WO2024111626A1 - Novel thiazole derivative - Google Patents

Abstract

The present invention provides a thiazole derivative that has an ALK5 inhibitory action and that is represented by formula (1) (refer to the description with respect to R1, R2, and Z in the formula), or a pharmaceutically acceptable salt thereof.

Description

New thiazole derivatives

The present invention relates to a medicine, in particular to a novel thiazole derivative or a pharma- ceutical acceptable salt thereof that has TGFβ type I receptor (ALK5) inhibitory activity.

Transforming growth factor β (TGF-β), a multifunctional cytokine, exists in three isoforms (TGF-β1, β2, β3) in mammals and is involved in physiological functions such as cell proliferation, differentiation control, migration, and adhesion (Non-Patent Document 1). TGF-β binds to a complex formed by a single-pass transmembrane type I receptor (ALK5) with a serine/threonine kinase domain and a type II receptor, and transmits a signal into the cell. When ALK5 is activated by the type II receptor upon binding of TGF-β, ALK5 phosphorylates the transcription factors Smad2 and Smad3 in the cell. After forming a complex with Smad4, phosphorylated Smad2 and Smad3 migrate to the nucleus and induce the transcription of target genes directly or together with other transcription factors (Non-Patent Documents 1 and 2).
Recent studies have reported that TGF-β signaling plays an important role in pathological conditions such as wound healing, inflammation/immunity, and cancer invasion/metastasis (Non-Patent Document 3). In particular, it has been reported that TGF-β signaling is directly involved in the promotion of epithelial-mesenchymal transition (EMT), angiogenesis, and the maintenance of cancer stem cells in cancer cells (Non-Patent Documents 4 and 5).
For example, it is known that TGF-β is involved in the proliferation of osteosarcoma, and it has been reported that ALK5 inhibitors suppress the proliferation of osteosarcoma cells stimulated with TGF-β (Non-Patent Document 6). In addition, it has been reported that anti-TGF-β antibodies suppress lung metastasis of osteosarcoma (Non-Patent Document 7), so it is considered that ALK5 inhibitors are useful for the treatment of solid cancers and metastasis in which TGF-β is involved.

In recent years, in the treatment of cancer, attention has been focused on cancer immunotherapy, which uses immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T lymphocyte antigen 4) antibody, anti-PD-1 (programmed death receptor 1) antibody, and anti-PD-L1 (programmed death ligand 1) antibody to enhance the host's antitumor immune response and obtain an antitumor effect. TGF-β controls the differentiation induction of regulatory T cells (Treg), which are responsible for immune control, and it is thought that in the cancer microenvironment, Treg cells suppress antitumor immunity and promote tumor growth (Non-Patent Document 8). Therefore, suppressing TGF-β signaling is expected to have an antitumor effect by cancer immunotherapy and a combined effect with immune checkpoint inhibitors.
TGF-β is also involved in fibrosis, a pathological excess state of the normal tissue repair process, and it has been reported that abnormal excess signaling of TGF-β is the cause of fibrosis (Non-Patent Document 9).
Therefore, a compound having an ALK5 inhibitory activity is useful for treating diseases in which TGF-β signaling is involved, such as cancer, and for expanding and enhancing the therapeutic effect in cancer immunotherapy by using it in combination with an immune checkpoint inhibitor, etc. It is also useful for treating and preventing fibrotic diseases, etc.

Massague, J., Annu. Rev. Biochem., 1998, 67, 753-791. Derynck, R. , Zhang, Y. E. , Nature, 2003, 425, 577. Akhurst, R. J., Hata, A., Nat. Rev. Drug Discov., 2012, 11, 790-811. Xu, J. , Lamouille, S. , Derynck, R. , Cell Res. , 2009, 19, 156-172. Padua, D., Massague, J., Cell Res., 2009, 19, 89-102. Matsuyama, S., et al., Cancer Res., 2003, 63(22), 7791-7798. Kawano, M. , et al. , Clin. Orthop. Relat. Res. , 2012, 470(8):2288-2294. Tauriello, D.V.F., Palomo-Ponce, S., Stork, D., Berenguer-Llergo, A. , Nature, 2018, 554, 538-543. Verrecchia, F, Mauviel, A., World J. Gastroenterol., 2007, 13(22), 3056-3062.

The objective of the present invention is to provide a pharmaceutical, in particular a novel thiazole derivative or a pharma- ceutical acceptable salt thereof that has TGFβ type I receptor (ALK5) inhibitory activity.

（式中、Ｒ^１は置換基を有してもよいアルキル基、置換基を有してもよい飽和ヘテロ環式基または置換基を有してもよいアミノ基を表わし、Ｒ^２は置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基または置換基を有してもよいアルキニル基を表し、Ｚは置換基を有してもよいアルキル基、置換基を有してもよいアルケニル基、置換基を有してもよいアルキニル基、置換基を有してもよい飽和ヘテロ環式基または置換基を有してもよいシクロアルキル基を表す。）で示されるチアゾール誘導体またはその薬学的に許容される塩。
（２）Ｒ^２が置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基である、上記（１）に記載のチアゾール誘導体またはその薬学的に許容される塩。
（３）Ｒ^２が置換基を有してもよいアルキニル基である、上記（１）に記載のチアゾール誘導体またはその薬学的に許容される塩。
（４）後記実施例１から２２６よりなる群から選択される、チアゾール誘導体またはその薬学的に許容される塩。 The present invention can be achieved by the following thiazole derivatives or pharma- ceutically acceptable salts thereof:
(1) The following formula (I):

(wherein R ¹ represents an optionally substituted alkyl group, an optionally substituted saturated heterocyclic group or an optionally substituted amino group; R ² represents an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted alkynyl group; and Z represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted saturated heterocyclic group or an optionally substituted cycloalkyl group), or a pharmacy acceptable salt thereof.
(2) The thiazole derivative or a pharma- ceutically acceptable salt thereof according to the above (1), wherein ^R2 is an aryl group which may have a substituent, or a heteroaryl group which may have a substituent.
(3) The thiazole derivative or a pharma- ceutically acceptable salt thereof according to the above (1), wherein ^R2 is an alkynyl group which may have a substituent.
(4) A thiazole derivative or a pharma- ceutically acceptable salt thereof selected from the group consisting of Examples 1 to 226 described below.

The present inventors conducted various studies to solve the above problems, and found that the novel thiazole derivative represented by the above formula (I) and its pharma- ceutical acceptable salt exhibit ALK5 inhibitory activity, and thus completed the present invention. The compounds provided by the present invention are useful for treating diseases known to be associated with abnormal cell responses via the TGFβ signal pathway, particularly cancer, and are also useful for preventing tumor metastasis and recurrence by targeting cancer stem cells. Furthermore, by using them in combination with immune checkpoint inhibitors, they are useful for expanding and enhancing the therapeutic effect in cancer immunotherapy. They are also useful for treating and preventing fibrotic diseases and the like. They are also useful as experimental and research reagents as ALK5 inhibitors and TGFβ signal inhibitors.

Showing the tumor growth suppression and tumor regression effect in the combined use of a representative compound of the embodiment and an anti-PD-1 antibody (Test Example 4) Tumor growth inhibition and tumor regression effects of representative compounds (single agent and in combination with anti-PD-1 antibody) are shown (Test Example 5)

（式中、Ｒ^１は置換基を有してもよいアルキル基、置換基を有してもよい飽和ヘテロ環式基または置換基を有してもよいアミノ基を表わし、Ｒ^２は置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基または置換基を有してもよいアルキニル基を表し、Ｚは置換基を有してもよいアルキル基、置換基を有してもよいアルケニル基、置換基を有してもよいアルキニル基、置換基を有してもよい飽和ヘテロ環式基または置換基を有してもよいシクロアルキル基を表す。）
で示される化合物である。 The present invention will be described in detail below.
The novel thiazole derivative of the present invention has the following formula (I):

(In the formula, ^R1 represents an alkyl group which may have a substituent, a saturated heterocyclic group which may have a substituent, or an amino group which may have a substituent, ^R2 represents an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or an alkynyl group which may have a substituent, and Z represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, a saturated heterocyclic group which may have a substituent, or a cycloalkyl group which may have a substituent.)
It is a compound represented by the formula:

The terminology used in this specification is explained in more detail below.
In the following description, "halogen" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
"C _1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1-6 carbon atoms, and "C ₆ alkyl" means a saturated hydrocarbon group having 6 carbon atoms. The same applies to other numbers. "C _1-3 alkyl" specifically means a methyl group, an ethyl group, a propyl group, or an isopropyl group. In addition to the above "C _1-3 alkyl", examples of "C _1-6 alkyl" include a butyl group, a 1-methylpropyl group, a 2-methylpropyl group, a tert-butyl group, a pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, and an n-hexyl group.
Similarly, "C _3-8 cycloalkyl" refers to a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. The same applies to other numbers. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
In addition, "C _1-6 alkoxy" means "C _1-6 alkyloxy", and the "C _1-6 alkyl" portion has the same meaning as the above-mentioned "C _1-6 alkyl". The same applies to other numbers.
Unless otherwise specified, the substituents may be one or more of any type of substituent at any chemically possible position, and when there are two or more substituents, the respective substituents may be the same or different.

1. ^R1
R ¹ represents an alkyl group which may have a substituent, a saturated heterocyclic group which may have a substituent, or an amino group which may have a substituent.
The alkyl group moiety of the alkyl group which may have a substituent may be any of _C1-6 alkyl, and particularly preferably _C1-3 alkyl.
A specific example of a preferred substituent in the C _1-6 alkyl or C _1-3 alkyl is a substituted amino group --NR ¹¹ R ^12. Here, R ¹¹ and R ¹² each independently represent , a 4- to 6-membered oxygen-containing saturated heterocycle, or a C _1-6 alkyl, or a 4- to 6-membered ring which, taken together with the nitrogen atom to which it is bonded, may further contain a nitrogen atom or an oxygen atom. Examples of the oxygen-containing saturated heterocycle include an oxetanyl group, a tetrahydropyranyl group, and a tetrahydrofuryl group, and examples of the nitrogen-containing saturated heterocycle include pyrrolidine, piperidine, piperazine, and morpholine. These may be substituted with halogen, a methyl group, a methoxy group, or the like.
A preferred embodiment of the alkyl group which may have a substituent is -CH ₂ NR ¹¹ R ¹² in which the above-mentioned substituted amino group is substituted with a methyl group.
The saturated heterocyclic group portion of the optionally substituted saturated heterocyclic group is a 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms arbitrarily selected from a sulfur atom, a nitrogen atom, and an oxygen atom. and can be substituted at any position where chemical substitution is possible. Specifically, the substituent can be an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, an oxetanyl group, or , tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyranyl group, thiomorpholinyl group, etc. The substituent of the saturated heterocyclic group may be a halogen atom, a hydroxy group, a methyl group, a methoxy group, a methanesulfonyl group, etc. Examples include a 2-hydroxyethyl group, an oxetanyl group, a tetrahydropyranyl group, a methyl-piperidinyl group, a methyl-piperazinyl group, a morpholinyl group, and a thiomorpholinyl group.
The amino group which may have a substituent in R ¹ is represented by the atomic group -NR ¹³ R ¹⁴ , R ¹³ and R ¹⁴ each independently represent _a C _1-6 alkyl, The _6- alkyl may be further substituted with a dimethylamino group, a methoxy group, etc. A preferred embodiment of the amino group which may have a substituent is a dimethylamino group.

