-1
N- (5- (5-Ethoxy-6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) -2- (2- (4-methylpiperazin-1-yl) Ethoxy) phenyl) acetamide

Step 1-1: 1- (2- (4-Bromo-2-nitrophenoxy) ethyl) -4-methylpiperazine
To a solution of 2- (4-methylpiperazin-1-yl) ethanol (3.25 g, 22.5 mmol) in DMF (25 mL) was added 55% sodium hydride (1.18 g, 27.0 mmol) at 0 ° C and stirred for 30 minutes. Later 4-bromo-1-fluoro-2-nitrobenzene (4.95 g, 2.77 mL, 22.5 mmol) was added. After stirring at room temperature for 30 minutes, the mixture was stirred at 100 ° C. for 4 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, and the residue was purified by medium pressure silica gel chromatography (chloroform / methanol; 0-10% methanol gradient) to give the title compound (5.22 g, 15.2 mmol, 67%). .
1H-NMR (DMSO-d6) δ 2.11 (s, 3H), 2.25 (br s, 4H), 2.44 (br s, 4H), 2.66 (t, J = 5.7 Hz, 2H), 4.24 (t, J = 5.7 Hz, 2H), 7.36 (d, J = 9.1 Hz, 1H), 7.80 (dd, J = 9.1, 2.5 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H).

Step 1-2: 5-bromo-2- (2- (4-methylpiperazin-1-yl) ethoxy) aniline The title compound (4.68) was synthesized according to the method of Example 2-123 (Step 3). g, 14.9 mmol, 98%).
1H-NMR (300 MHz, DMSO-d6) δ 2.13 (s, 5H), 2.29 (br s, 6H), 2.46 (br s, 4H), 2.64 (t, J = 5.8 Hz, 4H), 3.98 (t , J = 5.8 Hz, 4H), 5.05 (s, 3H), 6.56 (d, J = 2.5 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.72 (s, 1H), 6.75 (d , J = 2.5 Hz, 3H).

Step 1-3: N- (5-Bromo-2- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) acetamide
To a solution of 5-bromo-2- (2- (4-methylpiperazin-1-yl) ethoxy) aniline (4.68 g, 14.9 mmol) and triethylamine (1.66 g, 2.27 mL, 16.4 mmol) in THF (37 mL) Acetyl chloride (AcCl) (1.29 g, 1.17 mL, 16.4 mmol) was added at 0 ° C., and the mixture was stirred at room temperature overnight. 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 residue was purified by medium pressure silica gel chromatography (chloroform / methanol; 5-20% methanol gradient) to give the title compound (3.86 g, 10.8 mmol, 73%). .
1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 2.13 (s, 3H), 2.29 (brs, 4H), 2.47 (brs, 4H), 2.69 (t, J = 6.0 Hz, 2H ), 4.12 (t, J = 6.0 Hz, 2H), 7.04 (d, J = 8.7 Hz, 1H), 7.19 (dd, J = 8.7, 2.5 Hz, 1H), 8.15 (d, J = 2.5 Hz, 1H) ), 9.05 (s, 1H).

Process 1-4:
N- (5-bromo-2- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) acetamide (800 mg, 2.25 mmol), potassium acetate (KOAc) (441 mg, 4.49 mmol), and Pd To a solution of (OAc) ₂ (25.2 mg, 0.112 mmol) in dioxane (10 mL) was added pinacol diborane (684 mg, 2.69 mmol), and the mixture was stirred at 80 ° C. for 9 hours. Ethyl acetate was added to the reaction solution for dilution, and then the insoluble material was removed by Celite filtration, followed by concentration under reduced pressure to obtain the title compound (900 mg, 2.23 mmol, 99%) as a brown oil.
1H-NMR (300 MHz, DMSO-d6) δ 1.15 (s, 12H), 1.26 (s, 12H), 2.06 (s, 3H), 2.13 (s, 3H), 2.30 (br s, 4H), 2.46 ( br s, 4H), 2.70 (t, J = 5.9 Hz, 2H), 4.14 (t, J = 5.9 Hz, 2H), 7.05 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 8.2 Hz , 1H), 8.15 (s, 1H), 8.93 (s, 1H).

Step 2-1:
The title compound (96 mg, 0.155 mmol, 73%) was obtained by synthesis according to the method of Example 1-1 (Step 7).
1H-NMR (300 MHz, DMSO-d6) δ 1.48 (t, J = 6.8 Hz, 3H), 1.68 (s, 9H), 2.15 (s, 3H), 2.17 (s, 3H), 2.36 (s, 4H ), 2.53 (s, 4H), 2.78 (s, 2H), 3.91 (s, 3H), 4.19-4.26 (m, 4H), 7.26 (d, J = 8.2 Hz, 1H), 7.52 (s, 1H) , 7.66 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 8.20 (s, 1H), 8.25 (s, 1H), 8.64 (s, 1H), 9.16 (s, 1H).

Step 2-2: Title compound The title compound (62 mg, 0.120 mmol, 81%) was obtained by synthesis according to the method of Example 1-1 (Step 8).
1H-NMR (300 MHz, DMSO-d6) δ 1.48 (t, J = 6.9 Hz, 3H), 2.15 (s, 6H), 2.24-2.42 (m, 4H), 2.44-2.64 (m, 4H), 2.75 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 4.12-4.24 (m, 4H), 7.20 (d J = 8.7 Hz ,, 1H), 7.46 s, 2H), 7.63 (m, 1H ), 7.67 (s, 1H), 7.97 (s, 1H), 8.17 (s, 1H), 8.66 (s, 1H), 906 (s, 1H), 12.90 (s, 1H).
MS (ESI) m / z = 518 (M + H) ⁺ .
LC / MS t _R = 0.97 min.

Example 2-2
(E) -3- (5- (2-Cyclopropylvinyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) benzenesulfonamide

Step 1: tert-Butyl 5- (benzyloxy) -6-bromo-3-iodo-1H-indazole-1-carboxylate The title compound was synthesized according to the method of Example 1-1 (Step 5). (24.9 g, 47.1 mmol, 94%) was obtained.
1H-NMR (300 MHz, CDCl ₃ ) δ 1.71 (s, 9H), 5.23 (s, 2H), 6.90 (s, 1H), 7.32-7.44 (m, 3H), 7.52-7.55 (m, 2H), 8.44 (s, 1H).

Step 2: tert-Butyl 5- (benzyloxy) -6-bromo-3- (3-sulfamoylphenyl) -1H-indazole-1-carboxylate According to the method of Example 1-1 (Step 6) The title compound (2.20 g, 3.94 mmol, 47%) was obtained by synthesis.
1H-NMR (300 MHz, DMSO-d6) δ 1.67 (s, 9H), 5.35 (s, 2H), 7.31-7.37 (m, 1H), 7.40-7.45 (m, 2H), 7.52-7.56 (m, 4H), 7.67 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.97-8.00 (m, 1H), 8.18-8.20 (m, 1H), 8.37-8.38 (m, 1H), 8.39 (s, 1H).

Step 3: tert-Butyl 5- (Benzyloxy) -6- (1-methyl-1H-pyrazol-4-yl) -3- (3-sulfamoylphenyl) -1H-indazole-1-carboxylate The title compound (2.31 g, 4.13 mmol, 100%) was obtained by synthesis according to the method of 1-1 (Step 7).
1H-NMR (300 MHz, DMSO-d6) δ 1.69 (s, 9H), 3.86 (s, 3H), 3.92 (s, 2H), 5.36 (s, 2H), 7.34-7.36 (m, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.52-7.55 (m, 4H), 7.61 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.97-7.98 ( m, 1H), 8.17-8.20 (m, 2H), 8.28 (s, 1H), 8.40-8.41 (m, 1H).

Step 4: tert-Butyl 5-hydroxy-6- (1-methyl-1H-pyrazol-4-yl) -3- (3-sulfamoylphenyl) -1H-indazole-1-carboxylate Example 1-2 The title compound (1.05 g, 2.24 mmol, 57%) was obtained by synthesis according to the method of (Step 2).
1H-NMR (300 MHz, DMSO-d6) δ 1.69 (s, 9H), 3.90 (s, 3H), 7.47 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.91 (s, 1H ), 7.97 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.24 (s, 1H), 8.25 (s, 1H), 8.36 (s, 1H).

Step 5: tert-Butyl 6- (1-methyl-1H-pyrazol-4-yl) -3- (3-sulfamoylphenyl) -5- (trifluoromethylsulfonyloxy) -1H-indazole-1-carboxy Rate The title compound (116 mg, 0.193 mmol, 11%) was obtained by synthesis according to the method of Example 1-2 (Step 3).
1H-NMR (300 MHz, DMSO-d6) δ 1.70 (s, 9H), 3.94 (s, 3H), 7.56 (s, 2H), 7.80-7.85 (m, 2H), 7.99 (d, J = 7.9 Hz , 1H), 8.20-8.26 (m, 3H), 8.32 (s, 1H), 8.38-8.40 (m, 1H).

Step 6: (E) -tert-butyl 5- (2-cyclopropylvinyl) -6- (1-methyl-1H-pyrazol-4-yl) -3- (3-sulfamoylphenyl) -1H-indazole -1-Carboxylate The title compound (92.5 mg, 0.178 mmol, 97%) was obtained by synthesis according to the method of Example 1-1 (Step 7).
1H-NMR (300 MHz, DMSO-d6) δ 0.53-0.56 (m, 2H), 0.77-0.85 (m, 2H), 1.06 (s, 1H), 1.67 (s, 10H), 3.93 (s, 3H) , 5.88 (dd, J = 15.5, 9.0 Hz, 1H), 6.71 (d, J = 15.6 Hz, 1H), 7.55 (s, 2H), 7.65 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.96-7.99 (m, 2H), 8.04-8.07 (m, 2H), 8.24-8.27 (m, 1H), 8.41-8.42 (m, 1H).

Step 7: Title compound The title compound (30.5 mg, 0.073 mmol, 42%) was obtained by synthesis according to the method of Example 1-1 (Step 8).
1H-NMR (300 MHz, DMSO-d6) δ 0.53-0.54 (m, 2H), 0.79-0.80 (m, 2H), 1.59-1.62 (m, 1H), 3.93 (s, 3H), 5.79 (dd, J = 15.6, 9.1 Hz, 1H), 6.69 (d, J = 15.6 Hz, 1H), 7.47 (d, J = 7.7 Hz, 3H), 7.62 (s, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.93 (s, 1H), 8.06 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 8.46 (s, 1H), 13.32 ( s, 1H).
MS (ESI) m / z = 420 (M + H) ⁺ .
LC / MS t _R = 1.62 min.

Example 2-3
N- (3- (5- (cyclohexylidenemethyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) phenyl) acetamide

The title compound (68 mg, 0.16 mmol, 32%) was obtained by synthesis according to the method of Example 1-1 (Step 7 and Step 8).
1H-NMR (300 MHz, DMSO-d6) δ 1.44 (s, 2H), 1.59-1.62 (m, 4H), 2.09 (s, 3H), 2.25-2.27 (m, 4H), 3.90 (s, 3H) , 6.26 (s, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.60 (t, J = 7.8 Hz, 2H), 7.69 (s, 1H), 7.76 (s, 1H), 7.93 (s, 1H), 8.28 (s, 1H), 10.06 (s, 1H), 13.15 (s, 1H).
MS (ESI) m / z = 426 (M + H) ⁺ .
LC / MS t _R = 1.90 min.

Example 2-4
N- (3- (5- (cyclohexylmethyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) phenyl) acetamide

The title compound (24.3 mg, 0.057 mmol, 56%) was obtained by synthesis according to the method of Example 1-2 (Step 2).
1H-NMR (300 MHz, DMSO-d6) δ 0.86-0.88 (m, 2H), 1.06-1.09 (m, 2H), 1.25 (s, 2H), 1.53-1.57 (m, 5H), 2.10 (s, 3H), 2.71 (d, J = 6.9 Hz, 2H), 3.92 (s, 3H), 7.38 (s, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 7.7 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.32 (s, 1H), 10.06 (s, 1H), 13.08 (s, 1H).
MS (ESI) m / z = 428 (M + H) ⁺ .
LC / MS t _R = 1.97 min.