2. ^R2
R2 represents an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or an alkynyl group which may have a substituent.
Examples of the aryl group moiety of the aryl group which may have a substituent include a phenyl group and a naphthyl group.
The heteroaryl group portion of the heteroaryl group which may have a substituent is a 4- to 6-membered heteroaryl ring containing 1 to 4 heteroatoms arbitrarily selected from a sulfur atom, a nitrogen atom, and an oxygen atom. The formula includes a pyrrolyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a triazinyl group, etc. are examples.
The alkynyl group portion of the alkynyl group which may have a substituent is a straight-chain or branched-chain unsaturated hydrocarbon having at least one carbon-carbon triple bond and 2 to 6 carbon atoms. Specifically, it means an ethynyl group, a 2-propynyl group, a 2-butynyl group, a 2-pentynyl group, a 3-pentynyl group, _a 2-hexynyl group, a 3-hexynyl group. etc. are examples.
The substituents in the above-mentioned aryl group which may have a substituent, the heteroaryl group which may have a substituent, and the alkynyl group which may have a substituent are preferably _C1 Examples of the substituents _{of the C 1-6 alkyl} and C _1-6 alkoxy include halogen, cyano, hydroxyl, and benzyl. Examples of the substituents include 1 to 3 halogens, a hydroxyl group, a cyclopropyl group, a phenyl group, etc. Examples of the substituents that form a ring include a methylenedioxy group or an ethylenedioxy group. Examples can be given.

3. Z
Z represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, a saturated heterocyclic group which may have a substituent, or a cycloalkyl group which may have a substituent.
The alkyl group portion of the alkyl group which may have a substituent is a C _1-6 alkyl. Examples of the substituent of this C _1-6 alkyl include a C _3-6 cycloalkyl group, a halogeno C _3-6 cycloalkyl group, a C _1-3 alkoxy group, a halogen atom, a hydroxy group, a benzyloxy group, a methylamino group, a dimethylamino group, a pyranyl group, a piperidinyl group, and a C _1-3 alkylsulfonyl group.
The alkenyl group moiety of the alkenyl group which may have a substituent may be any of linear or branched alkenyl groups having 2 to 6 carbon atoms, such as an allyl group, a 2-butenyl group, an isobutenyl group, a 2-pentenyl group, a 3-pentenyl group, and a 2-hexenyl group.
The alkynyl group which may have a substituent in Z is the same as the alkynyl group which may have a substituent in ^R2 .
The cycloalkyl group portion of the cycloalkyl group which may have a substituent may be any cyclic saturated hydrocarbon group having 3 to 8 carbon atoms (C _cycloalkyl ), with a cyclopropyl group being particularly preferred. Examples of the substituent of this C _cycloalkyl include halogen atoms.
The saturated heterocyclic group portion of the optionally substituted saturated heterocyclic group may be any 4- to 6-membered saturated heterocyclic group containing 1 to 3 heteroatoms arbitrarily selected from sulfur atoms, nitrogen atoms, and oxygen atoms, and may be substituted at any chemically substitutable position. Specific examples thereof include a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a thiomorpholinyl group, and the like.

An embodiment of the compound (I) of the present invention is the above thiazole derivative (I) or a pharma- ceutically acceptable salt thereof, wherein Z is a cycloalkyl group which may be substituted.
An embodiment of compound (I) of the present invention is the above thiazole derivative (I) or a pharma- ceutically acceptable salt thereof, wherein Z is an alkyl group which may have a substituent.
Another embodiment of the compound (I) of the present invention is the above thiazole derivative (I) or a pharma- ceutically acceptable salt thereof, wherein ^R2 is a phenyl group which may be substituted.
Another embodiment of the compound (I) of the present invention is the above thiazole derivative (I) or a pharma- ceutically acceptable salt thereof, wherein ^R2 is an alkynyl group which may be substituted.
Another embodiment of the compound (I) of the present invention is the thiazole derivative (I) or a pharma- ceutically acceptable salt thereof, which is selected from the group consisting of Examples 1 to 226.

Compound (I) of the present invention may have isomers depending on, for example, the type of substituent. In this specification, the chemical structure of only one form of the isomer may be described, but the present invention also includes all isomers (geometric isomers, optical isomers, tautomers, etc.) that may occur due to the structure, and also includes a single isomer or a mixture thereof.
Pharmaceutically acceptable salts of compound (I) of the present invention include inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid, etc., and organic acid salts with formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. In addition, the present invention also includes alkali metal salts with sodium, potassium, etc., alkaline earth metal salts with magnesium, calcium, etc., organic amine salts with lower alkylamines, lower alcoholamines, etc., basic amino acid salts with lysine, arginine, ornithine, etc., as well as ammonium salts.
Compound (I) of the present invention and its pharma- ceutical acceptable salts can be prepared, for example, by the following method. In the preparation methods shown below, if the defined groups change under the conditions of the method or are not suitable for carrying out the method, the compound can be easily prepared by applying a method commonly used in organic synthesis chemistry, such as protection and deprotection of functional groups [T. W. Greene, Protective Groups in Organic Synthesis 4th Edition, John Wiley & Sons, Inc., 2007]. In addition, the order of reaction steps such as introduction of substituents can be changed as necessary.

The abbreviations and symbols used in the following description have the following meanings:
DMF: Dimethylformamide DMSO: Dimethylsulfoxide HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DIPEA: N,N-diisopropylethylamine THF: Tetrahydrofuran

（式中、Ｒ^１、Ｒ^２及びＺは前記と同義であり、Ｘはハロゲンを表す。） [Method for producing compound (I) of the present invention]
The process for producing the compound (I) of the present invention will be explained below.
The compound of the present invention represented by formula (I) can be produced, for example, according to Scheme 1.

(In the formula, R ¹ , R ² and Z are defined as above, and X represents a halogen.)

The compound (I) of the present invention can be produced by Ullmann condensation reaction or nucleophilic substitution reaction between the compound (II) and a compound R ² -X.
That is, when R ² is an aryl group which may have a substituent or a heteroaryl group which may have a substituent, a mixture of compound (II) and compound R ² -X is subjected to Ullmann condensation reaction in a solvent in the presence of a metal catalyst such as copper, using a base and an additive as necessary, to produce compound (I). The solvent used in the reaction may be any solvent inert to the reaction, and is not particularly limited, but preferably includes dioxane, toluene, dimethoxyethane, DMF, and the like. Compound R ² -X is preferably used in a molar equivalent or excess amount relative to compound (II), more preferably 1 to 10 molar equivalents. A base may be added to accelerate the reaction as necessary, and sodium carbonate, cesium carbonate, potassium carbonate, and the like are usually used as the base. The amount of the base used is 1 to 10 molar equivalents relative to compound (II), preferably 1 to 5 molar equivalents. As the metal catalyst, a commercially available copper catalyst (e.g., CuI, etc.) used in coupling can be used, and it is preferable to add a catalytic amount to compound (II). The reaction can be carried out by heating at 30 to 150° C. for 1 to 48 hours, preferably at 80 to 130° C. for 12 to 24 hours. Compound (I) can also be produced under Buchwald-Hartwig reaction conditions using a palladium catalyst instead of a copper catalyst.
Compound (I) can also be produced by a Chan-Lam-Evans coupling reaction using a compound in which the halogen X of compound R ² -X is converted to a boronic acid or a boronic acid ester thereof.
When R ² is an alkynyl group which may have a substituent, compound (I) of the present invention can be obtained by subjecting compound (II) to a nucleophilic substitution reaction in the presence of 1 to 5 molar equivalents, preferably 1 to 2.5 molar equivalents of compound R ² -X and 1 to 5 molar equivalents, preferably 1 to 3.5 molar equivalents of a base such as cesium carbonate, in a solvent.
The solvent may be any solvent inactive to the reaction, and is not particularly limited, but preferably DMSO or DMF can be used. The reaction can be carried out by heating at 30 to 150° C. for 1 to 24 hours, and preferably at 50 to 80° C. for 1 to 7 hours.

（式中、Ｒ^１、Ｒ^２及びＺは前記と同義である。） Compound (I) of the present invention can also be produced by the method shown in Scheme 2, for example, using compound (III).

(In the formula, R ¹ , R ² and Z are as defined above.)

Compound (I) of the present invention can be produced by Chan-Lam-Evans coupling reaction using compound (III) and boronic acid (IV). That is, compound (I) can be produced by reacting a mixture of compound (III) and boronic acid (IV) in a solvent in the presence of a metal catalyst such as copper or nickel, using a base and an additive as necessary. The solvent used in the reaction may be any solvent inert to the reaction, and is not particularly limited, but preferably dichloromethane or dichloroethane can be used.
The reaction can be carried out by heating at 30 to 150° C. for 1 to 24 hours, preferably at 50 to 80° C. for 1 to 7 hours.
Furthermore, the boronyl group of compound (IV) can be replaced with a boronic acid ester group for use in the reaction.
Compound (I) can also be produced by subjecting compound (III) to a nucleophilic substitution reaction with a Z-introducing agent in which the boronic acid moiety of compound (IV) is a suitable leaving group, in the presence of a suitable base.

（式中、Ｒ^１、Ｒ^２及びＺは前記と同義であり、Ｒ^３は低級アルキル基を表わす。）
　本発明の化合物（Ｉ）は、化合物（Ｖ）のエステル基をアミノリシス反応によりカルボキサミド基に変換することで製造することができる。すなわち、化合物（Ｖ）を溶媒中、アンモニアと加熱反応させることによって、化合物（Ｉ）を製造することができる。溶媒は反応に不活性なものであればいずれでも良く、特に限定されるものではないが、好ましくはエタノール、もしくはメタノールを用いることができ、アンモニアとしては、水溶液、アルコール溶液などを用いるか、直接、反応液にアンモニアガスを吹き込むことができる。
　反応は５０～１５０℃において、１～４８時間加熱することで実施することができるが、好ましくは８０～１００℃において１～１５時間反応させることにより実施することができる。
　当該カルボキサミド基への変換は、通常の有機合成で用いられる手法、すなわち、エステルの加水分解後、カップリング剤を用いたアミド化反応でも実施可能である。 Moreover, the compound (I) of the present invention can also be produced, for example, according to Scheme 3.

(In the formula, R ¹ , R ² and Z are defined as above, and R ³ represents a lower alkyl group.)
The compound (I) of the present invention can be produced by converting the ester group of the compound (V) to a carboxamide group by aminolysis reaction. That is, the compound (I) can be produced by reacting the compound (V) with ammonia in a solvent under heating. The solvent may be any solvent inert to the reaction, and is not particularly limited, but preferably ethanol or methanol can be used. As the ammonia, an aqueous solution, an alcohol solution, etc. can be used, or ammonia gas can be directly blown into the reaction solution.
The reaction can be carried out by heating at 50 to 150° C. for 1 to 48 hours, preferably at 80 to 100° C. for 1 to 15 hours.
The conversion to the carboxamide group can also be carried out by a method commonly used in organic synthesis, namely, hydrolysis of an ester followed by an amidation reaction using a coupling agent.

（式中、Ｒ^１、Ｒ^２及びＺは前記と同義であり、Ｘはハロゲンを表す。）
　本発明の化合物（Ｉ）は、化合物（ＶＩ）と化合物（ＶＩＩ）を用いて鈴木カップリング反応などのクロスカップリング反応により製造することができる（例えば、鈴木カップリング反応の条件については公知文献（Ｎ．Ｍｉｙａｕｒａ，ｅｔ ａｌ，Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１０７，９７２（１９８５）．，Ｎ．Ｍｉｙａｕｒａ，Ａ．Ｓｕｚｕｋｉ，Ｃｈｅｍ．Ｒｅｖ．９５，２４５７（１９９５））などを参照）。すなわち、化合物（ＶＩ）と化合物（ＶＩＩ）の混合物を溶媒中、パラジウムやニッケルなどの金属触媒の存在下、必要に応じて塩基および添加剤を使用して反応させることによって、化合物（Ｉ）を製造することができる。
　反応に用いる溶媒としてはＴＨＦ、ジオキサン、トルエン、ジメトキシエタン、メタノール、エタノール、アセトニトリルなどが挙げられる。また、これらの溶媒を２種以上混合して、或いはそれらを更に水と混合して用いても好適である。好ましくは、ジオキサンと水の混合溶媒、トルエンとメタノールおよび水との混合溶媒である。化合物（ＶＩＩ）は化合物（ＶＩ）に対しモル当量または過剰量用いることが好ましく、より好ましくは１モル当量から１０モル当量である。必要に応じて反応を加速させるために塩基を添加してもよく、塩基としては炭酸ナトリウム、炭酸セシウム、炭酸カリウム、フッ化セシウムなどが通常用いられる。使用する塩基の用量は化合物（ＶＩ）に対し１モル当量から１０モル当量が挙げられ、好ましくは１モル当量から５モル当量である。金属触媒としては、クロスカップリングに用いられている市販で入手容易なパラジウム触媒（例えば、ＰｄＣｌ_２（Ａｍｐｈｏｓ）、ＰｄＣｌ_２（ｄｐｐｆ）、Ｐｄ_２（ｄｂａ）_３、Ｐｄ（ＰＰｈ_３）_４など）を用いることができ、化合物（ＶＩ）に対して触媒量、すなわち０．１モル当量から０．５モル当量を添加することが好ましい。また、化合物（ＶＩＩ）のボロニル基は、ボロン酸エステル基に置き換えて反応に使用することもできる。
　スキーム４の原料の一つである化合物（ＶＩＩ）は市販品として、または公知の方法もしくはそれに準じた方法により得ることができる。 Moreover, the compound (I) of the present invention can also be produced, for example, according to Scheme 4.

(In the formula, R ¹ , R ² and Z are defined as above, and X represents a halogen.)
Compound (I) of the present invention can be produced by a cross-coupling reaction such as Suzuki coupling reaction using compound (VI) and compound (VII) (for example, see known literature (N. Miyaura, et al., J. Am. Chem. Soc., 107, 972 (1985)., N. Miyaura, A. Suzuki, Chem. Rev. 95, 2457 (1995)) for the conditions of Suzuki coupling reaction). That is, compound (I) can be produced by reacting a mixture of compound (VI) and compound (VII) in a solvent in the presence of a metal catalyst such as palladium or nickel, and using a base and an additive as necessary.
Examples of the solvent used in the reaction include THF, dioxane, toluene, dimethoxyethane, methanol, ethanol, and acetonitrile. It is also suitable to use two or more of these solvents in combination, or to further mix them with water. A mixed solvent of dioxane and water, or a mixed solvent of toluene, methanol, and water is preferred. Compound (VII) is preferably used in a molar equivalent or excess amount relative to compound (VI), more preferably 1 to 10 molar equivalents. If necessary, a base may be added to accelerate the reaction, and sodium carbonate, cesium carbonate, potassium carbonate, cesium fluoride, and the like are usually used as the base. The amount of the base used is 1 to 10 molar equivalents relative to compound (VI), preferably 1 to 5 molar equivalents. As the metal catalyst, a commercially available palladium catalyst (e.g., _PdCl2 (Amphos), _PdCl2 (dppf), _Pd2 (dba) ₃ , Pd( _PPh3 ) ₄ , etc.) used in cross-coupling can be used, and it is preferable to add a catalytic amount, i.e., 0.1 to 0.5 molar equivalents, to compound (VI). In addition, the boronyl group of compound (VII) can be replaced with a boronic acid ester group for use in the reaction.
Compound (VII), which is one of the raw materials in Scheme 4, is a commercially available product or can be obtained by a known method or a method analogous thereto.

（式中、Ｒ^２、Ｒ^１３、Ｒ^１４及びＺは前記と同義である。）
　化合物（Ｉ－ａ）は、化合物（ＶＩＩＩ）のカルボキシル基とアミン（ＩＸ）を縮合反応させることで製造できる。すなわち、化合物（ＶＩＩＩ）と０．９～５モル当量、好ましくは１～２モル当量のアミン（ＩＸ）を溶媒中、有機化学で一般的に用いられるアミド縮合剤存在下、反応させることによって得ることができる。溶媒は反応に不活性なものであればいずれでも良く、特に限定されるものではないが、例えば、ＤＭＦ、ＴＨＦなどを用いることができる。反応は０～１５０℃において、１～４８時間撹拌することで実施することができるが、好ましくは室温～８０℃において１時間から終夜反応させることにより実施することができる。
　スキーム５の原料の一つであるアミン（ＩＸ）は市販品として、または公知の方法もしくはそれに準じた方法により得ることができる。 Moreover, the compound (Ia) of the present invention, in which R ¹ in formula (I) is an amino group which may have a substituent, can also be produced according to scheme 5, for example.

(In the formula, R ² , R ¹³ , R ¹⁴ and Z are the same as defined above.)
Compound (I-a) can be produced by condensation reaction of the carboxyl group of compound (VIII) with amine (IX). That is, compound (VIII) can be obtained by reacting 0.9 to 5 molar equivalents, preferably 1 to 2 molar equivalents, of amine (IX) in a solvent in the presence of an amide condensing agent commonly used in organic chemistry. The solvent may be any solvent inert to the reaction, and is not particularly limited, but for example, DMF, THF, etc. can be used. The reaction can be carried out by stirring at 0 to 150°C for 1 to 48 hours, but preferably by reacting at room temperature to 80°C for 1 hour to overnight.
The amine (IX), which is one of the raw materials in Scheme 5, is a commercially available product or can be obtained by a known method or a method similar thereto.

（式中、Ｒ^２、Ｚ、Ｒ^１１およびＲ^１２は前記と同義であり、Ｘはハロゲンを表わす。）
　化合物（Ｉ－ｂ）は、化合物（Ｉ－ｃ）とアミン（ＩＸ）を反応させることで製造することができる。すなわち、化合物（Ｉ－ｃ）と０．９～５モル当量、好ましくは１～２モル当量のアミン（ＩＸ）を溶媒中、塩基存在下、反応させることによって得ることができる。溶媒は反応に不活性なものであればいずれでも良く、特に限定されるものではないが、例えば、ＤＭＦ、ＴＨＦなどを用いることができる。
　反応は０～１５０℃において、１～４８時間撹拌することで実施することができるが、好ましくは室温～８０℃において１時間から終夜反応させることにより実施することができる。 Furthermore, among the compounds in formula (I) in which R ¹ is represented by an alkyl group which may have a substituent, compound (I-b) of the present invention having an "amino group which may have a substituent" as a substituent can also be produced using compound (I-c) of the present invention in which R ¹ is represented by an alkyl group which may have a substituent and has a halogen as a substituent, for example, according to Scheme 6.

(In the formula, R ² , Z, R ¹¹ and R ¹² are the same as defined above, and X represents a halogen.)
Compound (I-b) can be produced by reacting compound (I-c) with amine (IX). That is, compound (I-c) can be reacted with 0.9 to 5 molar equivalents, preferably 1 to 2 molar equivalents, of amine (IX) in a solvent in the presence of a base. The solvent may be any solvent inert to the reaction, and is not particularly limited. For example, DMF, THF, etc. can be used.
The reaction can be carried out at 0 to 150° C. with stirring for 1 to 48 hours, preferably at room temperature to 80° C. for 1 hour to overnight.

（式中、Ｒ^１及びＺは前記と同義であり、Ｘはハロゲンを表し、ＰＧは保護基を表わす。）
　化合物（ＩＩ）は、化合物（Ｘ）と化合物（ＶＩＩ）を用いて鈴木カップリング反応などのクロスカップリング反応により得た生成物を脱保護することに製造することができる。すなわち、化合物（Ｘ）と化合物（ＶＩＩ）をスキーム４と同様の条件で反応させることにより、化合物（ＩＩ）の保護体を得ることができる。得られた化合物（ＩＩ）の保護体の脱保護反応は、用いた保護基に適した有機化学で一般的に用いられる脱保護条件に供することで実施できる。化合物（ＶＩＩ）のボロニル基は、ボロン酸エステル基に置き換えて反応に使用することもできる。 Compound (II) used as the starting material in Scheme 1 can be produced, for example, by the method shown in Scheme 7.