  Example 2-5

The title compound was synthesized according to the method of Patent Application 2008-285971 (Example 2-4) using the corresponding boronic acid ester.
1H NMR (400MHz, DMSO-d ₆ ) δ 1.49 (t, J = 7.0 Hz, 3H), 4.25 (q, J = 7.0 Hz, 2H), 7.48 (s, 2H), 7.53 (s, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.93 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.44 (s, 1H), 9.27 (s, 1H), 9.36 (s, 1H), 13.46 (s, 1H).
MS (ESI) m / z = 385 (M + H) ⁺ .
LC / MS t _R = 1.58 min.

  Example 2-6

The title compound was synthesized according to the method of Patent Application 2008-285971 (Example 2-4) using the corresponding alcohol and boronic acid ester.
1H NMR (400MHz, DMSO-d ₆ ) δ 1.24-1.70 (m, 8H), 1.99-2.01 (m, 2H), 4.53-4.58 (m, 1H), 7.50 (d, J = 7.5 Hz, 3H), 7.71 (t, J = 7.9 Hz, 2H), 7.81 (d, J = 7.9 Hz, 1H), 8.09-8.16 (m, 3H), 8.42 (s, 1H), 12.93 (s, 1H), 13.23 (s , 1H).
MS (ESI) m / z = 438 (M + H) ⁺ .
LC / MS t _R = 1.57 min.

  Example 2-7

The title compound was synthesized according to the method of Patent Application 2008-285971 (Example 2-4) using the corresponding boronic acid ester.
1H-NMR (400 MHz, DMSO-d6) δ 1.50 (t, J = 6.7 Hz, 3H), 2.52 (s, 3H), 4.26 (q, J = 6.7 Hz, 2H), 7.46-7.51 (m, 4H ), 7.71-7.73 (m, 1H), 7.82-7.84 (m, 2H), 8.21 (d, J = 6.8 Hz, 1H), 8.42 (s, 1H), 13.40 (s, 1H).

Example 2-8
3- (6- (1-Methyl-1H-pyrazol-4-yl) -5- (phenylamino) -1H-indazol-3-yl) benzenesulfonamide

Step 1: 4-Bromo-2-fluoro-5-nitrobenzaldehyde To a solution of potassium nitrate (38 g, 379 mmol) in concentrated sulfuric acid (288 mL) was added 4-bromo-3-fluorotoluene (70 g, 345 mmol) at 0 ° C. And stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and the precipitated solid was collected by filtration and washed with water and saturated aqueous sodium bicarbonate to give the title compound (80 g, 323 mmol, 94%) as a skin-colored solid.
1H-NMR (300 MHz, DMSO-d6) δ 8.22 (d, J = 9.9 Hz, 1H), 8.48 (d, J = 6.6 Hz, 1H), 10.12 (s, 1H).

Step 2: 6-Bromo-5-nitro-1H-indazole
To a solution of 4-bromo-2-fluoro-5-nitrobenzaldehyde (80.2 g, 323 mmol) in DMF (1280 mL) at room temperature was added hydrazine hydrate (17.8 g, 17.3 mL, 356 mmol) at 150 ° C. For 1.5 hours. The solvent was removed by concentration under reduced pressure, and water and ethyl acetate were added to the resulting residue for separation. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine. Dried over magnesium sulfate. The organic phase was filtered, concentrated under reduced pressure, and solidified with an ethyl acetate / hexane solution to give the title compound (72.4 g, 299 mmol, 93%) as a brown solid.
1H-NMR (300 MHz, DMSO-d6) δ 8.07 (t, J = 0.6 Hz, 1H), 8.35 (d, J = 0.9 Hz, 1H), 8.62 (s, 1H), 13.71 (brs, 1H).

Step 3: 6-Bromo-5-nitro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole
2- (Trimethylsilyl) ethoxymethyl chloride (3.62) was added to a solution of 6-bromo-5-nitro-1H-indazole (5.0 g, 20.7 mmol) and 60% sodium hydride (909 mg, 22.7 mmol) in DMF (40 mL). g, 3.83 mL, 21.7 mmol) was added at 0 ° C., and the mixture was stirred for 1.5 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 and then concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (ethyl acetate / hexane; 5-20% ethyl acetate gradient) to give the title compound (3.62 g, 9.71 mmol, 47%), And 6-bromo-5-nitro-2-((2- (trimethylsilyl) ethoxy) methyl) -2H-indazole (2.20 g, 5.92 mmol, 29%). These were combined and used for the next reaction.
1H-NMR (300 MHz, DMSO-d6) δ -0.11 (s, 9H), 0.88 (t, J = 8.1 Hz, 2H), 3.63 (t, J = 8.1 Hz, 2H), 5.93 (s, 2H) , 8.51 (d, J = 0.9 Hz, 1H), 8.52 (t, J = 0.6 Hz, 1H), 8.74 (d, J = 0.3 Hz, 1H).

Step 4: 6- (1-Methyl-1H-pyrazol-4-yl) -5-nitro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole Compound obtained in Step 3 (6.08 g , 16.3 mmol), 2N aqueous potassium carbonate solution (31.9 mL, 63.8 mmol), and PdCl ₂ (dtbpf) (520 mg, 0.797 mmol) in THF (37 mL) in 1-methyl-4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (3.98 g, 19.1 mmol) was added, and the mixture was stirred under reflux with heating for 3.5 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 and concentrated under reduced pressure to give the title compound (7.74 g, 20.7 mmol,> 100%) (6- (1-methyl-1H-pyrazol-4-yl) -5-nitro-2 -(Mixture with (2- (trimethylsilyl) ethoxy) methyl) -1H-indazole).
MS (ESI) m / z = 374 (M + H) ⁺ .
LC / MS t _R = 2.10 min.

Step 5: 6- (1-Methyl-1H-pyrazol-4-yl) -5-nitro-1H-indazole The compound obtained in Step 4 (7.7 g) and ethylenediamine (4.93 g, 5.54 mL, 82 mmol) TBAF (1M THF solution; 82 mL, 82 mmol) was added to a THF (32 mL) solution at room temperature, and the mixture was stirred with heating under reflux for 8 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 residue was purified by medium pressure silica gel chromatography (ethyl acetate / hexane; 30-100% ethyl acetate gradient) to give the title compound (3.11 g, 12.8 mmol, 79%). Obtained as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 3.88 (s, 3H), 7.57 (d, J = 0.9 Hz, 1H), 7.59 (dd, J = 0.6 Hz, 0.9 Hz, 1H), 7.93 (d, J = 0.6 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H), 8.43 (d, J = 0.6 Hz, 1H), 13.56 (brs, 1H).

Step 6: 3-iodo-6- (1-methyl-1H-pyrazol-4-yl) -5-nitro-1H-indazole
To a solution of 6- (1-methyl-1H-pyrazol-4-yl) -5-nitro-1H-indazole (3.10 g, 12.8 mmol) in DMF (34 mL), iodine (4.69 g, 18.5 mmol) and water Potassium oxide (3.58 g, 63.7 mmol) was added at room temperature and stirred for 2 hours. The reaction solution was added to 1N hydrochloric acid aqueous solution at 0 ° C., 5% Na ₂ S ₂ O ₃ aqueous solution was further added, and the mixture was stirred at 0 ° C. for 20 minutes. The obtained solid was collected by filtration, dissolved with heating in ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (4.62 g, 12.5 mmol, 98%) as a brown solid.
1H-NMR (300 MHz, DMSO-d6) δ 3.88 (s, 3H), 7.59 (d, J = 0.9 Hz, 1H), 7.64 (d, J = 0.6 Hz, 1H), 7.95 (d, J = 0.3 Hz, 1H), 8.05 (d, J = 0.6 Hz, 1H), 13.97 (s, 1H).

Step 7: 3-iodo-6- (1-methyl-1H-pyrazol-4-yl) -5-nitro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole
DMF of 3-iodo-6- (1-methyl-1H-pyrazol-4-yl) -5-nitro-1H-indazole (4.62 g, 12.5 mmol) and 60% sodium hydride (651 mg, 16.3 mmol) (40 mL) To the solution was added 2- (trimethylsilyl) ethoxymethyl chloride (2.61 g, 2.76 mL, 15.7 mmol) at 0 ° C., and the mixture was stirred at room temperature for 40 minutes. 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 residue was purified by medium pressure silica gel chromatography (ethyl acetate / hexane; 10-50% ethyl acetate gradient) to give the title compound (5.51 g, 11.0 mmol, 88%) ^* Was obtained as a yellow solid.
^{* The} title compound was obtained as a mixture of 2-SEM bodies. In subsequent reactions, it was used as a mixture of isomers.
1H-NMR (300 MHz, DMSO-d6) δ -0.11 (s, 9H), 0.82 (t, J = 7.8 Hz, 2H), 3.62 (t, J = 7.8 Hz, 2H), 3.83 (s, 3H) , 5.78 (s, 2H), 7.52 (d, J = 0.6 Hz, 1H), 7.78 (d, J = 0.3 Hz, 1H), 7.85 (s, 1H), 8.09 (d, J = 0.3 Hz, 1H) .

Step 8: 3- (6- (1-Methyl-1H-pyrazol-4-yl) -5-nitro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) benzenesulfone Amide
3-Iodo-6- (1-methyl-1H-pyrazol-4-yl) -5-nitro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole (5.49 g, 11 mmol), 2M To a solution of Na ₂ CO ₃ aqueous solution (22 mL, 44 mmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (898 mg, 1.1 mmol) in THF (52 mL) was added 3-sulfamoylphenylboronic acid (3.74 g). , 13.2 mmol) was added, and the mixture was stirred for 3 hours under heating to 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 20-100% ethyl acetate gradient) to give the title compound (5.16 g, 9.76 mmol, 89%). Obtained as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ -0.11 (s, 9H), 0.84 (t, J = 7.8 Hz, 2H), 3.63 (t, J = 7.8 Hz, 2H), 3.91 (s, 3H) , 5.92 (s, 2H), 7.52 (brs, 2H), 7.65 (d, J = 0.6 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.91 (m, 1H), 7.97 (s, 1H), 8.07 (s, 1H), 8.27 (m, 1H), 8.42 (t, J = 1.5 Hz, 1H), 8.69 (s, 1H).

Step 9: 3- (5-Amino-6- (1-methyl-1H-pyrazol-4-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) benzenesulfone Amide
3- (6- (1-Methyl-1H-pyrazol-4-yl) -5-nitro-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) benzenesulfonamide (5.09 g, 9.63 mmol) and ammonium chloride (558 mg, 10.4 mmol) in ethanol (40 mL) / water (44 mL) were added with iron powder (2.33 g, 41.7 mmol) and stirred for 45 minutes under heating to reflux. did. The reaction solution was filtered through celite, and then the solvent was concentrated. Water and ethyl acetate were added to the resulting residue for separation, 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 residue was purified by medium pressure silica gel chromatography (ethyl acetate / hexane; 30-100% ethyl acetate gradient) to give the title compound (4.27 g, 8.57 mmol, 89%). Obtained as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ -0.11 (s, 9H), 0.82 (t, J = 7.8 Hz, 2H), 3.57 (t, J = 7.8 Hz, 2H), 3.91 (s, 3H) , 4.81 (s, 2H), 5.74 (s, 2H), 7.39 (s, 1H), 7.46 (brs, 2H), 7.63 (s, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.77- 7.83 (m, 2H), 8.07-8.14 (m, 2H), 8.39 (s, 1H).
MS (ESI) m / z = 499 (M + H) ⁺ .
LC / MS t _R = 1.79 min.