(In the formula, ^R1 and Z are defined as above, X represents a halogen, and PG represents a protecting group.)
Compound (II) can be produced by deprotecting the product obtained by a cross-coupling reaction such as Suzuki coupling reaction using compound (X) and compound (VII). That is, a protected form of compound (II) can be obtained by reacting compound (X) and compound (VII) under the same conditions as in Scheme 4. The deprotection reaction of the obtained protected form of compound (II) can be carried out by subjecting it to deprotection conditions generally used in organic chemistry that are suitable for the protecting group used. The boronyl group of compound (VII) can also be replaced with a boronic acid ester group and used in the reaction.

（式中、Ｚは前記と同義であり、Ｘはハロゲンを表し、Ｒ^３は低級アルキル基を表わし、ＰＧは保護基を表わす。）
　化合物（Ｘ）は、化合物（ＸＩ）のエステル基をアミノリシス反応によりカルボキサミド基に変換することで製造することができる。反応は、スキーム３と同様の条件を用いることで実施できる。また当該カルボキサミド基への変換は、通常の有機合成で用いられる手法、すなわち、エステルの加水分解後、カップリング剤を用いたアミド化反応でも実施可能である。 Compound (X) used as the starting material in Scheme 7 can be produced, for example, by the method shown in Scheme 8.

(In the formula, Z is defined as above, X represents a halogen, ^R3 represents a lower alkyl group, and PG represents a protecting group.)
Compound (X) can be produced by converting the ester group of compound (XI) to a carboxamide group by aminolysis reaction. The reaction can be carried out under the same conditions as in Scheme 3. The conversion to the carboxamide group can also be carried out by a method used in ordinary organic synthesis, that is, by hydrolysis of the ester followed by an amidation reaction using a coupling agent.

（式中、Ｚは前記と同義であり、Ｘはハロゲンを表し、Ｒ^３は低級アルキル基を表わし、ＰＧは保護基を表わす。）
　化合物（ＸＩ）は、化合物（ＸＩＩ）を通常の有機化学で用いられるハロゲン化剤、例えばＮ-ブロモコハク酸イミド（ＮＢＳ）やＮ-クロロコハク酸イミド（ＮＣＳ）などで処理することで製造することができる。すなわち、化合物（ＸＩ）は、溶媒中、化合物（ＸＩＩ）と、０．５～２モル当量、好ましくは０．８～１．１モル当量のＮＢＳあるいはＮＣＳを反応させることによって得ることができる。
　溶媒は反応に不活性なものであればいずれでもよく、特に限定されるものではないが、好ましくはジクロロメタン、もしくはＤＭＦを用いることができる。反応は－２０～３０℃において、０．２５～１０時間撹拌することで実施することができるが、好ましくは－１０～１０℃において０．５～５時間撹拌することで実施することができる。 Compound (XI) used as the starting material in Scheme 8 can be produced, for example, by the method shown in Scheme 9.

(In the formula, Z is as defined above, X represents a halogen, ^R3 represents a lower alkyl group, and PG represents a protecting group.)
Compound (XI) can be produced by treating compound (XII) with a halogenating agent typically used in organic chemistry, such as N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS), etc. That is, compound (XI) can be obtained by reacting compound (XII) with 0.5 to 2 molar equivalents, preferably 0.8 to 1.1 molar equivalents, of NBS or NCS in a solvent.
The solvent may be any solvent inert to the reaction, and is not particularly limited, but preferably dichloromethane or DMF can be used. The reaction can be carried out by stirring at -20 to 30°C for 0.25 to 10 hours, preferably at -10 to 10°C for 0.5 to 5 hours.

（式中、Ｚは前記と同義であり、Ｒ^３は低級アルキル基を表わし、ＰＧは保護基を表わす。）
　化合物（ＸＩＩ）は、化合物（ＸＩＩＩ）とボロン酸（ＩＶ）を用いて、Ｃｈａｎ－Ｌａｍ－Ｅｖａｎｓカップリング反応により製造することができる。反応条件は、スキーム２と同様の条件で実施可能である。
また、化合物（ＩＶ）のボロニル基は、ボロン酸エステル基に置き換えて反応に使用することもできる。
　また、化合物（ＸＩＩＩ）を、化合物（ＩＶ）のボロン酸部分が適当な脱離基であるＺ導入剤等と、適当な塩基存在下、求核置換反応を行うことによっても化合物（ＸＩＩ）を製造することができる。 Compound (XII) used as the starting material in Scheme 9 can be produced, for example, by the method shown in Scheme 10.

(In the formula, Z is defined as above, ^R3 represents a lower alkyl group, and PG represents a protecting group.)
Compound (XII) can be produced by Chan-Lam-Evans coupling reaction using compound (XIII) and boronic acid (IV). The reaction conditions can be the same as those in Scheme 2.
Furthermore, the boronyl group of compound (IV) can be replaced with a boronic acid ester group for use in the reaction.
Compound (XII) can also be produced by subjecting compound (XIII) to a nucleophilic substitution reaction with a Z-introducing agent in which the boronic acid moiety of compound (IV) is a suitable leaving group, in the presence of a suitable base.

（式中、Ｒ^３は低級アルキル基を表わし、ＰＧは保護基を表わす。）
　化合物（ＸＩＩＩ）は、アミノピラゾール（ＸＩＶ）をチオホスゲンと反応させたのち、アンモニア水溶液で処理することで得られるチオアミド（ＸＶ）を、ブロモピルビン酸エチルと反応させてチアゾール環を形成させることで製造することができる。すなわち、ジクロロメタンなどの溶媒中、アミノピラゾール（ＸＩＶ）を、必要に応じて塩基存在下、０．５～２モル当量、好ましくは０．９～１．５モル当量のチオホスゲンと反応させたのち、アンモニア水溶液を加えることでチオアミド（ＸＶ）を得ることができる。このチオアミド（ＸＶ）を、エタノールなどの溶媒中、炭酸カリウムなどの塩基存在下、０．５～２モル当量、好ましくは０．８～１．５モル当量のブロモピルビン酸エチルと反応させることで、化合物（ＸＩＩＩ）を得ることができる。
　スキーム１１の原料として用いられるアミノピラゾール（ＸＩＶ）は、市販品として入手するか、または４－ニトロピラゾールなどを出発原料として有機合成化学で通常用いられる方法を用いて容易に製造することができる。 Compound (XIII) used as the starting material in Scheme 10 can be produced, for example, by the method shown in Scheme 11.

(In the formula, ^R3 represents a lower alkyl group, and PG represents a protecting group.)
Compound (XIII) can be produced by reacting aminopyrazole (XIV) with thiophosgene, treating with aqueous ammonia to obtain thioamide (XV), and reacting the thioamide (XV) with ethyl bromopyruvate to form a thiazole ring. That is, in a solvent such as dichloromethane, aminopyrazole (XIV) is reacted with 0.5 to 2 molar equivalents, preferably 0.9 to 1.5 molar equivalents of thiophosgene, if necessary, in the presence of a base, and then an aqueous ammonia solution is added to obtain thioamide (XV). Compound (XIII) can be obtained by reacting this thioamide (XV) with 0.5 to 2 molar equivalents, preferably 0.8 to 1.5 molar equivalents of ethyl bromopyruvate in a solvent such as ethanol in the presence of a base such as potassium carbonate.
The aminopyrazole (XIV) used as a starting material in Scheme 11 is either commercially available or can be easily prepared using a method commonly used in organic synthesis using 4-nitropyrazole or the like as a starting material.

（式中、Ｒ^１、Ｒ^２は前記と同義であり、Ｘはハロゲンを表わす。）
　化合物（ＩＩＩ）は、化合物（ＸＶＩ）と化合物（ＶＩＩ）を用いて鈴木カップリング反応などのクロスカップリング反応により製造することができる。当該クロスカップリング反応は、スキーム４と同様の条件で実施することができる。また化合物（ＶＩＩ）のボロニル基は、ボロン酸エステル基に置き換えて反応に使用することもできる。 Compound (III) used as a starting material in Scheme 2 can be produced, for example, by the method shown in Scheme 12.

(In the formula, R ¹ and R ² are defined as above, and X represents a halogen.)
Compound (III) can be produced by a cross-coupling reaction such as Suzuki coupling reaction using compound (XVI) and compound (VII). The cross-coupling reaction can be carried out under the same conditions as in Scheme 4. The boronyl group of compound (VII) can also be replaced with a boronic acid ester group for use in the reaction.

（式中、Ｒ²は前記と同義であり、Ｒ^３は低級アルキル基を表わし、Ｘはハロゲンを表わす。）
　化合物（ＸＶＩ）は、化合物（ＸＶＩＩ）のエステル基をアミノリシス反応によりカルボキサミド基に変換することで製造することができる。反応は、スキーム３と同様の条件を用いることで実施できる。また当該カルボキサミド基への変換は、通常の有機合成で用いられる手法、すなわち、エステルの加水分解後、カップリング剤を用いたアミド化反応でも実施可能である。 Compound (XVI) used as the starting material in Scheme 12 can be produced, for example, by the method shown in Scheme 13.

(wherein ^R2 is as defined above, ^R3 represents a lower alkyl group, and X represents a halogen.)
Compound (XVI) can be produced by converting the ester group of compound (XVII) to a carboxamide group by aminolysis reaction. The reaction can be carried out under the same conditions as in Scheme 3. The conversion to the carboxamide group can also be carried out by a method used in ordinary organic synthesis, that is, hydrolysis of the ester followed by an amidation reaction using a coupling agent.

（式中、Ｒ²は前記と同義であり、Ｒ^３は低級アルキル基を表わし、Ｘはハロゲンを表わす。）
　化合物（ＸＶＩＩ）は、化合物（ＸＶＩＩＩ）を通常の有機化学で用いられるハロゲン化剤で処理することで製造することができる。反応条件は、スキーム９と同様の条件で実施可能である。
　スキーム１４の原料として用いられる化合物（ＸＶＩＩＩ）は、例えばスキーム１０において、化合物（ＸＩＩＩ）の保護基の代わりにＲ^２基を有するアミノピラゾール誘導体を出発原料に用いることで製造することができる。 Compound (XVII) used as the starting material in Scheme 13 can be produced, for example, by the method shown in Scheme 14.

(wherein ^R2 is as defined above, ^R3 represents a lower alkyl group, and X represents a halogen.)
Compound (XVII) can be produced by treating compound (XVIII) with a halogenating agent commonly used in organic chemistry. The reaction conditions can be the same as those in Scheme 9.
Compound (XVIII) used as a starting material in Scheme 14 can be produced, for example, in Scheme 10, by using an aminopyrazole derivative having an R ² group instead of the protecting group of compound (XIII) as a starting material.

（式中、Ｒ^１、Ｒ^２及びＺは前記と同義であり、Ｒ^３は低級アルキル基を表わし、ＰＧは保護基を表わし、Ｘはハロゲンを表わす。）
　Ｒ^２が置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基の場合、化合物（Ｖ）は、化合物（ＸＩＸ）の保護基を脱保護した後、化合物Ｒ^２－ＸとのＵｌｌｍａｎｎ縮合反応あるいはＢｕｃｈｗａｌｄ－Ｈａｒｔｗｉｇ反応などのカップリング反応により製造することができる。反応条件は、スキーム１と同様の条件で実施可能である。
　また、化合物Ｒ^２－ＸのハロゲンＸをボロン酸もしくはそのボロン酸エステルに変換した化合物を用いたＣｈａｎ－Ｌａｍ－Ｅｖａｎｓカップリング反応によっても化合物（Ｖ）を製造することができる。
　Ｒ^２が置換基を有してもよいアルキニル基である場合、化合物（Ｖ）は、化合物（ＸＩＸ）の保護基を脱保護した後、化合物Ｒ^２－Ｘとの求核置換反応により製造することができる。反応条件は、スキーム１と同様の条件で実施可能である。 Compound (V) used as a starting material in Scheme 3 can be produced, for example, by the method shown in Scheme 15.

(In the formula, R ¹ , R ² and Z are defined as above, R ³ represents a lower alkyl group, PG represents a protecting group, and X represents a halogen.)
When R ² is an optionally substituted aryl group or an optionally substituted heteroaryl group, compound (V) can be produced by deprotecting the protecting group of compound (XIX) and then subjecting the resulting compound to a coupling reaction such as Ullmann condensation reaction or Buchwald-Hartwig reaction with compound R ² -X. The reaction conditions can be the same as those in Scheme 1.
Compound (V) can also be produced by a Chan-Lam-Evans coupling reaction using a compound in which the halogen X of compound R ² -X is converted to a boronic acid or a boronic acid ester thereof.
When R ² is an alkynyl group which may have a substituent, compound (V) can be produced by deprotecting the protecting group of compound (XIX) and then subjecting it to a nucleophilic substitution reaction with compound R ² -X. The reaction can be carried out under the same reaction conditions as in Scheme 1.

（式中、Ｒ^１及びＺは前記と同義であり、Ｒ^３は低級アルキル基を表わし、ＰＧは保護基を表わし、Ｘはハロゲンを表わす。）
　化合物（ＸＩＸ）は、化合物（ＸＩ）と化合物（ＶＩＩ）を用いて、鈴木カップリング反応などのクロスカップリング反応により製造することができる。当該クロスカップリング反応は、スキーム４と同様の条件で実施することができる。また化合物（ＶＩＩ）のボロニル基は、ボロン酸エステル基に置き換えて反応に使用することもできる。 Compound (XIX) used as the starting material in Scheme 15 can be produced, for example, by the method shown in Scheme 16.

(In the formula, ^R1 and Z are defined as above, ^R3 represents a lower alkyl group, PG represents a protecting group, and X represents a halogen.)
Compound (XIX) can be produced by a cross-coupling reaction such as Suzuki coupling reaction using compound (XI) and compound (VII). The cross-coupling reaction can be carried out under the same conditions as in Scheme 4. The boronyl group of compound (VII) can also be replaced with a boronic acid ester group for use in the reaction.

（式中、Ｒ^２及びＺは前記と同義であり、ＰＧは保護基を表わし、Ｘはハロゲンを表わす。）
　Ｒ^２が置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基の場合、化合物（ＶＩ）は、化合物（Ｘ）の保護基を脱保護したのち、化合物Ｒ^２－ＸとのＵｌｌｍａｎｎ縮合反応あるいはＢｕｃｈｗａｌｄ－Ｈａｒｔｗｉｇ反応などのカップリング反応により製造することができる。反応条件は、スキーム１と同様の条件で実施可能である。
　また、化合物Ｒ^２－ＸのハロゲンＸをボロン酸もしくはそのボロン酸エステルに変換した化合物を用いたＣｈａｎ－Ｌａｍ－Ｅｖａｎｓカップリング反応によっても化合物（ＶＩ）を製造することができる。
Ｒ^２が置換基を有してもよいアルキニル基である場合、化合物（ＶＩ）は、化合物（Ｘ）の保護基を脱保護したのち、化合物Ｒ^２－Ｘとの求核置換反応により製造することができる。反応条件は、スキーム１と同様の条件で実施可能である。 Compound (VI) used as the starting material in Scheme 4 can be produced, for example, by the method shown in Scheme 17.

(In the formula, ^R2 and Z are defined as above, PG represents a protecting group, and X represents a halogen.)
When R ² is an optionally substituted aryl group or an optionally substituted heteroaryl group, compound (VI) can be produced by deprotecting the protecting group of compound (X) and then subjecting the compound to a coupling reaction such as Ullmann condensation reaction or Buchwald-Hartwig reaction with compound R ² -X. The reaction conditions can be the same as those in Scheme 1.
Compound (VI) can also be produced by a Chan-Lam-Evans coupling reaction using a compound in which the halogen X of compound R ² -X is converted into a boronic acid or a boronic acid ester thereof.
When R ² is an alkynyl group which may have a substituent, compound (VI) can be produced by deprotecting the protecting group of compound (X) and then subjecting the compound to a nucleophilic substitution reaction with compound R ² -X. The reaction can be carried out under the same reaction conditions as in Scheme 1.

（式中、Ｒ^２及びＺは前記と同義であり、Ｒ^６は低級アルキルを表わす。）
　化合物（ＶＩＩＩ）は、化合物（ＸＸ）のエステル基を加水分解することにより製造できる。加水分解反応は、有機化学で一般的に用いられる反応条件で実施することができ、アルカリ性条件（水酸化ナトリウム、水酸化リチウムなど）もしくは酸性条件（塩酸、硫酸など）を用いることができる。 Compound (VIII) used as the starting material in Scheme 5 can be produced, for example, by the method shown in Scheme 18.

(In the formula, ^R2 and Z are as defined above, and ^R6 represents lower alkyl.)
Compound (VIII) can be produced by hydrolyzing the ester group of compound (XX). The hydrolysis reaction can be carried out under reaction conditions generally used in organic chemistry, and alkaline conditions (sodium hydroxide, lithium hydroxide, etc.) or acidic conditions (hydrochloric acid, sulfuric acid, etc.) can be used.

（式中、Ｒ^２及びＺは前記と同義であり、Ｒ^６は低級アルキルを表わし、Ｘはハロゲンを表わす。）
　Ｒ^２が置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基の場合、化合物（ＸＸ）は、化合物（ＸＸＩ）の保護基を脱保護した後、化合物Ｒ^２－ＸとのＵｌｌｍａｎｎ縮合反応あるいはＢｕｃｈｗａｌｄ－Ｈａｒｔｗｉｇ反応などのカップリング反応により製造することができる。反応条件は、スキーム１と同様の条件で実施可能である。
　また、化合物Ｒ^２－ＸのハロゲンＸをボロン酸もしくはそのボロン酸エステルに変換した化合物を用いたＣｈａｎ－Ｌａｍ－Ｅｖａｎｓカップリング反応によっても化合物（ＸＸ）を製造することができる。
Ｒ^２が置換基を有してもよいアルキニル基である場合、化合物（ＸＸ）は、化合物（ＸＸＩ）の保護基を脱保護した後、化合物Ｒ^２－Ｘとの求核置換反応により製造することができる。反応条件は、スキーム１と同様の条件で実施可能である。 Compound (XX) used as the starting material in Scheme 18 can be produced, for example, by the method shown in Scheme 19.

(In the formula, ^R2 and Z are as defined above, ^R6 represents lower alkyl, and X represents halogen.)
When R ² is an optionally substituted aryl group or an optionally substituted heteroaryl group, compound (XX) can be produced by deprotecting the protecting group of compound (XXI) and then subjecting the compound to a coupling reaction such as Ullmann condensation reaction or Buchwald-Hartwig reaction with compound R ² -X. The reaction can be carried out under the same reaction conditions as in Scheme 1.
Compound (XX) can also be produced by a Chan-Lam-Evans coupling reaction using a compound in which the halogen X of compound R ² -X is converted to a boronic acid or a boronic acid ester thereof.
When ^R2 is an alkynyl group which may have a substituent, compound (XX) can be produced by deprotecting the protecting group of compound (XXI) and then subjecting the compound to a nucleophilic substitution reaction with compound ^R2 -X. The reaction can be carried out under the same reaction conditions as in Scheme 1.

（式中、Ｚは前記と同義であり、Ｒ^６は低級アルキルを表わし、ＰＧは保護基を表わし、Ｘはハロゲンを表わす。）
　化合物（ＸＸＩ）は、化合物（Ｘ）と化合物（ＸＸＩＩ）を用いて、鈴木カップリング反応などのクロスカップリング反応により製造することができる。当該クロスカップリング反応は、スキーム４と同様の条件で実施することができる。また化合物（ＸＸＩＩ）のボロニル基は、ボロン酸エステル基に置き換えて反応に使用することもできる。 Compound (XXI) used as the starting material in Scheme 19 can be produced, for example, by the method shown in Scheme 20.

(In the formula, Z is as defined above, ^R6 represents a lower alkyl group, PG represents a protecting group, and X represents a halogen.)
Compound (XXI) can be produced by a cross-coupling reaction such as Suzuki coupling reaction using compound (X) and compound (XXII). The cross-coupling reaction can be carried out under the same conditions as in Scheme 4. In addition, the boronyl group of compound (XXII) can be replaced with a boronic acid ester group and used in the reaction.