Step 10: 3- (6- (1-Methyl-1H-pyrazol-4-yl) -5- (phenylamino) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl ) Benzenesulfonamide
3- (5-Amino-6- (1-methyl-1H-pyrazol-4-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) benzenesulfonamide (300 mg, 0.602 mmol), cesium carbonate (294 mg, 0.902 mmol), Xantphos (104 mg, 0.180 mmol) and Pd (OAc) ₂ (27 mg, 0.120 mmol) in dioxane (6 mL) in bromobenzene (113 mg) , 0.722 mmol), and the mixture was stirred for 6 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 and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (ethyl acetate / hexane; 30-100% ethyl acetate gradient) to give the title compound (153 mg, 0.266 mmol, 44%). Obtained as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ -0.11 (s, 9H), 0.84 (t, J = 7.8 Hz, 2H), 3.63 (t, J = 7.8 Hz, 2H), 3.80 (s, 3H) , 5.86 (s, 2H), 6.57-6.67 (m, 3H), 7.06 (dd, J = 7.5 Hz, 8.4 Hz, 2H), 7.45 (brs, 2H), 7.59 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.80-7.85 (m, 2H), 7.89 (s, 1H), 8.13 (s, 2H), 8.11 (m, 1H), 8.37 (t, J = 1.8 Hz, 1H).

Step 11: Title compound
3- (6- (1-Methyl-1H-pyrazol-4-yl) -5- (phenylamino) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) benzenesulfone TBAF (1M THF solution; 2.06 mL, 2.06 mmol) was added to a THF (1 mL) solution of amide (148 mg, 0.257 mmol) and ethylenediamine (124 mg, 0.139 mL, 2.06 mmol) at room temperature. Stir for 18 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 ammonium chloride solution and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure to give the title compound (85 mg, 0.191 mmol, 74%) as a pale yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 3.81 (s, 3H), 6.56-6.67 (m, 3H), 7.02-7.10 (m, 2H), 7.45 (brs, 2H), 7.54 (s, 1H) , 7.68 (t, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.77-7.83 (m, 2H), 7.90 (s, 1H), 8.01 (s, 1H), 8.13 (m, 1H), 8.39 (m, 1H), 13.38 (brs, 1H).
MS (ESI) m / z = 445 (M + H) ⁺ .
LC / MS t _R = 1.50 min.

Example 2-9
3- (5- (Cyclohexylamino) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) benzenesulfonamide

Step 1: 3- (5- (Cyclohexylamino) -6- (1-methyl-1H-pyrazol-4-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl ) Benzenesulfonamide
3- (5-Amino-6- (1-methyl-1H-pyrazol-4-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) benzenesulfonamide (150 mg, 0.301 mmol), cyclohexanone (37 μL, 0.361 mmol), and acetic acid (34 μL, 0.602 mmol) in dichloromethane (3.0 mL) were added NaBH (OAc) ₃ (128 mg, 0.602 mmol) at room temperature. Stir for hours. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction solution and separated, and then the aqueous phase was extracted with ethyl acetate. 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 to obtain the title compound (175 mg, 0.301 mmol, 100%) as a pale yellow amorphous.
1H-NMR (300 MHz, DMSO-d6) δ -0.10 (s, 9H), 0.82 (t, J = 7.9 Hz, 2H), 1.16-1.48 (m, 5H), 1.55-1.77 (m, 3H), 1.96-2.06 (m, 2H), 3.57 (t, J = 7.9 Hz, 2H), 3.93 (s, 3H), 4.25 (d, J = 7.8 Hz, 1H), 5.74 (s, 2H), 7.07 (s , 1H), 7.47 (s, 2H), 7.59 (s, 1H), 7.70-7.77 (m, 3H), 7.82-7.85 (m, 1H), 8.04 (s, 1H), 8.11-8.17 (m, 1H ), 8.40-8.43 (m, 1H).
MS (ESI) m / z = 581 (M + H) ⁺ .
LC / MS t _R = 2.35 min.

Step 2: Title Compound The title compound (104 mg, 0.231 mmol, 79%) was obtained as a flesh-colored solid by synthesis according to the method of Example 2-8 (Step 11).
1H-NMR (300 MHz, DMSO-d6) δ 1.13-1.29 (m, 3H), 1.31-1.48 (m, 2H), 1.54-1.72 (m, 3H), 1.95-2.06 (m, 2H), 3.37 ( m, 1H), 3.92 (s, 3H), 4.15 (d, J = 7.8 Hz, 1H), 7.07 (s, 1H), 7.32 (S, 1H), 7.46 (brs, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 0.6 Hz, 1H), 7.79 (dt, J = 1.5 Hz, 7.8 Hz, 1H), 8.03 (s, 1H), 7.14 (m, 1H), 8.42 ( t, J = 1.5 Hz, 1H), 13.04 (s, 1H).
MS (ESI) m / z = 451 (M + H) ⁺ .
LC / MS t _R = 1.44 min.

The compounds listed in Table 2-1 were synthesized according to the methods of Examples 2-1, 2-4, and 2-8.

The compounds listed in Table 2-2 were synthesized according to the method of Example 2-9.

Example 2-116
N- (3- (6- (1-Methyl-1H-pyrazol-4-yl) -4- (phenylamino) -1H-indazol-3-yl) phenyl) acetamide

Step 1: 5-bromo-2-methyl-1,3-dinitrobenzene
To a solution of 2-methyl-1,3-dinitrobenzene (30.5 g, 165 mmol) in sulfuric acid (140 mL), 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (25 g, 87 mmol) ) Was added at room temperature (maintaining an internal temperature of 37 ° C. or lower). After stirring for 1 hour, the reaction solution was added to ice water and the precipitated solid was collected by filtration and washed with water to give the title compound (43.2 g, 165 mmol, 99%) as a white solid.
1H NMR (300 MHz, CDCl ₃ ) δ 2.52 (s, 3H), 8.12 (s, 2H).

Process 2: 5-bromo-2-methyl-3-nitroaniline
Activated carbon (6 g) and FeCl ₃ 6H ₂ O (4.4 g, 16.3 mmol) were added to a solution of 5-bromo-2-methyl-1,3-dinitrobenzene (43 g, 153 mmol) in ethanol (140 mL). And heated to reflux for 10 minutes. An aqueous solution obtained by diluting hydrazine hydrate (16.9 g, 16.4 mL, 331 mmol) with water (10 mL) was added dropwise to the reaction solution over 1 hour while heating to reflux, and the mixture was further heated to reflux for 50 minutes. . The reaction solution was filtered through Celite and concentrated under reduced pressure to give the title compound (35.3 g, 153 mmol, 93%) as a white solid.
1H NMR (300 MHz, CDCl ₃ ) δ 2.18 (s, 3H), 3.97 (brs, 2H), 6.69 (d, J = 2.1, 1H), 7.29 (d, J = 2.1, 1H).
LC / MS t _R = 1.67 min.
mp 100-101 ℃.

Step 3: 1-acetyl-6-bromo-4-nitro-1H-indazole
A solution of 5-bromo-2-methyl-3-nitroaniline (10 g, 43.3 mmol) in acetic acid (140 mL) / acetic anhydride (50 mL) was stirred at 100 ° C. for 10 minutes. Sodium nitrite (4.5 g, 69.6 mmol) was added to the reaction solution so that the internal temperature was maintained at 30 ° C. or lower at room temperature, and the mixture was stirred at 70 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the precipitated solid was collected by filtration to give the title compound (10.7 g, 37.7 mmol, 87%) as a pale yellow solid.
1H NMR (300 MHz, CDCl ₃ ) δ 2.84 (s, 3H), 8.40 (d, J = 1.5, 1H), 8.74 (d, J = 0.6, 1H), 9.05 (dd, J = 1.5, 0.6, 1H ).
LC / MS t _R = 2.25 min.
mp 156.5-157.5 ° C.

Process 4: 6-bromo-4-nitro-1H-indazole
To a solution of 1-acetyl-6-bromo-4-nitro-1H-indazole (23.4 g, 82 mmol) in methanol (120 mL) / THF (240 mL) was added 2 mol / L aqueous sodium hydroxide (2 mL). And stirred at room temperature for 15 minutes. The reaction solution was neutralized with 2 mol / L hydrochloric acid aqueous solution and concentrated under reduced pressure, and the obtained residue was washed with water to give the title compound (16.9 g, 70 mmol, 85%) as a colorless solid.
1H NMR (300 MHz, DMSO-d ₆ ) δ 8.20 (d, J = 1.5, 1H), 8.35 (m, 1H), 8.54 (d-like, 1H), 13.9 (brs, 1H).
LC / MS t _R = 1.68 min.
mp 247-249 ° C.

Step 5: 6-Bromo-4-nitro- (1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole The title compound was prepared according to the method of Example 2-8 (Step 7). Synthesized (obtained as a mixture of 1-SEM body: 2-SEM body = 2: 1, 93%).
1-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.47 (s, 9H), 0.89 (m, 2H), 3.55 (m, 2H), 5.78 (s, 2H), 8.13 (m, 1H) , 8.29 (d, J = 1.5, 1H), 8.59 (m, 1H) .; mp 113-114 ° C; LC / MS t _R = 3.06 min.
2-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.13 (s, 9H), 0.97 (m, 2H), 3.66 (m, 2H), 5.77 (s, 2H), 8.28 (m, 2H) , 8.72 (m, 1H) .; mp 113-114 ° C; LC / MS t _R = 3.06 min.

Step 6: 6- (1-Methyl-1H-pyrazol-4-yl) -4-nitro- (1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole
6-Bromo-4-nitro- (1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole (222 mg, 0.597 mmol), 2 mol / L aqueous sodium carbonate (1.19 mL, 0.774 mmol) ) And PdCl ₂ (dtbpf) (12 mg, 0.018 mmol) in THF (2.4 mL) were added 1-methylpyrazole-4-boronic acid pinacol ester (161 mg, 0.774 mmol), and heated under reflux for 4 hours. Stir. 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 20-50% ethyl acetate gradient) to give the title compound (219 mg, 0.585 mmol, 98%). Obtained.
1-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.53 (s, 9H), 0.90 (m, 2H), 3.58 (m, 2H), 4.01 (s, 3H), 5.82 (s, 2H) , 7.81 (d-like, 1H), 7.91 (d, J = 0.9, 1H), 7.96 (dd, J = 0.9, 0.9, 1H), 8.29 (d, J = 0.9, 1H), 8.57 (d, J = 0.9, 1H) .; LC / MS t _R = 2.25 min.
2-SEM: -0.01 (s, 9H), 0.98 (m, 2H), 3.68 (m, 2H), 4.00 (s, 3H), 5.77 (s, 2H), 7.77 (s, 1H), 7.88 ( d, J = 0.6, 1H), 8.14 (m, 1H), 8.34 (d, J = 0.9, 1H), 8.69 (d, J = 0.9, 1H) .; LC / MS t _R = 2.41 min.

Step 7: 6- (1-Methyl-1H-pyrazol-4-yl)-(1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-amine The title compound is Example 2. -8 (57%).
1-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.06 (s, 9H), 0.90 m, 2H), 3.56 (m, 2H), 3.95 (s, 3H), 4.16 (brs, 2H), 5.69 (s, 2H), 6.53 (s, 1H), 7.04 (s, 1H), 7.65 (s, 1H), 7.79 (s, 1H), 7.91 (s, 1H) .; LC / MS t _R = 1.83 min .
2-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.03 (s, 9H), 0.94 (m, 2H), 3.63 (m, 2H), 3.94 (s, 3H), 4.05 (brs, 2H), 5.67 (s, 2H), 6.44 (s, 1H), 7.26 (s, 1H), 7.62 (s, 2H), 7.78 (s, 2H), 8.01 (s, 1H) .; LC / MS t _R = 1.71 min.

Step 8: 6- (1-Methyl-1H-pyrazol-4-yl) -N-phenyl- (1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-amine
6- (1-Methyl-1H-pyrazol-4-yl)-(1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-amine (152 mg, 0.442 mmol), sodium -t-butoxide (NaOt-Bu) (63 mg, 0.656 mmol) and bromobenzene (89 mg, 0.57 mmol) in dimethoxyethane (1 mL) in Pd (OAc) ₂ (2.5 mg), and CyPF-tBu A solution of (1-dicyclohexylphosphino-2-di-tert-butylphosphinoethylferrocene) (6.8 mg) in dimethoxyethane (0.3 mL) was added, and the mixture was stirred at 80 ° C. for 20 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 70-100% ethyl acetate gradient) to give the title compound (178 mg, 0.424 mmol, 96%). Obtained as a colorless oil.
1-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.40 (s, 9H), 0.92 (m, 2H), 3.59 (m, 2H), 3.94 (s, 3H), 5.72 (s, 2H), 6.11 (brs, 1H), 7.02-7.37 (m, 6H), 7.03 (d, J = 1.2, 1H), 7.62 (s, 1H), 7.78 (d, J = 0.9, 1H), 7.86 (d, J = 1.2, 1H) .; LC / MS t _R = 2.51 min.
2-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ 0.0 (s, 9H), 0.94 (m, 2H), 3.63 (m, 2H), 3.96 (s, 3H), 5.67 (s, 3H), 6.01 (brs, 1H), 6.95 (d, J = 0.9, 1H), 7.01 (m, 1H), 7.13-7.16 (m, 2H), 7.31 (m, 2H), 7.41 (m, 2H), 7.60 (s , 1H), 7.77 (s, 1H), 7.91 (d, J = 0.9, 1H) .; LC / MS t _R = 2.38 min.