（式中、Ｒ^２及びＺは前記と同義であり、Ｘはハロゲンを表わす。）
　化合物（Ｉ－ｃ）は、化合物（Ｉ－ｄ）を通常の有機化学で用いられるハロゲン化剤、例えばベンジルトリメチルアンモニウムジクロロヨージド、ＮＢＳ、ＮＣＳなどで処理することで製造することができる。すなわち、化合物（Ｉ－ｃ）は、溶媒中、化合物（Ｉ－ｄ）と、０．５～５．０モル当量、好ましくは０．８～２．０モル当量のハロゲン化剤を反応させることによって得ることができる。溶媒は反応に不活性なものであればいずれでも良く、特に限定されるものではなく、ジクロロメタン、ＴＨＦ、ＤＭＦなどを用いることができる。反応は－２０～１００℃において、０．２５～１０時間撹拌することで実施することができるが、好ましくは室温～８０℃において０．５～５時間撹拌することで実施することができる。
　なお、上記の方法を適宜組み合わせ、有機合成化学で通常用いられる方法（例えば、アミノ基のアルキル化反応、アルキルチオ基をスルホキシド基もしくはスルホン基へ酸化する反応、アルコキシ基をヒドロキシル基、もしくはその逆へ変換する反応）を実施することにより、所望の位置に所望の官能基を有する本発明の化合物（Ｉ）を得ることができる。 The compound (Ic) of the present invention used as the starting material in Scheme 6 can be produced from the compound (Id) of the present invention, which is represented by formula (I) in which R ¹ is a methyl group, by, for example, the method shown in Scheme 21.

(In the formula, ^R2 and Z are defined as above, and X represents a halogen.)
Compound (I-c) can be produced by treating compound (I-d) with a halogenating agent used in ordinary organic chemistry, such as benzyltrimethylammonium dichloroiodide, NBS, NCS, etc. That is, compound (I-c) can be obtained by reacting compound (I-d) with 0.5 to 5.0 molar equivalents, preferably 0.8 to 2.0 molar equivalents of a halogenating agent in a solvent. The solvent may be any one inert to the reaction, and is not particularly limited, and dichloromethane, THF, DMF, etc. can be used. The reaction can be carried out by stirring at -20 to 100°C for 0.25 to 10 hours, but preferably at room temperature to 80°C for 0.5 to 5 hours.
In addition, by appropriately combining the above methods and carrying out a method commonly used in organic synthetic chemistry (e.g., alkylation reaction of an amino group, oxidation reaction of an alkylthio group to a sulfoxide group or a sulfone group, conversion of an alkoxy group to a hydroxyl group, or vice versa), it is possible to obtain compound (I) of the present invention having a desired functional group at a desired position.

[Use of compound (I) of the present invention]
The compound (I) of the present invention or a pharma- ceutically acceptable salt thereof can be prepared in the form of a conventional pharmaceutical preparation (pharmaceutical composition) suitable for oral, parenteral or topical administration.
Preparations for oral administration include solid preparations such as tablets, granules, powders, capsules, and liquid preparations such as syrups. These preparations can be prepared by conventional methods. Solid preparations can be prepared by using conventional pharmaceutical carriers such as lactose, starch such as corn starch, crystalline cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose, talc, magnesium stearate, etc. Capsules can be prepared by encapsulating the granules or powders thus prepared. Syrups can be prepared by dissolving or suspending the compound (I) of the present invention or a pharma- ceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethyl cellulose, etc.
Preparations for parenteral administration include injections such as drip infusions. Injection preparations can also be prepared by conventional methods, and can be appropriately incorporated into isotonic agents (e.g., mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose), stabilizers (e.g., sodium sulfite, albumin), and preservatives (e.g., benzyl alcohol, methyl p-oxybenzoate).
The dose of the compound (I) of the present invention or a pharma- ceutically acceptable salt thereof can be varied according to the severity of the disease, the age and body weight of the patient, the dosage form, etc., but is usually in the range of 1 mg to 1,000 mg per day for an adult, which can be administered orally or parenterally in a single dose, or in two or three divided doses.
In addition, the compound (I) of the present invention or a pharma- ceutical acceptable salt thereof can be used as an ALK5 inhibitor and as a reagent for experiments and research. Furthermore, the compound (I) of the present invention that is radiolabeled can also be used as a molecular probe for PET.

The present invention will be explained in more detail below by way of examples and test examples, but the present invention is not limited to these examples.
Compounds were identified by hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectroscopy (MS). ¹ H-NMR was measured at 400 MHz unless otherwise specified, and exchangeable hydrogen may not be clearly observed depending on the compound and measurement conditions. Note that br. means broad signal (broad). For HPLC preparative chromatography, a commercially available ODS column was used, and unless otherwise specified, separation was performed in gradient mode using water/methanol (containing formic acid) as the eluent.

（第１工程）
１－[１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル]チオ尿素

　１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－アミン（８０ｇ，４７９ｍｍｏｌ）のジクロロメタン溶液（７５０ｍＬ）に、０℃でチオホスゲン（３６．７ｍＬ，４７９ｍｍｏｌ）とＤＩＰＥＡ（４１．８ｍＬ，２３９．５ｍｍｏｌ）を加え、混合物を室温で２時間撹拌した。反応混合物を減圧下で濃縮し、４－イソチオシアナート－１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール（８０ｇ）を得た。得られた化合物（８０ｇ，３８２ｍｍｏｌ）のジクロロメタン溶液（７５０ｍＬ）に、０℃で濃アンモニア水溶液（２５０ｍＬ）を滴下し、混合物を室温で３時間撹拌した。反応混合物に水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（シリカゲル、酢酸エチル）で精製し、標記化合物（３３ｇ）を得た。
LCMS (m/z): 227.2 [M+H]⁺. Reference Example 1
Preparation of 5-bromo-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxamide

(First step)
1-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]thiourea

Thiophosgene (36.7 mL, 479 mmol) and DIPEA (41.8 mL, 239.5 mmol) were added to a dichloromethane solution (750 mL) of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine (80 g, 479 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 4-isothiocyanato-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (80 g). A concentrated aqueous ammonia solution (250 mL) was added dropwise to a dichloromethane solution (750 mL) of the obtained compound (80 g, 382 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to obtain the title compound (33 g).
LCMS (m/z): 227.2 [M+H] ⁺ .

　第１工程を繰り返し得られた１－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］チオ尿素（６５ｇ，２８７．６ｍｍｏｌ）のエタノール溶液（２００ｍＬ）に、０℃で炭酸カリウム（１１９．１ｇ，８６２．８ｍｍｏｌ）および３－ブロモ－２－オキソプロパン酸（８４．１ｇ，４３１．４ｍｍｏｌ）を加え、混合物を室温で１６時間撹拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲル、酢酸エチル）で精製し、標記化合物（６０ｇ）を得た。
LC-MS (m/z): 323.3 [M+H]⁺. (Second step)
2-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate ethyl

To an ethanol solution (200 mL) of 1-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]thiourea (65 g, 287.6 mmol) obtained by repeating the first step, potassium carbonate (119.1 g, 862.8 mmol) and 3-bromo-2-oxopropanoic acid (84.1 g, 431.4 mmol) were added at 0° C., and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to obtain the title compound (60 g).
LC-MS (m/z): 323.3 [M+H] ⁺ .

　２－｛［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボン酸エチル（３０ｇ，９３．２ｍｍｏｌ）の１，２－ジクロロエタン溶液（５００ｍＬ）にシクロプロピルボロン酸 （３９．６ｇ，４６５．８ｍｍｏｌ）、酢酸銅（ＩＩ）（３３．７ｇ，１８６．３ｍｍｏｌ）、２，２’－ビピリジン（１７．４ｇ，１１１．８ｍｍｏｌ）および炭酸ナトリウム（１９．８ｇ，１８６．３ｍｍｏｌ）を室温で加え、混合物を酸素雰囲気下、５０℃で２時間撹拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲル、石油エーテル／酢酸エチル）で精製し、標記化合物（１７ｇ）を得た。
LC-MS (m/z): 363.2 [M+H]⁺. (Third process)
2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate ethyl

Cyclopropylboronic acid (39.6 g, 465.8 mmol), copper(II) acetate (33.7 g, 186.3 mmol), 2,2'-bipyridine (17.4 g, 111.8 mmol) and sodium carbonate (19.8 g, 186.3 mmol) were added to a 1,2-dichloroethane solution (500 mL) of ethyl 2-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate (30 g, 93.2 mmol), and the mixture was stirred at 50°C for 2 hours under an oxygen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to obtain the title compound (17 g).
LC-MS (m/z): 363.2 [M+H] ⁺ .

　第３工程を繰り返し得られた２－｛シクロプロピル［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボン酸エチル（３５ｇ，９６．７ｍｍｏｌ）のジクロロメタン溶液（５００ｍＬ）に、０℃でＮＢＳ（１３．８ｇ，７７．４ｍｍｏｌ）を加え、混合物を０℃で２時間撹拌した。反応混合物に氷水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（シリカゲル、石油エーテル／酢酸エチル）で精製し、標記化合物（２２ｇ）を得た。
¹H-NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 0.8 Hz, 1H), 7.75 (d, J = 0.8 Hz, 1H), 5.37 (dd, J = 9.6, 2.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.11 - 4.00 (m, 1H), 3.76 - 3.62 (m, 1H), 3.04 - 2.91 (m, 1H), 2.24 - 1.96 (m, 3H), 1.84 - 1.52 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H), 1.35 - 1.17 (m, 2H), 1.15 - 1.04 (m, 2H), 0.96 - 0.90 (m, 2H); LC-MS (m/z): 443.1 ([M+2+H]⁺, isotopic mass). (Fourth step)
5-Bromo-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate ethyl

NBS (13.8 g, 77.4 mmol) was added to a dichloromethane solution (500 mL) of ethyl 2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate (35 g, 96.7 mmol) obtained by repeating the third step, and the mixture was stirred at 0° C. for 2 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to obtain the title compound (22 g).
^1H -NMR (500 MHz, _CDCl3 ) δ 8.22 (d, J = 0.8 Hz, 1H), 7.75 (d, J = 0.8 Hz, 1H), 5.37 (dd, J = 9.6, 2.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.11 - 4.00 (m, 1H), 3.76 - 3.62 (m, 1H), 3.04 - 2.91 (m, 1H), 2.24 - 1.96 (m, 3H), 1.84 - 1.52 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H), 1.35 - 1.17 (m, 2H), 1.15 - 1.04 (m, 2H), 0.96 - 0.90 (m, 2H); LC-MS (m/z): 443.1 ([M+2+H] ⁺ , isotopic mass).