Step 9: tert-butyl 6- (1-methyl-1H-pyrazol-4-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl (fail) carbamate
6- (1-Methyl-1H-pyrazol-4-yl) -N-phenyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-amine (64 mg, 0.153 mmol) in THF A 1 mol / L lithium hexamethyldisilazane THF solution (0.2 mL, 0.2 mmol) and Boc ₂ O (50 mg, 0.23 mmol) were added to the (1 mL) solution, and the mixture was stirred at room temperature for 2 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 40-100% ethyl acetate gradient) to give the title compound (69 mg, 0.133 mmol, 87%). Obtained as a yellow oil.
1H NMR (300 MHz, CDCl ₃ ) δ -0.07 (s, 9H), 0.89 (m, 2H), 1.45 (s, 9H), 3.57 (m, 2H), 3.94 (s, 3H), 5.72 (s, 2H), 7.14 (d, J = 0.9, 1H), 7.28-7.30 (m, 5H), 7.49 (t-like, 1H), 7.64 (brs, 1H), 7.69 (d, J = 0.9, 1H), 7.78 (d, J =-. 6, 1H) .; LC / MS t _R = 2.84 min.

Step 10: tert-butyl 6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-4-yl (phenyl) carbamate The title compound was prepared according to the method of Example 2-8 (Step 11). Synthesized (58%).
1H NMR (300 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 3.90 (s, 3H), 7.10 (d, J = 1.2, 1H), 7.13-7.29 (m, 5H), 7.32 (t-like, 1H), 7.54 (s, 1H), 7.29 (d, J = 0.6, 1H), 7.77 (d, J = 0.9, 1H).

Step 11: tert-Butyl 3-iodo-6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-4-yl (phenyl) carbamate The title compound was obtained in Example 2-8 (Step 6). Synthesized according to method (94%).
1H NMR (300 MHz, CDCl ₃ ) δ 1.47 (s, 9H), 3.92 (s, 3H), 7.04 (d, J = 1.2, 1H), 7.27-7.35 (m, 4H), 7.45, d-like, 1H), 7.61 (s, 1H), 7.74 (d-like, 1H).

Step 12: tert-butyl 3-iodo-6- (1-methyl-1H-pyrazol-4-yl)-(1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole-4- Ile (phenyl) carbamate The title compound was synthesized according to the method of Example 2-8 (Step 7) (obtained as a mixture of 1-SEM: 2-SEM = 4: 1, 78%).
1H NMR (300 MHz, CDCl ₃ ) δ -0.38 (s, major), -0.16 (s, minor), 0.91 (m, 2H), 1.43 (s, minor), 1.45 (s, major), 3.63 (m , major), 3.71 (t-like, minor), 3.93 (s, 3H), 5.74 (s, major), 5.84 (s, minor), 7.04 (d, J = 1.2, minor), 7.08 (d, J = 1.2, major), 7.13 (m, 2H), 7.25-7.37 (m), 7.59 (d, J = 1.2, major), 7.62 (d-like, minor), 7.65 (d-like, major), 7.76 (minor x 2), 7.78 (d, J = 0.6, major).

Step 13: tert-butyl 3- (3-acetamidophenyl) -6- (1-methyl-1H-pyrazol-4-yl)-(1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H -Indazol-4-yl (phenyl) carbamate
tert-Butyl 3-iodo-6- (1-methyl-1H-pyrazol-4-yl)-(1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-4-yl (phenyl ) 3-acetylphenyl in a solution of carbamate (350 mg, 0.542 mmol), 2 mol / L aqueous potassium carbonate (1.0 mL, 2.0 mmol), and PdCl ₂ (dtbpf) (35 mg, 0.054 mmol) in THF (3.5 mL) Boronic acid (140 mg, 0.782 mmol) was added, and the mixture was stirred with heating under reflux for 23 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 60-100% ethyl acetate gradient) to give the title compound (5.16 g, 9.76 mmol, 86%). Obtained.
1-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.06 (s, 9H), 0.92 (m, 2H), 1.20 (s, 9H), 2.04 (s, 3H), 3.65 (t-like, 2H ), 3.95 (s, 3H), 5.78 (s, 2H), 6.93-7.43 (m, 9H), 7.14 (d, J = 1.2, 1H), 7.61 (d, J = 1.2, 1H), 7.68 (d -like, 1H), 7.81 (d, J = 0.9, 1H), 7.92 (brd, J = 7.8).
2-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.05 (s, 9H), 0.87 (m, 2H), 1.36 (s, 9H), 2.12 (s, 3H), 3.65 (t-like, 2H ), 3.98 (s, 3H), 5.48 (J = 10.5, 2H), 6.7-7.4 (m, 9H), 7.14 (d, J = 1.2, 1H), 7.68 (s, 1H), 7.79 (d, J = 1.2, 1H), 7.83 (d, J = 0.6, 1H), 7.91 (brd, J = 7.5).

Step 14: tert-butyl 3- (3-acetamidophenyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-4-yl (phenyl) carbamate The title compound is Example 2-8 Synthesized according to the method of (Step 11) (65%).
MS (ESI) m / z = 525 (M + H) ⁺ .
LC / MS t _R = 1.68 min.

Step 15: Title compound The title compound (128 mg, 0.303 mmol, 88%) was obtained by synthesis according to the method of Example 1-1 (Step 8).
1H NMR (300 MHz, CDCl ₃ ) δ 2.00 (s, 3H), 3.85 (s, 3H), 6.07 (brs, 1H), 6.91-6.98 (m, 4H), 7.19-7.35 (m, 5H), 7.59 (s, 1H), 7.70 (br, 2H), 8.01 (brs, 1H).
MS (ESI) m / z = 423 (M + H) ⁺ .
LC / MS t _R = 1.61 min.
mp 142 ° C.

Example 2-117
N- (3- (4- (cyclopentylamino) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) phenyl) acetamide

Step 1: tert-butyl 6-bromo-4-nitro-1H-indazole-1-carboxylate
To a solution of 6-bromo-4-nitro-1H-indazole (242 mg, 1.00 mmol) and Boc ₂ O (324 mg, 1.49 mmol) in DMF (3.0 mL) was added triethylamine (0.208 mL, 1.50 mmol) at room temperature. Stir for 1 hour. The reaction solution was diluted with water and separated by adding ethyl acetate. 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 obtained solid was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 10% ethyl acetate) to give the title compound (217 mg, 0.634 mmol, 63%) as a colorless solid.
1H NMR (300 MHz, DMSO-d ₆ ) δ 1.75 (s, 9H), 8.37 (d, J = 1.5, 1H), 8.76 (d, J = 0.9, 1H), 8.85 (m, 1H).
LC / MS t _R = 2.65 min.
mp 125-126 ° C.

Step 2: 6- (1-Methyl-1H-pyrazol-4-yl) -4-nitro-1H-indazole
tert-Butyl 6-bromo-4-nitro-1H-indazole-1-carboxylate (2.0 g, 5.85 mmol), 2 mol / L aqueous potassium carbonate solution (11 mL, 22 mmol), and PdCl ₂ (dppf) · CH _{2 Cl 2 (0.405 g, 0.496} mmol) in dioxane (50 mL) was added 1-methyl-4-boronic acid pinacol ester (1.9 g, 9.13 mmol) of the mixture was stirred for 8.5 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 concentrated under reduced pressure, and the obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 70% ethyl acetate) to give the title compound (855 mg, 3.52 mmol, 60%).
1H NMR (300 MHz, DMSO-d ₆ ) δ 3.90 (s, 3H), 8.12 (br, 1H), 8.17 (br, 1H), 8.32 (d, J = 0.9, 1H), 8.46 (s, 1H) , 8.47 (s, 1H), 13.83 (br, 1H)
LC / MS t _R = 1.25 min.
mp 272 ° C.

Step 3: 3-Iodo-6- (1-methyl-1H-pyrazol-4-yl) -4-nitro-1H-indazole The title compound was synthesized according to the method of Example 2-8 (Step 6) ( 971 mg, 2.63 mmol, 76%; brown solid).
1H NMR (300 MHz, DMSO-d ₆ ) δ 3.89 (s, 3H), 8.04 (d-like, J = 1.2, 1H), 8.07 (d-like, J = 1.2, 1H), 8.11 (d-like , 1H), 8.31 (s, 1H), 8.43 (d-like, 1H)
LC / MS t _R = 1.54 min.

Step 4: 3-iodo-6- (1-methyl-1H-pyrazol-4-yl) -4-nitro- (1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole Title compound Was synthesized according to the method of Example 2-8 (step 7) (obtained as a mixture of 1-SEM body: 2-SEM body = 7: 3, 50%; yellow oil).
1-SEM: 1H NMR (300 MHz, DMSO-d ₆ ) δ -0.07 (s, 9H), 0.85 (t, J = 7.8, 2H), 3.62 (t, J = 7.8, 2H), 3.94 (s , 3H), 5.89 (s, 2H), ca. 8.18 (m, 2H), 8.44 (d-like, 1H), 8.48 (s, 1H) .; LC / MS t _R = 2.73 min.
2-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ
LC / MS t _R = 2.62 min.

Step 5: N- (3- (6- (1-methyl-1H-pyrazol-4-yl) -4-nitro- (1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole -3-yl) phenyl) acetamide The title compound was synthesized according to the method of Example 2-116 (Step 13) (obtained as a mixture of 1-SEM: 2-SEM = 7: 3, 95%; Yellow solid).
1-SEM: 1H NMR (300 MHz, DMSO-d ₆ ) δ -0.08 (s, 9H), 0.88 (t, J = 8.0, 2H), 2.10 (s, 3H), 3.68 (t, J = 8.0 , 2H), 3.95 (s, 3H), 5.96 (s, 2H), 7.03 (d, J = 7.8, 1H), 7.39 (t, J = 7.8, 1H), 7.64 (d, J = 7.8, 1H) , 7.81 (m, 1H), 8.20 (s, 1H), 8.22 (d, J = 1.2, 1H), 8.49 (d, J = 1.2, 1H), 8.51 (s, 1H), 10.07 (brs, 1H) .; LC / MS t _R = 2.24 min.
2-SEM: 1H NMR (300 MHz, DMSO-d ₆ ) δ -0.05 (s, 9H), 1.21 (t-like, 2H), 2.09 (s, 3H), 3.60 (t-like, 2H), 3.94 (s, 3H), 5.60 (s, 2H), 7.14 (d, J = 7.5, 1H), 7.47 (t, J = 7.5, 1H), 7.71 (m, 1H), 7.72 (d, J = 7.5 , 1H), 8.17 (s, 1H), 8.25 (d, J = 1.2, 1H), 8.39 (d, J = 1.2, 1H), 8.46 (s, 1H), 10.12 (brs, 1H) .; LC / MS t _R = 2.24 min.

Step 6: N- (3- (4-Amino-6- (1-methyl-1H-pyrazol-4-yl)-(1 and 2)-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole -3-yl) phenyl) acetamide The title compound was synthesized according to the method of Example 2-8 (Step 9) (1-SEM form: obtained as a mixture of 2-SEM form, 93%; colorless oil).
1-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.04 (s, 9H), 0.93 (dd, J = 8.4, 8.1, 2H), 2.20 (s, 3H), 3.64 (dd, J = 8.4 , 8.1, 2H), 3.96 (s, 3H), 4.31 (brs, 1H), 5.71 (s, 2H), 6.50 (s, 1H), 7.02 (s, 1H), 7.35 (brs, 1H), 7.46 ( m, 2H), 7.62 (m, 1H), 7.66 (s, 1H), 7.74 (br, 1H), 7.81 (s, 1H) .; LC / MS t _R = 1.96 min.
2-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.01 (s, 9H), 0.91 (dd, J = 8.2, 8.2, 2H), 2.22 (s, 3H), 3.75 (dd, J = 8.2 , 8.2, 2H), 3.96 (s, 3H), 5.50 (s, 2H), 6.35 (d, J-0.9, 1H), 7.24 (d, J = 0.9, 1H), 7.36-7.52 (m, 4H) , 7.60 (brs, 1H), 7.63 (s, 1H), 7.77-7.81 (m, 1H), 7.79 (s, 1H) .; LC / MS t _R = 1.85 min.

Step 7: N- (3- (4- (cyclopentylamino) -6- (1-methyl-1H-pyrazol-4-yl)-(1 and 2)-((2- (trimethylsilyl) ethoxy) methyl)- 1H-Indazol-3-yl) phenyl) acetamide The title compound was synthesized according to the method of Example 2-9 (Step 1) (1-SEM form: obtained as a mixture of 2-SEM form, 68%).
1-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.06 (s, 9H), 0.91 (m, 2H), 1.38 (m, 2H), 1.57 (m, 4H), 1.95 (m, 2H) , 2.15 (s, 3H), 3.62 (m, 2H), 3.88 (m, 1H), 3.95 (s, 3H), 4.40 (brd, 1H), 5.67 (s, 2H), 6.32 (s, 1H), 6.92 (s, 1H), 7.35 (d, J = 7.5, 1H), 7.42 (t, J = 7.5, 1H), 7.65 (s, 1H), 7.67 (s, 1H), 7.73 (s, 1H), 7.79 (d, J = 7.5, 1H), 7.82 (s, 1H) .; LC / MS t _R = 2.51 min.
2-SEM: 1H NMR (300 MHz, CDCl ₃ ) δ -0.03 (s, 9H), 0.88 (m, 2H), 1.28 (brm, 2H), 1.51 (m, 4H), 1.86 (brm, 2H) , 2.21 (s, 3H), 3.71 (m, 2H), 3.81 (m, 1H), 3.88 (brs, 1H), 3.95 (s, 3H), 5.47 (s, 3H), 6.11 (d, J = 0.9 , 1H), 7.12 (d, J = 0.9, 1H), 7.28 (d, J = 7.8, 1H), 7.48 (t, J = 7.8, 1H), 7.57 (s, 1H), 7.61 (s, 1H) , 7.63 (s, 1H), 7.80 (d, J =-. 4, 1H), 7.86 (d, J = 7.8, 1H) .; LC / MS t _R = 2.39 min.

Step 8: Title Compound The title compound was synthesized according to the method of Example 2-8 (Step 11) (40 mg, 0.097 mmol, 54%).
1H NMR (300 MHz, CDCl ₃ ) δ 1.36 (m, 2H), 1.56 (m, 4H), 1.92 (m, 2H), 2.03 (s, 3H), 3.85 (m, 1H), 3.91 (s, 3H ), 4.37 (brs, 1H), 6.25 (s, 1H), 6.54 (s, 1H), 7.33-7.40 (m, 2H), 7.51 (s, 1H), 7.61 (s, 1H), 7.72 (s, 1H), 7.86 (d, J = 7.5, 1H), 8.10 (s, 1H)
MS (ESI) m / z = 415 (M + H) ⁺ .
LC / MS t _R = 1.62 min.
mp 147 ° C.

The compounds described in Table 2-3 were synthesized according to the method of Example 2-117.

Example 2-123
3- (4- (Cyclohexyloxy) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) benzenesulfonamide

Step 1: 5-bromo-2-methyl-3-nitrophenol
5-Bromo-2-methyl-3-nitroaniline (84 g, 364 mmol) in concentrated sulfuric acid (150 mL) / water (450 mL) solution in sodium nitrite (30 g, 437 mmol) in water (50 mL) The solution was added at 0 ° C. and stirred at room temperature for 1 hour. The reaction solution was added dropwise to a 60% aqueous sulfuric acid solution (750 mL) stirred at a bath temperature of 140 ° C. After dropping, the mixture was stirred until the internal temperature reached 130 ° C., and then returned to room temperature. After the reaction solution was poured into ice water, 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 then dried over magnesium sulfate. The organic phase was concentrated under reduced pressure, and the obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 15% ethyl acetate) to give the title compound (28 g, 34%) as a pale yellow solid. .
1H NMR (300 MHz, CDCl ₃ ) δ 2.33 (s, 3H), 5.84 (brs, 1H), 7.16 (d, J = 1.8, 1H), 7.56 (d, J = 1.8, 1H).
LC / MS t _R = 1.92 min.
mp 143-145 ° C.

Step 2: 5-bromo-1- (cyclohexyloxy) -2-methyl-3-nitrobenzene
DEAD was added to a solution of 5-bromo-2-methyl-3-nitrophenol (20 g, 87 mmol), cyclohexanol (25.8 g, 258 mmol), and triphenylphosphine (67.6 g, 258 mmol) in dichloromethane (500 mL). (45 g, 258 mmol) was added at 0 ° C., and the mixture was stirred at room temperature overnight. 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 concentrated under reduced pressure, and the obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 10% ethyl acetate) to give the title compound (22 g, 75%) as a colorless oil.
MS (ESI) m / z = 314 (M + H) ⁺ .

Step 3: 5-bromo-3- (cyclohexyloxy) -2-methylaniline
To a solution of 5-bromo-1- (cyclohexyloxy) -2-methyl-3-nitrobenzene (1.0 g, 3.17 mmol) and ammonium chloride (847 mg, 15.8 mmol) in ethanol (15 mL) / water (6.0 mL) Iron powder (710 mg, 12.7 mmol) was added, and the mixture was stirred with heating under reflux for 1 hour. The reaction solution was filtered through celite, and then the solvent was concentrated. Water and ethyl acetate were added to the resulting residue for separation, 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 concentrated under reduced pressure, and the obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 10% ethyl acetate) to give the title compound (3.4 g, 65%).
MS (ESI) m / z = 284 (M + H) ⁺ .

Step 4: 6-bromo-4- (cyclohexyloxy) -1H-indazole
To a solution of 5-bromo-3- (cyclohexyloxy) -2-methylaniline (17 g, 60 mmol) in acetic acid (260 mL) was added sodium nitrite (4.97 g, 72 mmol) at 0 ° C. For 2 hours. The reaction solution was diluted with ethyl acetate and water. 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 concentrated under reduced pressure to obtain the title compound (6.9 g, 38%).
MS (ESI) m / z = 295 (M + H) ⁺ .

Step 5: 6-Bromo-4- (cyclohexyloxy) -3-iodo-1H-indazole The title compound was synthesized according to the method of Example 2-8 (Step 6) (5.2 g, 53%).
MS (ESI) m / z = 421 (M + H) ⁺ .

Step 6: 6-Bromo-4- (cyclohexyloxy) -3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole The title compound was obtained as described in Example 2-8 (Step 7). (6.2 g, 93%).
MS (ESI) m / z = 551 (M + H) ⁺ .

Step 7: 3- (6-Bromo-4- (cyclohexyloxy) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) -N-tert-butylbenzenesulfonamide Title compound Was synthesized according to the method of Example 1-1 (Step 6) (2.2 g, 57%).
MS (ESI) m / z = 636 (M + H) ⁺ .

Step 8: N-tert-butyl-3- (4- (cyclohexyloxy) -6- (1-methyl-1H-pyrazol-4-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H -Indazol-3-yl) benzenesulfonamide The title compound was synthesized according to the method of Example 1-1 (Step 6) (1.4 g, 63%).
MS (ESI) m / z = 638 (M + H) ⁺ .

Step 9: N-tert-Butyl-3- (4- (cyclohexyloxy) -6- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl) benzenesulfonamide Synthesized according to the method of Example 2-8 (Step 11) (0.8 g, 72%).
MS (ESI) m / z = 508 (M + H) ⁺ .

Step 10: Title Compound The title compound was synthesized according to the method of Example 1-1 (Step 8) (200 mg, 28%).
1H NMR (400 MHz, DMSO-d ₆ ) δ 1.23-1.25 (1H, m), 1.36-1.39 (2H, m), 1.47-1.53 (3H, m), 1.61-1.64 (2H, m), 1.95- 1.98 (2H, m), 3.89 (3H, s), 4.66 (1H, s), 6.83 (1H, s), 7.21 (1H, s), 7.37 (2H, s), 7.60-7.68 (1H, m) , 7.81-7.83 (1H, m), 7.97 (1H, s), 8.11-8.13 (1H, d, J = 8Hz), 8.27 (1H, s), 8.33-8.34 (1H, m), 13.23 (1H, s).
MS (ESI) m / z = 452 (M + H) ⁺ .

The compounds described in Table 2-4 were synthesized according to the method of Example 2-123.

(Example 3)
Example 3-1
3- (5-Ethoxy-6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl) benzenesulfonamide

Step 1: 6-Methyl-5-nitropyridin-2-amine 2-Amino-6-picoline (49.7 g, 459 mmol) was added to concentrated sulfuric acid (185 mL) at 0 ° C., followed by nitric acid (22.5 mL, 503 mmol) was added dropwise at 0 ° C. over 30 minutes, followed by stirring at 0 ° C. for 3 hours. The reaction solution was poured into ice water and made basic with 28% aqueous ammonia (500 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with water and recrystallized from toluene to give the title compound (24.5 g, 160 mmol, 35%) as an ocherous solid.
1H-NMR (300MHz, DMSO- d 6) δ 2.60 (s, 3H), 6.37 (d, J = 9.1 Hz, 1H), 7.33 (s, 2H), 8.08 (d, J = 9.1 Hz, 1H).

Step 2: 3-bromo-6-methyl-5-nitropyridin-2-amine
NBS (32.6 g, 183 mmol) was added to a DMF (234 mL) solution of 6-methyl-5-nitropyridin-2-amine (23.4 g, 153 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and the precipitated solid was collected by filtration. The obtained solid was washed with water to give the title compound (30.4 g, 131 mmol, 86%) as an ocherous solid.
1H-NMR (300MHz, DMSO- d 6) δ 2.59 (s, 3H), 8.38 (s, 1H).

Step 3: 3-bromo-2-chloro-6-methyl-5-nitropyridine
To a solution of 3-bromo-6-methyl-5-nitropyridin-2-amine (30.1 g, 130 mmol) in 37% hydrochloric acid (370 mL) was added sodium nitrite (13.4 g, 195 mmol) at 0 ° C. Stir at room temperature overnight. After the reaction solution was poured into ice water, ethyl acetate was added and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (18.4 g, 73.1 mmol, 56%) as an orange solid.
1H-NMR (300 MHz, CDCl ₃ ) δ 2.82 (s, 3H), 8.54 (s, 1H).

Step 4: 3-bromo-2-ethoxy-6-methyl-5-nitropyridine
To a solution of 3-bromo-2-chloro-6-methyl-5-nitropyridine (6.75 g, 26.8 mmol) in ethanol (68 mL) was added 2M sodium ethoxide / ethanol solution (11.6 mL, 29.5 mmol) at 0 ° C. And stirred at room temperature for 1 hour. The reaction solution was separated by adding 5% aqueous citric acid solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over magnesium sulfate. The organic phase was filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (2.48 g, 9.50 mmol, 35%).
1H-NMR (300 MHz, CDCl ₃ ) δ 1.46 (t, J = 7.1 Hz, 3H), 2.78 (s, 3H), 4.54 (q, J = 7.1 Hz, 2H), 7.25 (s, 1H), 8.52 (s, 1H).