(Fifth step)
Preparation of 5-bromo-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxamide Concentrated aqueous ammonia (10 mL) was added to an ethanol solution (10 mL) of ethyl 5-bromo-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate (1 g, 2.7 mmol), and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.82 g).
^1H -NMR (DMSO-d6) δ 8.27 (d, J = 0.8 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 7.61 - 7.47 (m, 2H), 5.39 (dd, J = 10.1, 2.5 Hz, 1H), 3.99 - 3.80 (m, 1H), 3.70 - 3.49 (m, 1H), 3.14 - 2.96 (m, 1H), 2.26 - 2.05 (m, 1H), 2.01 - 1.81 (m, 2H), 1.76 - 1.58 (m, 1H), 1.59 - 1.44 (m, 2H), 1.14 - 1.01 (m, 2H), 0.84 - 0.69 (m, 2H); LC-MS (m/z): 412.1 ([M+2+H] ⁺ , isotopic mass).

　１－（１Ｈ－ピロール－３－イル）エタン－１－オン（２００ｍｇ，１．８ｍｍｏｌ）と４，４，４’，４’，５，５，５’，５’－オクタメチル－２，２’－ビ（１，３，２－ジオキサボロラン）（２３３ｍｇ，０．９２ｍｍｏｌ）および４，４’－ジ－ｔｅｒｔ－ブチル－２，２’－ビピリジン（７．４ｍｇ，０．０２７ｍｍｏｌ）のシクロヘキサン溶液（３ｍＬ）に、(１，５－シクロオクタジエン）（メトキシ）イリジウム（Ｉ）（ダイマー）（９．４ｍｇ，０．０１４ｍｍｏｌ）を室温で加えて、混合物を９０℃で６時間攪拌した。反応混合物を室温まで冷却し、析出した固体をろ取し、ｎ－ヘキサンと水で洗浄して、標記化合物（２７０ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 11.81 (s, 1H), 7.62 (dd, J = 3.2, 1.5 Hz, 1H), 6.95 - 6.91 (m, 1H), 2.32 (s, 3H), 1.28 (s, 12H); LC-MS (m/z): 236.2 [M+H]⁺. Reference Example 2
Preparation of 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-3-yl]ethanone

1-(1H-pyrrol-3-yl)ethan-1-one (200 mg, 1.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (233 mg, 0.92 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (7.4 mg, 0.027 mmol) were added to a cyclohexane solution (3 mL) at room temperature, and the mixture was stirred at 90° C. for 6 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with n-hexane and water to obtain the title compound (270 mg).
^1H -NMR (DMSO-d6) δ 11.81 (s, 1H), 7.62 (dd, J = 3.2, 1.5 Hz, 1H), 6.95 - 6.91 (m, 1H), 2.32 (s, 3H), 1.28 (s, 12H); LC-MS (m/z): 236.2 [M+H] ⁺ .

　１Ｈ－ピロール－３－カルボン酸メチル（２５０ｍｇ，２ｍｍｏｌ）と４，４，４’，４’，５，５，５’，５’－オクタメチル－２，２’－ビ（１，３，２－ジオキサボロラン）（２５４ｍｇ，１ｍｍｏｌ）および４，４’－ジ－ｔｅｒｔ－ブチル－２，２’－ビピリジン（８ｍｇ，０．０３ｍｍｏｌ）のシクロヘキサン溶液（３ｍＬ）に(１，５－シクロオクタジエン）（メトキシ）イリジウム（Ｉ）（ダイマー）（９．９ｍｇ，０．０１５ｍｍｏｌ）を室温で加えて、混合物を９０℃で２時間攪拌した。反応混合物を室温まで冷却し、析出した固体をろ取、ｎ－ヘキサンと水で洗浄し、標記化合物（３１４ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 11.84 (s, 1H), 7.48 (dd, J = 3.2, 1.4 Hz, 1H), 6.88 (dd, J = 2.5, 1.4 Hz, 1H), 3.69 (s, 3H), 1.27 (s, 12H); LC-MS (m/z): 252.2 [M+H]⁺. Reference Example 3
Preparation of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate

To a cyclohexane solution (3 mL) of 1H-pyrrole-3-methyl carboxylate (250 mg, 2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (254 mg, 1 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (8 mg, 0.03 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I)(dimer) (9.9 mg, 0.015 mmol) was added at room temperature, and the mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with n-hexane and water to obtain the title compound (314 mg).
^1H -NMR (DMSO-d6) δ 11.84 (s, 1H), 7.48 (dd, J = 3.2, 1.4 Hz, 1H), 6.88 (dd, J = 2.5, 1.4 Hz, 1H), 3.69 (s, 3H), 1.27 (s, 12H); LC-MS (m/z): 252.2 [M+H] ⁺ .

　５－ブロモ－２－（シクロプロピル（１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル）アミノ）チアゾール－４－カルボキサミド（参考例１）（５．０ｇ，１２．２ｍｍｏｌ）と５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－１Ｈ－ピロール－３－カルボン酸メチル（参考例３）（４．５ｇ，１８．２ｍｍｏｌ）の１，４－ジオキサン／水の混合液（１００ｍＬ／１０ｍＬ）に、ジクロロビス［ジ‐ｔｅｒｔ‐ブチル（４‐ジメチルアミノフェニル）ホスフィン］パラジウム（ＩＩ）（８５６ｍｇ，１．２２ｍｍｏｌ）とフッ化セシウム（３．６５ｇ，２４．３ｍｍｏｌ）を加え、混合物を窒素気流下、１００℃で２時間攪拌した。反応混合物を室温まで冷却後、水を加えて析出した固体をろ取し、標記化合物（５ｇ）を得た。
¹H-NMR (DMSO-d₆) δ 13.25 (br.s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.83 - 7.80 (m, 2H), 7.59 (t, J = 0.8 Hz, 1H), 6.67 (m. 1H), 5.40 (m, 1H), 3.86 (d, J = 4.3 Hz, 1H), 3.71 (s, 3H), 3.68 - 3.61 (m, 2H), 2.21 - 2.03 (m, 2H), 1.94 - 1.88 (m, 2H), 1.55 - 1.35 (m, 2H), 1.16 - 1.10 (m, 2H), 0.82 - 0.77 (m, 2H); LC-MS (m/z): 457.1 [M+H]⁺. Reference Example 4
Preparation of methyl 5-(4-carbamoyl-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazol-5-yl)-1H-pyrrole-3-carboxylate

To a mixture (100 mL/10 mL) of 5-bromo-2-(cyclopropyl(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino)thiazole-4-carboxamide (Reference Example 1) (5.0 g, 12.2 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-methyl carboxylate (Reference Example 3) (4.5 g, 18.2 mmol) in 1,4-dioxane/water, dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) (856 mg, 1.22 mmol) and cesium fluoride (3.65 g, 24.3 mmol) were added, and the mixture was stirred at 100° C. for 2 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, water was added, and the precipitated solid was collected by filtration to obtain the title compound (5 g).
^1H -NMR (DMSO- _d6 ) δ 13.25 (br.s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.83 - 7.80 (m, 2H), 7.59 (t, J = 0.8 Hz, 1H), 6.67 (m. 1H), 5.40 (m, 1H), 3.86 (d, J = 4.3 Hz, 1H), 3.71 (s, 3H), 3.68 - 3.61 (m, 2H), 2.21 - 2.03 (m, 2H), 1.94 - 1.88 (m, 2H), 1.55 - 1.35 (m, 2H), 1.16 - 1.10 (m, 2H), 0.82 - 0.77 (m, 2H); LC-MS (m/z): 457.1 [M+H] ⁺ .

　５－（４－カルバモイル－２－｛シクロプロピル［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－５－イル）－１Ｈ－ピロール－３－カルボン酸メチル（参考例４）（５ｇ，１０．９ｍｍｏｌ）の１，４－ジオキサン（５０ｍＬ）溶液に、塩化水素・１，４－ジオキサン溶液（約４ｍｏｌ／Ｌ）（５０ｍＬ）を加え、室温で１６時間攪拌した。溶媒を減圧留去し、標記化合物（４ｇ）を得た。
¹H-NMR (DMSO-d₆) δ 13.24 (br.s, 1H), 12.86 (br.s, 1H), 8.01 - 7.81 (m, 3H), 7.58 (br.s, 1H), 7.25 - 7.16 (m, 1H), 6.65 (s, 1H), 3.71 (s, 3H), 3.16 - 3.14 (m, 1H), 1.08 - 1.05 (m, 2H), 0.86 - 0.76 (m, 2H); LC-MS (m/z): 373.2 [M+H]⁺. Reference Example 5
Preparation of methyl 5-{4-carbamoyl-2-[cyclopropyl(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-carboxylate

To a solution of 5-(4-carbamoyl-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazol-5-yl)-1H-pyrrole-3-methyl carboxylate (Reference Example 4) (5 g, 10.9 mmol) in 1,4-dioxane (50 mL), hydrogen chloride-1,4-dioxane solution (about 4 mol/L) (50 mL) was added and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure to obtain the title compound (4 g).
^1H -NMR (DMSO- _d6 ) δ 13.24 (br.s, 1H), 12.86 (br.s, 1H), 8.01 - 7.81 (m, 3H), 7.58 (br.s, 1H), 7.25 - 7.16 (m, 1H), 6.65 (s, 1H), 3.71 (s, 3H), 3.16 - 3.14 (m, 1H), 1.08 - 1.05 (m, 2H), 0.86 - 0.76 (m, 2H); LC-MS (m/z): 373.2 [M+H] ⁺ .