Step 5: 5-bromo-6-ethoxy 2-methylpyridin-3-amine
Tin chloride dihydrate (5.19 g, 23.0 mmol) was added to a solution of 3-bromo-2-chloro-6-methyl-5-nitropyridine (2.00 g, 7.66 mmol) in acetonitrile (30 mL) at room temperature. Stir overnight. Saturated aqueous sodium hydrogen carbonate 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, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (1.04 g, 4.50 mmol, 59%) as a yellow solid.
1H-NMR (300 MHz, CDCl ₃ ) δ 1.39 (t, J = 7.0 Hz, 3H), 2.28 (s, 3H), 3.27 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 7.18 (s, 1H), 7.26 (s, 1H).

Step 6: 6-Bromo-5-ethoxy-1H-pyrazolo [4,3-b] pyridine
Sodium nitrite (434 mg, 6.28 mmol) is added to a solution of 5-bromo-6-ethoxy-2-methylpyridin-3-amine (1.32 g, 5.71 mmol) in acetic acid (70 mL), and the mixture is stirred at 70 ° C. for 2.5 hours. did. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added and separated, and the aqueous phase was extracted with ethyl acetate. 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 residue was purified by medium pressure silica gel chromatography (ethyl acetate: chloroform = 1: 3) to give the title compound (450 mg, 1.86 mmol, 33%) as an orange solid. It was.
1H-NMR (300 MHz, CDCl ₃ ) δ 1.48 (t, J = 7.1 Hz, 3H), 4.49 (q, J = 7.1 Hz, 2H), 8.05-8.06 (m, 2H).

Step 7: 6-Bromo-5-ethoxy-3-iodo-1H-pyrazolo [4,3-b] pyridine By synthesis according to the method of Example 3-48 (Step 5) of Japanese Patent Application No. 2008-285971. To give the title compound (650 mg, 1.77 mmol, 95%).
1H-NMR (300 MHz, DMSO-d6) δ 1.37 (q, J = 6.5 Hz, 3H), 4.43 (q, J = 7.1 Hz, 2H), 8.38 (s, 1H).

Step 8: 6-Bromo-5-ethoxy-3-iodo-1-trityl-1H-pyrazolo [4,3-b] pyridine According to the method of Example 3-48 (Step 6) of Japanese Patent Application No. 2008-285971 The title compound (710 mg, 1.16 mmol, 67%) was obtained by synthesis.
1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J = 7.0 Hz, 3H), 4.42 (q, J = 7.1 Hz, 2H), 6.55 (s, 1H), 7.12-7.36 (m, 15H ).

Step 9: 3- (6-Bromo-5-ethoxy-1-trityl-1H-pyrazolo [4,3-b] pyridin-3-yl) benzenesulfonamide According to the method of Example 1-1 (Step 6) To give the title compound (508 mg, 0.794 mmol, 81%).
1H-NMR (300 MHz, CDCl ₃ ) δ 1.52 (t, J = 7.1 Hz, 3H), 4.59 (q, J = 7.1 Hz, 2H), 6.64 (s, 1H), 7.18-7.36 (m, 21H) , 7.55 (t, J = 8.0 Hz, 1H), 7.83-7.86 (m, 1H), 8.52-8.53 (m, 1H), 9.16-9.17 (m, 1H).

Step 10: 3- (5-Ethoxy-6- (1-methyl-1H-pyrazol-4-yl) -1-trityl-1H-pyrazolo [4,3-b] pyridin-3-yl) benzenesulfonamide The title compound (477 mg, 0.744 mmol, 95%) was obtained by synthesis according to the method of Example 1-1 (Step 7).
1H-NMR (300 MHz, DMSO-d6) δ 1.56 (t, J = 7.1 Hz, 3H), 3.91 (s, 3H), 4.65 (q, J = 7.1 Hz, 2H), 6.42 (s, 1H), 7.21-7.35 (m, 20H), 7.54 (t, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.80-7.84 (m, 1H), 8.55-8.59 (m, 1H), 9.23 (t, J = 1.6 Hz, 1H).

Step 11: Title compound The title compound (50 mg, 0.125 mmol, 62%) was obtained by synthesis according to the method of Example 1-1 (Step 8).
1H-NMR (300 MHz, DMSO-d6) δ 1.51 (t, J = 7.1 Hz, 3H), 3.91 (s, 3H), 4.60 (q, J = 7.1 Hz, 2H), 7.41 (br s, 2H) , 7.69 (t, J = 7.7 Hz, 1H), 7.78-7.80 (m, 1H), 8.09 (s, 1H), 8.18 (s, 1H), 8.26 (s, 1H), 8.65 (d, J = 7.7 Hz, 1H), 8.98 (s, 1H), 13.43 (br s, 1H).

Example 3-2
(E) -N- (3- (5- (2-Cyclopropylvinyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridine-3- Yl) phenyl) acetamide

Step 1: 3-bromo-2-methoxy-6-methyl-5-nitropyridine
To a solution of 3-bromo-2-chloro-6-methyl-5-nitropyridine (18.3 g, 72.9 mmol) in methanol (183 mL) was added 1M sodium methoxide / methanol solution (80.0 mL, 80.0 mmol) at 0 ° C. And stirred at room temperature for 1 hour. The reaction solution was separated by adding 5% aqueous citric acid solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain the title compound (17.8 g, 72.1 mmol, 99%).
1H-NMR (300 MHz, CDCl ₃ ) δ 2.79 (s, 3H), 4.09 (s, 3H), 8.52 (s, 1H).

Step 2: 5-bromo-6-methoxy-2-methylpyridin-3-amine
3-Bromo-2-methoxy-6-methyl-5-nitropyridine (17.8 g, 72.1 mmol) and ammonium chloride (17.4 g, 404 mmol) in methanol (180 mL) / THF (180 mL) / water (72 mL) Iron powder (22.6 g, 404 mmol) was added to the solution, and the mixture was stirred for 2 hours with heating under reflux. The reaction solution was filtered through celite, and then the solvent was concentrated. Water and ethyl acetate were added to the resulting residue for separation, 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 to give the title compound (13.2 g, 60.6 mmol, 84%) as a yellow solid.
1H-NMR (300 MHz, CDCl ₃ ) δ 2.29 (s, 3H), 3.28 (s, 2H), 3.92 (s, 3H), 7.18 (s, 1H).

Step 3: 6-Bromo-5-methoxy-1H-pyrazolo [4,3-b] pyridine
To a solution of 5-bromo-6-methoxy-2-methylpyridin-3-amine (11.6 g, 5.71 mmol) in acetic acid (1156 mL) was added sodium nitrite (4.04 g, 58.6 mmol), and then at 70 ° C. for 3 hours. Stir. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added and separated, and the aqueous phase was extracted with ethyl acetate. 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 residue was purified by medium pressure silica gel chromatography (ethyl acetate: chloroform = 1: 3) to give the title compound (7.01 g, 30.7 mmol, 58%) as an orange solid. It was.
1H-NMR (300 MHz, DMSO-d6) δ 3.94 (s, 3H), 8.10 (s, 1H), 8.35 (s, 1H), 13.28 (s, 1H).

Step 4: 6-Bromo-3-iodo-5-methoxy-1H-pyrazolo [4,3-b] pyridine
To a solution of 6-bromo-5-methoxy-1H-pyrazolo [4,3-b] pyridine (7.30 g, 32.0 mmol) in dichloromethane (365 mL), iodine (12.2 g, 48.0 mmol), and 5% sodium bicarbonate Aqueous solution (81 mL) was added at room temperature and stirred overnight. The reaction solution was separated by adding an aqueous sodium thiosulfate solution and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The organic phase was filtered and concentrated under reduced pressure to give the title compound (9.26 g, 26.2 mmol, 82%) as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 3.99 (s, 3H), 8.37 (s, 1H), 13.67 (s, 1H).

Step 5: 6-Bromo-3-iodo-5-methoxy-1-trityl-1H-pyrazolo [4,3-b] pyridine
A solution of 6-bromo-3-iodo-5-methoxy-1H-pyrazolo [4,3-b] pyridine (202 mg, 0.571 mmol) and triethylamine (116 mg, 0.158 mL, 1.14 mmol) in dichloromethane (4 mL) Trityl chloride (207 mg, 0.742 mmol) was added at room temperature and stirred for 3 hours. After water and chloroform were added to the reaction solution and separated, the aqueous phase was extracted with chloroform. The combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered, concentrated under reduced pressure, and solidified with hexane / ethyl acetate to give the title compound (360 mg, 0.604 mmol) as a yellow solid.
1H-NMR (300 MHz, CDCl ₃ ) δ 6.56 (s, 1H), 7.14-7.33 (m, 15H).

Step 6: N- (3- (6-Bromo-5-methoxy-1-trityl-1H-pyrazolo [4,3-b] pyridin-3-yl) phenyl) acetamide
6-bromo-3-iodo-5-methoxy-1-trityl-1H-pyrazolo [4,3-b] pyridine (3.0 g, 5.0 mmol), 2M Na ₂ CO ₃ aqueous solution (10.1 mL, 20.1 mmol), and 3-acetamidophenylboronic acid (1.80 g, 10.1 mmol) was added to a THF (60 mL) solution of PdCl ₂ (dppf) · CH ₂ Cl ₂ (205 mg, 0.252 mmol), and the mixture was stirred for 2 hours under heating to 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 50-100% ethyl acetate gradient) to give the title compound (2.12 g, 3.51 mmol, 70%). Obtained as a pale yellow solid.
1H-NMR (300 MHz, DMSO-d6) δ 4.08 (s, 3H), 6.53 (s, 1H), 7.17-7.47 (m, 19H), 7.91 (d, J = 7.7 Hz, 1H), 8.82 (s , 1H), 10.00 (s, 1H).

Step 7: N- (3- (5-Methoxy-6- (1-methyl-1H-pyrazol-4-yl) -1-trityl-1H-pyrazolo [4,3-b] pyridin-3-yl) phenyl ) Acetamide The title compound (1.33 g, 2.20 mmol, 62%) was obtained by synthesis according to the method of Example 1-1 (Step 6) using the corresponding boronic ester.
1H-NMR (300 MHz, DMSO-d6) δ 2.06 (s, 3H), 3.82 (s, 3H), 4.11 (s, 3H), 6.38 (s, 1H), 7.19-7.45 (m, 20H), 7.92 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 8.80 (s, 1H), 9.98 (s. 1H).

Step 8: N- (3- (5-hydroxy-6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl) phenyl) acetamide
N- (3- (5-methoxy-6- (1-methyl-1H-pyrazol-4-yl) -1-trityl-1H-pyrazolo [4,3-b] pyridin-3-yl) phenyl) acetamide ( 1.48 g, 2.54 mmol) was added with pyridine hydrochloride (7.37 g, 63.8 mmol) and stirred at 150 ° C. for 20 minutes. Water was added to the reaction solution for dilution, and the precipitated solid was collected by filtration to give the title compound (399 mg, 1.15 mmol, 47%) as an ocher solid.
MS (ESI) m / z = 349 (M + H) ⁺ .
LC / MS t _R = 0.80 min.

Step 9: 3- (3-acetamidophenyl) -6- (1-methyl-1H-pyrazol-4-yl) -1- (trifluoromethylsulfonyl) -1H-pyrazolo [4,3-b] pyridine-5 -Il trifluoromethanesulfonate
N- (3- (5-hydroxy-6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl) phenyl) acetamide (399 mg, 1.15 mmol) and triethylamine (1.16 g, 1.59 mL, 11.5 mmol) in DMF (8 mL) were added N-phenylbis (trifluoromethanesulfonamide) (2.05 g, 5.73 mmol) and stirred at room temperature for 2 hours. The reaction solution was diluted with water, and the precipitated solid was collected by filtration. The obtained solid was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 50-100% ethyl acetate gradient) to give the title compound (507 mg, 0.828 mmol, 72%) as a colorless solid.
MS (ESI) m / z = 613 (M + H) ⁺ .
LC / MS t _R = 2.36 min.

Step 10: (E) -N- (3- (5- (2-cyclopropylvinyl) -6- (1-methyl-1H-pyrazol-4-yl) -1- (trifluoromethylsulfonyl) -1H- Pyrazolo [4,3-b] pyridin-3-yl) phenyl) acetamide The title compound (53.5 mg, 5 mg, 5 mg, by synthesizing according to the method of Example 1-1 (Step 6) using the corresponding boronic ester 0.101 mmol, 41%).
MS (ESI) m / z = 531 (M + H) ⁺ .
LC / MS t _R = 2.49 min.

Step 11: title compound
(E) -N- (3- (5- (2-Cyclopropylvinyl) -6- (1-methyl-1H-pyrazol-4-yl) -1- (trifluoromethylsulfonyl) -1H-pyrazolo [4 , 3-b] pyridin-3-yl) phenyl) acetamide (51.2 mg, 0.097 mmol) in DMSO (0.50 mL) was added 2N aqueous sodium hydroxide solution (0.097 mL, 0.193 mmol) and stirred at room temperature for 15 minutes. . The reaction solution was diluted with water, and the precipitated solid was collected by filtration. The obtained solid was purified by medium pressure silica gel chromatography (chloroform / methanol; 3-10% methanol gradient) to give the title compound (29.5 mg, 0.074 mmol, 77%) as a colorless solid.
1H-NMR (300MHz, DMSO-d ₆ ) δ 0.68-0.73 (m, 2H), 0.82-0.88 (m, 2H), 1.60-1.72 (m, 1H), 2.08 (s, 3H), 3.94 (s, 3H), 6.75 (dd, J = 15.0, 9.5 Hz, 1H), 6.88 (d, J = 15.1 Hz, 1H), 7.34-7.42 (m, 2H), 7.67 (s, 1H), 7.76 (s, 1H ), 8.00 (s, 1H), 8.12-8.15 (m, 1H), 9.17 (s, 1H), 10.00 (s, 1H), 13.22 (s, 1H).
MS (ESI) m / z = 424 (M + H) ⁺ .
LC / MS t _R = 1.64 min.

Example 3-3
(E) -3- (5- (2-Cyclopropylvinyl) -6- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-b] pyridin-3-yl) benzene Sulfonamide

The title compound was synthesized according to the method of Example 1-1.
1H-NMR (300MHz, DMSO-d ₆ ) δ 0.66-0.67 (m, 2H), 0.84-0.90 (m, 2H), 1.63-1.74 (m, 1H), 3.94 (s, 3H), 4.10 (q, J = 5.2 Hz, 1H), 6.61 (dd, J = 14.9, 9.8 Hz, 1H), 6.90 (d, J = 15.1 Hz, 1H), 7.41 (s, 2H), 7.67-7.72 (m, 2H), 7.79-7.81 (m, 2H), 8.02 (s, 1H), 8.62 (d, J = 7.8 Hz, 1H), 9.31 (s, 1H), 13.43 (s, 1H).

Example 3-4
N- (3- (6- (1-Methyl-1H-pyrazol-4-yl) -5- (phenylamino) -1H-pyrazolo [4,3-b] pyridin-3-yl) phenyl) acetamide

Step 1: N- (3- (6- (1-methyl-1H-pyrazol-4-yl) -5- (phenylamino) -1- (trifluoromethylsulfonyl) -1H-pyrazolo [4,3-b ] Pyridin-3-yl) phenyl) acetamide
3- (3-Acetamidophenyl) -6- (1-methyl-1H-pyrazol-4-yl) -1- (trifluoromethylsulfonyl) -1H-pyrazolo [4,3-b] pyridin-5-yl trifluoro Aniline (276 mg, 0.270 mL, 2.96 mmol) was added to a solution of lomethanesulfonate (121 mg, 0.198 mmol) in NMP (2.2 mL), and the mixture was stirred at 200 ° C. for 30 minutes under microwave irradiation. Saturated aqueous sodium hydrogen carbonate 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 2N aqueous hydrochloric acid, water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate; 50-100% ethyl acetate gradient) to give the title compound (100 mg, 0.181 mmol, 91%) as pale yellow Obtained as amorphous.
MS (ESI) m / z = 556 (M + H) ⁺ .
LC / MS t _R = 2.34 min.

Step 2: title compound
N- (3- (6- (1-Methyl-1H-pyrazol-4-yl) -5- (phenylamino) -1- (trifluoromethylsulfonyl) -1H-pyrazolo [4,3-b] pyridine- To a solution of 3-yl) phenyl) acetamide (98 mg, 0.176 mmol) in methanol (2 mL) was added 2N aqueous sodium hydroxide solution (0.180 mL, 0.360 mmol), and the mixture was stirred at room temperature for 40 min. The reaction solution was diluted with water, and the precipitated solid was collected by filtration. The obtained solid was purified by medium pressure silica gel chromatography (chloroform / methanol; 3-10% methanol gradient) to give the title compound (32 mg, 0.076 mmol, 43%) as a pale yellow solid.
MS (ESI) m / z = 424 (M + H) ⁺ .
LC / MS t _R = 1.87 min.

Example 3-5
3- (6- (1-Methyl-1H-pyrazol-4-yl) -5- (phenylamino) -1H-pyrazolo [4,3-b] pyridin-3-yl) benzenesulfonamide

The title compound was synthesized according to the method of Example 3-4.
1H-NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 6.93-6.95 (m, 1H), 7.33-7.36 (m, 2H), 7.65 (t, J = 7.8 Hz, 1H), 7.76 -7.87 (m, 8H), 8.18 (s, 1H), 8.72 (d, J = 7.6 Hz, 1H), 8.78-8.79 (m, 1H), 13.27 (brs, 1H).

Example 3-6
4- (5- (Cyclopentyloxy) -7-((tetrahydro-2H-pyran-4-yl) methylamino) -1H-pyrazolo [4,3-b] pyridin-3-yl) -N-cyclopropylbenzamide

Step 1: 6-chloro-2-methylpyridin-3-amine
To a solution of 6-chloro-2-methyl-3-nitropyridine (10.0 g, 56.8 mmol) and ammonium chloride (12.1 g, 226 mmol) in THF (150 mL) / methanol (100 mL) / water (40.0 mL) Iron powder (15.9 g, 284 mmol) was added and stirred at 60 ° C. for 4 hours. The reaction solution was filtered through celite, and then the solvent was concentrated. Water and ethyl acetate were added to the resulting residue for separation, 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 concentrated under reduced pressure to give the title compound (7.07 g, 49.6 mmol, 87%) as a skin-colored solid.
1H NMR (400 MHz, DMSO-d ₆ ) δ 2.40 (d, J = 11.2 Hz, 3H), 3.60 (s, 2H), 6.90 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H).
MS (ESI) m / z = 143 (M + H) ⁺ .
LC / MS t _R = 0.89 min.

Step 2: 4-bromo-6-chloro-2-methylpyridin-3-amine
Bromine (2.51 mL, 48.7 mmol) was added to a solution of 6-chloro-2-methylpyridin-3-amine (3.86 g, 27.1 mmol) and acetic acid (3.10 mL, 54.1 mmol) in methanol (77 mL) at 0 ° C. The mixture was stirred at the same temperature for 5 hours. Sodium sulfite (2.73 g) was added to the reaction solution, and the solvent was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 50% ethyl acetate) to give the title compound (4.63 g, 20.9 mmol, 77%) as a pale orange solid. Got as.
1H NMR (400 MHz, CDCl ₃ ) δ 2.44 (s, 3H), 4.06 (br s, 2H), 7.29 (s, 1H).
MS (ESI) m / z = 221 (M + H) ⁺ .
LC / MS t _R = 1.58 min.

Step 3: 7-Bromo-5-chloro-1H-pyrazolo [4,3-b] pyridine
4-Bromo-6-chloro-2-methylpyridin-3-amine (3.0 g, 13.6 mmol) and potassium acetate (KOAc) (3.32 g, 33.9 mmol) in toluene (120 mL) / acetic acid (12 mL) Was added with isoamyl nitrite (2.38 g, 2.74 mmol) at room temperature and stirred for 5 hours. The reaction solution was diluted with ethyl acetate and water. 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 50% ethyl acetate) to give the title compound (1.14 g, 4.86 mmol, 36%) as a skin-colored solid. Obtained.
1H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 8.40 (s, 1H), 14.12 (s, 1H).
MS (ESI) m / z = 232 (M + H) ⁺ .
LC / MS t _R = 1.37 min.

Step 4: 7-Bromo-5-chloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridine
4-Methoxybenzyl bromide in a DMF (1.0 mL) solution of 7-bromo-5-chloro-1H-pyrazolo [4,3-b] pyridine (100 mg, 0.43 mmol) and cesium carbonate (280 mg, 0.860 mmol) (93 μL, 0.645 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was diluted with ethyl acetate and water. 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 25% ethyl acetate) to give the title compound (86.4 mg, 0.245 mmol, 57%), and 1- The (4-methoxybenzyl) form (67.8 mg, 0.192 mmol, 45%) was obtained as a white solid.
1H NMR (400 MHz, DMSO-d ₆ ) δ 3.81 (s, 3H), 5.57 (s, 2H), 6.88-6.94 (m, 2H), 7.27-7.32 (m, 2H), 7.47 (s, 1H) , 8.03 (s, 1H).
MS (ESI) m / z = 352 (M + H) ⁺ .

Step 5: tert-butyl 5-chloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4-yl) methyl) carbamate
7-bromo-5-chloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridine (635 mg, 1.80 mmol) and (tetrahydro-2H-pyran-4-yl) methanamine ( 2.07 g, 18.0 mmol) in NMP (12 mL) was stirred at 120 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over magnesium sulfate, and the organic phase was concentrated under reduced pressure. The obtained residue, Boc ₂ O (983 mg, 4.50 mmol), and DMAP (46.1 mg) were added, and the mixture was stirred at 50 ° C. for 8 hr. 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; 0-50% ethyl acetate gradient) to give the title compound (675 mg, 1.39 mmol, 77%) as a colorless oil.
MS (ESI) m / z = 487 (M + H) ⁺ .
LC / MS t _R = 2.50 min.

Step 6: tert-butyl 5- (cyclopentyloxy) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4-yl) methyl Carbamate
After stirring a solution of 1-methylcyclohexanol (747 mg, 6.54 mmol) and 60% sodium hydride (262 mg, 6.54 mmol) in toluene (30 mL) at 40 ° C. for 30 minutes, tert-butyl 5-chloro- 2- (4-Methoxybenzyl) -2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4-yl) methyl) carbamate (70 mg, 0.144 mmol), Pd ₂ ( dba) ₃ (13.2 mg, 0.014 mmol) and X-Phos (14.1 mg, 0.029 mmol) were added and stirred at 100 ° C. 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 obtained residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 0-50% ethyl acetate gradient) to give the title compound (20.7 mg, 0.039 mmol, 27%) as a colorless oil.
MS (ESI) m / z = 537 (M + H) ⁺ .
LC / MS t _R = 2.84 min.

Step 7: tert-butyl 5- (cyclopentyloxy) -3-iodo-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4 -Il) methyl) carbamate
tert-butyl 5- (cyclopentyloxy) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4-yl) methyl) carbamate ( NIS (41.9 mg, 0.186 mmol) was added to a DMF (1.0 mL) solution of 20 mg, 0.037 mmol) at room temperature, and the mixture was stirred at 110 ° C. for 3 hours. 5% Na ₂ S ₂ O ₃ aqueous solution was added to the reaction solution and stirred for 20 minutes. Ethyl acetate was added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. 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 to give the title compound (22.9 mg, 0.035 mmol, 93%) as a pale yellow solid.
1H NMR (400 MHz, CDCl ₃ ) δ 1.20-1.33 (m, 6H), 1.39 (s, 9H), 1.51-1.87 (m, 4H), 1.99-2.10 (m, 3H), 3.21 (t, J = 11.7 Hz, 2H), 3.77 (s, 3H), 3.79-3.93 (m, 4H), 5.51-5.58 (m, 1H), 5.57 (br s, 2H), 6.65 (s, 1H), 6.82 (d, J = 7.1 Hz, 2H), 7.23 (d, J = 7.1 Hz, 2H).
MS (ESI) m / z = 663 (M + H) ⁺ .
LC / MS t _R = 3.18 min.

Step 8: tert-butyl 5- (cyclopentyloxy) -3- (4- (cyclopropylcarbamoyl) phenyl) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridin-7-yl ((Tetrahydro-2H-pyran-4-yl) methyl) carbamate
tert-Butyl 5- (cyclopentyloxy) -3-iodo-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4-yl) Methyl) carbamate (20 mg, 0.030 mmol), 4- (cyclopropylcarbamoyl) phenylboronic acid pinacol ester (13.0 mg, 0.045 mmol), and potassium bicarbonate (12.5 mg, 0.091 mmol) in DMF / water (1.0 mL / 0.1 mL) solution was added with PdCl ₂ (dtbpf) (2.95 mg, 4.53 μmol) and stirred at 50 ° C. 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; 0-25% ethyl acetate gradient) to give the title compound (15.5 mg, 0.22 mmol, 74 %) Was obtained as a white amorphous.
1H NMR (400 MHz, CDCl ₃ ) δ 0.62-0.67 (m, 2H), 0.87-0.94 (m, 2H), 1.23-1.34 (m, 4H), 1.44 (s, 9H), 1.55-1.65 (m, 4H), 1.70-2.00 (m, 6H), 3.25 (t, J = 10.9 Hz, 2H), 3.76 (s, 3H), 3.86-3.93 (m, 2H), 3.99 (d, J = 7.6 Hz, 2H ), 5.35-5.42 (m, 1H), 5.57 (s, 2H), 6.26 (s, 1H), 6.69 (s, 1H), 6.78 (d, J = 9.1 Hz, 2H), 7.02 (d, J = 9.1 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H).
MS (ESI) m / z = 696.4 (M + H) ⁺ .
LC / MS t _R = 2.87 min.

Step 9: title compound
tert-Butyl 5- (cyclopentyloxy) -3- (4- (cyclopropylcarbamoyl) phenyl) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro A solution of -2H-pyran-4-yl) methyl) carbamate (15 mg, 0.022 mmol) in TFA (1.0 mL) was stirred at 65 ° C. for 1.5 hours. The reaction solution was neutralized by adding 2 mol / L potassium carbonate aqueous solution, and then separated by adding ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The obtained residue was solidified with ethyl acetate / hexane to give the title compound (4.1 mg, 8.62 μmol, 40%) as a white solid.
MS (ESI) m / z = 476.3 (M + H) ⁺ .
LC / MS t _R = 1.72 min.

Example 3-7
4- (5- (Cyclopentyloxy) -2-methyl-7-((tetrahydro-2H-pyran-4-yl) methylamino) -2H-pyrazolo [4,3-b] pyridin-3-yl) -N -Cyclopropylbenzamide

Step 1: 7-Bromo-5-chloro-2-methyl-2H-pyrazolo [4,3-b] pyridine
7-Bromo-5-chloro-1H-pyrazolo [4,3-b] pyridine (200 mg, 0.86 mmol) and cesium carbonate (561 mg, 1.72 mmol) in a solution of methyl iodide (183 mL) in DMF (3.0 mL) mg, 1.29 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was diluted with ethyl acetate and water. 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 concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel chromatography (hexane / ethyl acetate; 0-25% ethyl acetate) to give the title compound (66.6 mg, 0.270 mmol, 31%), and 1-methyl bodies (109.8 mg, 0.445 mmol, 52%) were obtained as white solids, respectively.
1H NMR (400 MHz, CDCl ₃ ) δ 4.29 (s, 3H), 7.49 (s, 1H), 8.16 (s, 1H).
MS (ESI) m / z = 246 (M + H) ⁺ .
LC / MS t _R = 1.53 min.
(1-methyl form: 1H-NMR (400 MHz, CDCl ₃ ) δ 4.39 (s, 3H), 7.52 (s, 1H), 8.12 (s, 1H) .; LC / MS t _R = 1.79 min.)

Step 2: tert-butyl 5-chloro-2-methyl-2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4-yl) methyl) carbamate Synthesized according to the method of 3-6 (Step 5) (73.5 mg, 0.193 mmol, 73%).
1H NMR (400 MHz, CDCl ₃ ) δ 1.22-1.35 (m, 2H), 1.46 (s, 9H), 1.54-1.60 (m, 2H), 1.69-1.81 (m, 1H), 3.27 (t, J = 11.2 Hz, 2H), 3.91 (dd, J = 11.2, 3.5 Hz, 2H), 4.05 (d, J = 7.1 Hz, 2H), 4.23 (s, 3H), 7.16 (s, 1H), 8.08 (s, 1H).
MS (ESI) m / z = 381 (M + H) ⁺ .
LC / MS t _R = 2.02 min.

Step 3: tert-Butyl 5- (cyclopentyloxy) -2-methyl-2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4-yl) methyl) carbamate The title compound is This was synthesized according to the method of Example 3-6 (Step 6) (13 mg, 0.030 mmol, 16%; colorless oil).
MS (ESI) m / z = 431 (M + H) ⁺ .
LC / MS t _R = 2.47 min.

Step 4: tert-butyl 5- (cyclopentyloxy) -3-iodo-2-methyl-2H-pyrazolo [4,3-b] pyridin-7-yl ((tetrahydro-2H-pyran-4-yl) methyl) Carbamate The title compound was synthesized according to the method of Example 3-6 (Step 7) (16.8 mg, 0.030 mmol, 100%; pale yellow oil).
MS (ESI) m / z = 557 (M + H) ⁺ .
LC / MS t _R = 2.97 min.

Step 5: tert-butyl 5- (cyclopentyloxy) -3- (4- (cyclopropylcarbamoyl) phenyl) -2-methyl-2H-pyrazolo [4,3-b] pyridin-7-yl (( Tetrahydro-2H-pyran-4-yl) methyl) carbamate The title compound was synthesized according to the method of Example 3-6 (Step 8) (16.8 mg, 0.030 mmol, 100%; pale yellow oil).
MS (ESI) m / z = 590.3 (M + H) ⁺ .
LC / MS t _R = 2.83 min.

Step 6: Title Compound The title compound was synthesized according to the method of Example 3-6 (Step 9) (5.8 mg, 0.012 mmol, 53%; white solid).
1H NMR (400 MHz, DMSO-d ₆ ) δ 0.58-0.62 (m, 2H), 0.69-0.74 (m, 2H), 1.18-1.27 (m, 2H), 1.51-1.75 (m, 8H), 1.87- 2.00 (m, 3H), 2.85-2.92 (m, 1H), 3.14 (t, J = 6.6 Hz, 2H), 3.24-3.26 (m, 2H), 3.81-3.88 (m, 2H), 4.16 (s, 3H), 5.31 (s, 1H), 5.61 (s, 1H), 6.85 (t, J = 6.1 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H), 8.51 (d, J = 4.1 Hz, 1H).
MS (ESI) m / z = 490.3 (M + H) ⁺ .
LC / MS t _R = 1.41 min.

Example 4
Results of TTK assay and A549 assay The following are representative results of the TTK assay and A549 assay.

(Example 5) CYP3A4 fluorescence MBI test
The CYP3A4 fluorescence MBI test is a test to examine the enhancement of CYP3A4 inhibition of compounds by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (BFC) is debenzylated by CYP3A4 enzyme using E. coli-expressed CYP3A4 as the enzyme, and fluorescence The reaction that produces the metabolite 7-Hydroxytrifluoromethylcoumarin (HFC), which emits, was performed as an index.

  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-reaction time 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 of the solution was transferred so that it was diluted by 10/10, and the reaction using NADPH, a coenzyme, was started as an indicator (no pre-reaction). After a predetermined time of reaction, 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). After the pre-reaction for a predetermined time, add another plate and dilute 1/10 with the substrate and K-Pi buffer. The reaction was started by shifting 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 using 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 6 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), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the amount of each metabolite produced was inhibited by the test compound was evaluated.

  The reaction conditions are 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, add 5 types of each substrate, human liver microsome and test drug in 50 mM Hepes buffer with the above composition, add coenzyme NADPH, and perform 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 multi-label 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 7) FAT test 20 μL of Salmonella typhimurium TA98 and TA100 strains cryopreserved were inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) for 10 hours at 37 ° C. Incubated before shaking. For TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution, and 9 mL of Micro F buffer solution (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), and 110 mL of exposure medium (biotin) : 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 of the test bacterial solution (498 μL of the 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 bacterial growth wells that turn yellow in 48 wells per dose. Evaluation was made in comparison with the negative control group.

(Example 8) 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 (0.2 mol / L potassium dihydrogen phosphate reagent 250 mL, 0.2 mL / L NaOH reagent 118 mL, and water to 1000 mL. 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 9) Metabolic stability test Using commercially available pooled human liver microsomes, the target compound was reacted for a certain period of time, and the residual rate 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 pH7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes 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 10) 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 a membrane potential of -80 mV by 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 11: 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 12: 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 13: 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 mentioned above, although this invention has been illustrated using preferable embodiment of this invention, this invention should not be limited and 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 documents cited herein should be incorporated by reference in their entirety, as if the contents themselves were specifically described herein. Understood.

  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 examples described above.

Claims (8)

Formula (I):

(Where
X is -C (-R ') = or -N =
Y is -C (-R ") = or -N =
R ′ and R ″ are each independently hydrogen, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino or substituted Or unsubstituted acyl,

The group represented by

Wherein R ^1A is hydrogen or substituted or unsubstituted alkyl;
R ^1B is hydrogen or substituted or unsubstituted alkyl).
R ² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R ³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted carbamoyl,
Formula: —OR ^c , where R ^c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Or a group represented by the formula: —NR ^d R ^e , wherein R ^d and R ^e are each independently hydrogen, substituted or unsubstituted acyl, substituted or Unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or R ^d and R ^e are (It may be combined with the adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing heterocycle.) A group represented,
R ⁴ is substituted or unsubstituted carbamoyl, cyano, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A compound that is heterocyclyl, amino substituted with a substituted or unsubstituted heteroaryl, or amino substituted with a substituted or unsubstituted heterocyclyl, provided that
(I) X is -C (-H) =, Y is -C (-H) =,
R ³ is substituted alkyl, formula: —NR ^d R ^e, where R ^d is hydrogen;
R ^e is hydrogen or substituted acyl. ) Or a cyano compound wherein R ⁴ is fluorine,
(Ii) a compound wherein R ⁴ is cyano and R ³ is substituted or unsubstituted alkyloxy, or phenyl;
(Iii) compounds wherein R ⁴ is chloro or phenyl and R ³ is substituted or unsubstituted alkyloxy, and (iv) compounds shown below:




Or a pharmaceutically acceptable salt thereof or a solvate thereof.
A group represented by

(Wherein R ^1A is a hydrogen atom),
R ² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, formula: —OR ^c , wherein R ^c is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero A group represented by the formula: —NR ^d R ^e , wherein R ^d and R ^e are each independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted Substituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or R ^d and R ^e together with the adjacent nitrogen atom And may form a substituted or unsubstituted nitrogen-containing heterocycle.)
R ⁴ is substituted or unsubstituted carbamoyl, cyano, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, amino substituted with substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl The compound according to claim 1, its pharmaceutically acceptable salt, or a solvate thereof, which is substituted amino. R ² is substituted or unsubstituted aryl,
R ³ is a group represented by the formula: —OR ^c (wherein R ^c is substituted or unsubstituted alkyl or substituted or unsubstituted aryl), or a formula: —NR ^d R ^e (where R is ^d is hydrogen, R ^e is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and
The compound according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ⁴ is substituted or unsubstituted carbamoyl or substituted or unsubstituted heteroaryl. R ³ is a group represented by the formula: —OR ^c (wherein R ^c is as defined in claim 3) or a formula: —NR ^d R ^e (wherein R ^d and R ^e are as defined in claim 3) The group shown,
The compound according to claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ⁴ is substituted or unsubstituted heteroaryl. The compound according to claim 4, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ³ is a group represented by the formula: -OR ^c (wherein R ^c is as defined in claim 3). . R ³ is a group represented by the formula: —NR ^d R ^e (wherein R ^d and R ^e are as defined in claim 3), the compound according to claim 4, a pharmaceutically acceptable salt thereof, or Their solvates. The pharmaceutical composition containing the compound in any one of Claims 1-6, its pharmaceutically acceptable salt, or those solvates. The pharmaceutical composition according to claim 7, which is a TTK inhibitor.