　５－｛４－カルバモイル－２－［シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ］チアゾール－５－イル｝－１Ｈ－ピロール－３－カルボン酸メチル（参考例５）（０．７８ｇ，２．１ｍｍｏｌ）のメタノール溶液（７ｍＬ）に４Ｍ水酸化ナトリウム水溶液（７ｍＬ）を加え、混合物を７０℃で３時間攪拌した。反応混合物に濃塩酸を加えて酸性にし、析出した固体をろ取し、標記化合物（０．５４ｇ）を得た。
¹H-NMR (DMSO-d₆) δ 13.18 (br.s, 1H), 8.00 - 7.94 (m, 3H), 7.77 (br.s, 1H), 7.52 - 7.48 (m, 1H), 6.60 (t, J = 0.4 Hz, 1H), 3.19 - 3.12 (m, 1H), 1.23 - 1.12 (m, 2H), 0.85 - 0.76 (m, 2H); LC-MS (m/z): 359.1 [M+H]⁺. Reference Example 6
Preparation of 5-{4-carbamoyl-2-[cyclopropyl(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-carboxylic acid

A 4M aqueous sodium hydroxide solution (7 mL) was added to a methanol solution (7 mL) of methyl 5-{4-carbamoyl-2-[cyclopropyl(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-carboxylate (Reference Example 5) (0.78 g, 2.1 mmol), and the mixture was stirred for 3 hours at 70° C. The reaction mixture was acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration to obtain the title compound (0.54 g).
^1H -NMR (DMSO- _d6 ) δ 13.18 (br.s, 1H), 8.00 - 7.94 (m, 3H), 7.77 (br.s, 1H), 7.52 - 7.48 (m, 1H), 6.60 (t, J = 0.4 Hz, 1H), 3.19 - 3.12 (m, 1H), 1.23 - 1.12 (m, 2H), 0.85 - 0.76 (m, 2H); LC-MS (m/z): 359.1 [M+H] ⁺ .

　５－｛４－カルバモイル－２－［シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ］チアゾール－５－イル｝－１Ｈ－ピロール－３－カルボン酸（参考例６）（２ｇ，５．５９ｍｏｌ）のＤＭＦ溶液（１０ｍＬ）に、ジメチルアミン塩酸塩（０．９１ｇ，１１．１７ｍｏｌ）及びＥＤＣ・ＨＣｌ（２．１４ｇ，１１．１７ｍｏｌ）を加え、室温で３時間攪拌した。反応混合物を水で希釈し、析出した固体をろ取し、標記化合物（０．９ｇ）を得た。
¹H-NMR (500 MHz, DMSO-d₆) δ 13.08 (br.s, 1H), 12.79 (br.s, 1H), 8.16 (s, 1H), 7.96 (br.s, 1H), 7.74 (d, J = 9.8 Hz, 2H), 7.33 (dd, J = 1.5, 2.7 Hz, 1H), 6.55 (dd, J = 1.7, 2.3 Hz, 1H), 3.18 - 3.14 (m, 1H), 3.13 - 2.95 (m, 6H), 1.11 - 1.01 (m, 2H), 0.82 - 0.75 (m, 2H); LC-MS (m/z): 386.1 [M+H]⁺. Reference Example 7
Preparation of 2-[cyclopropyl(1H-pyrazol-4-yl)amino]-5-[4-(dimethylcarbamoyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide

Dimethylamine hydrochloride (0.91 g, 11.17 mol) and EDC.HCl (2.14 g, 11.17 mol) were added to a DMF solution (10 mL) of 5-{4-carbamoyl-2-[cyclopropyl(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-carboxylic acid (Reference Example 6) (2 g, 5.59 mol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the precipitated solid was collected by filtration to obtain the title compound (0.9 g).
^1H -NMR (500 MHz, DMSO- _d6 ) δ 13.08 (br.s, 1H), 12.79 (br.s, 1H), 8.16 (s, 1H), 7.96 (br.s, 1H), 7.74 (d, J = 9.8 Hz, 2H), 7.33 (dd, J = 1.5, 2.7 Hz, 1H), 6.55 (dd, J = 1.7, 2.3 Hz, 1H), 3.18 - 3.14 (m, 1H), 3.13 - 2.95 (m, 6H), 1.11 - 1.01 (m, 2H), 0.82 - 0.75 (m, 2H); LC-MS (m/z): 386.1 [M+H] ⁺ .

　５－｛４－カルバモイル－２－［シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ］チアゾール－５－イル｝－１Ｈ－ピロール－３－カルボン酸（参考例６）（２ｇ，５．５９ｍｏｌ）のＤＭＦ溶液（１０ｍＬ）にモルホリン（０．９７ｇ，１１．１７ｍｏｌ）、ＨＡＴＵ（４．２４ｇ，１１．１７ｍｏｌ）及びＤＩＰＥＡ（１．９４ｍｌ，１１．１７ｍｏｌ）を加え、室温で一晩攪拌した。混合物を水で希釈し、析出した固体をろ取した。固体をカラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、標記化合物（０．８ｇ）を得た。
¹H-NMR (DMSO-d6) δ 13.0 (br.s, 1H), 8.23 - 8.16 (m, 2H), 7.80 (s, 2H), 7.38 (d, J = 9.7 Hz, 1H), 7.13 (t, J = 9.7 Hz, 1H), 6.56 (dd, J = 1.7, 2.3 Hz, 1H), 4.11 - 4.07 (m, 1H), 3.60 - 3.41 (m, 8H), 1.22 - 1.05 (m, 2H), 0.90 - 0.89 (m, 2H); LC-MS (m/z): 428.2 [M+H]⁺. Reference Example 8
Preparation of 2-[cyclopropyl(1H-pyrazol-4-yl)amino]-5-[4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide

Morpholine (0.97 g, 11.17 mol), HATU (4.24 g, 11.17 mol) and DIPEA (1.94 ml, 11.17 mol) were added to a DMF solution (10 mL) of 5-{4-carbamoyl-2-[cyclopropyl(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-carboxylic acid (Reference Example 6) (2 g, 5.59 mol), and the mixture was stirred at room temperature overnight. The mixture was diluted with water, and the precipitated solid was collected by filtration. The solid was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (0.8 g).
^1H -NMR (DMSO-d6) δ 13.0 (br.s, 1H), 8.23 - 8.16 (m, 2H), 7.80 (s, 2H), 7.38 (d, J = 9.7 Hz, 1H), 7.13 (t, J = 9.7 Hz, 1H), 6.56 (dd, J = 1.7, 2.3 Hz, 1H), 4.11 - 4.07 (m, 1H), 3.60 - 3.41 (m, 8H), 1.22 - 1.05 (m, 2H), 0.90 - 0.89 (m, 2H); LC-MS (m/z): 428.2 [M+H] ⁺ .

　５－ブロモ－２－｛シクロプロピル［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボキサミド（参考例１）（５ｇ，１２．２ｍｍｏｌ）と１－［５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－１Ｈ－ピロール－３－イル］エタノン（参考例２）（４．２８ｇ，１８．２５ｍｍｏｌ）の１，４－ジオキサン／水の混合液（１００ｍＬ／１０ｍＬ）に、ジクロロビス［ジ‐ｔｅｒｔ‐ブチル（４‐ジメチルアミノフェニル）ホスフィン］パラジウム（ＩＩ）（８６１ｍｇ，１．２２ｍｍｏｌ）とフッ化セシウム（３．６５ｇ，２４．３ｍｍｏｌ）を加え、混合物を窒素気流下、１００℃で２時間攪拌した。反応混合物を室温まで冷却後、溶媒を減圧留去して得られた残渣をカラムクロマトグラフィー（シリカゲル、石油エーテル／酢酸エチル）で精製し、標記化合物（４ｇ）を得た。
¹H-NMR (CDCl₃) δ 13.16 (br.s, 1H), 7.77 (dd, J = 0.7, 14.2 Hz, 2H), 7.44 (dd, J = 1.6, 3.1 Hz, 1H), 7.36 (br.s, 1H), 6.83 (dd, J = 1.5, 2.2 Hz, 1H), 5.64 (d, J = 3.2 Hz, 1H), 5.37 (dd, J = 3.7, 8.6 Hz, 1H), 4.12 - 4.05 (m, 1H), 3.78 - 3.68 (m, 1H), 3.06 - 3.01 (m, 1H), 2.43 (s, 3H), 2.17 - 2.01 (m, 3H), 1.76 - 1.62 (m, 3H), 1.11 - 1.01 (m, 2H), 0.94 - 0.88 (m, 2H); LC-MS(m/z): 441.08 [M+H]⁺. Reference Example 9
Preparation of 5-(4-acetyl-1H-pyrrol-2-yl)-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxamide

5-Bromo-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxamide (Reference Example 1) (5 g, 12.2 mmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-3-yl]ethanone (Reference Example 2) (4.28 g, 18.25 mmol) in 1,4-dioxane/water mixture (100 mL/10 mL) were added dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) (861 mg, 1.22 mmol) and cesium fluoride (3.65 g, 24.3 mmol), and the mixture was stirred at 100° C. for 2 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to obtain the title compound (4 g).
^1H -NMR ( _CDCl3 ) δ 13.16 (br.s, 1H), 7.77 (dd, J = 0.7, 14.2 Hz, 2H), 7.44 (dd, J = 1.6, 3.1 Hz, 1H), 7.36 (br.s, 1H), 6.83 (dd, J = 1.5, 2.2 Hz, 1H), 5.64 (d, J = 3.2 Hz, 1H), 5.37 (dd, J = 3.7, 8.6 Hz, 1H), 4.12 - 4.05 (m, 1H), 3.78 - 3.68 (m, 1H), 3.06 - 3.01 (m, 1H), 2.43 (s, 3H), 2.17 - 2.01 (m, 3H), 1.76 - 1.62 (m, 3H), 1.11 - 1.01 (m, 2H), 0.94 - 0.88 (m, 2H); LC-MS(m/z): 441.08 [M+H] ⁺ .

　５－（４－アセチル－１Ｈ－ピロール－２－イル）－２－｛シクロプロピル［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボキサミド（参考例９）（１．５ｇ，３．４１ｍｍｏｌ）の１，４－ジオキサン（１５ｍＬ）溶液に、塩化水素・１，４－ジオキサン溶液（約４ｍｏｌ／Ｌ）（１０ｍＬ）を加え、室温で４時間攪拌した。溶媒を減圧留去し、標記化合物（１ｇ）を得た。
¹H-NMR (DMSO-d₆) δ 13.27 (br.s, 1H), 12.80 (br.s, 1H), 8.16 (br.s, 1H), 8.00 (s, 1H), 7.76 (br.s, 2H), 7.68 (dd, J = 1.6, 2.8 Hz, 1H), 6.68 (s, 1H), 3.22 - 3.13 (m, 1H), 2.33 (s, 3H), 1.13 - 1.01 (m, 2H), 0.83 - 0.76 (m, 2H); LC-MS(m/z): 357.09 [M+H]⁺. Reference Example 10
Preparation of 5-(4-acetyl-1H-pyrrol-2-yl)-2-[cyclopropyl(1H-pyrazol-4-yl)amino)thiazole-4-carboxamide

To a solution of 5-(4-acetyl-1H-pyrrol-2-yl)-2-{cyclopropyl[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxamide (Reference Example 9) (1.5 g, 3.41 mmol) in 1,4-dioxane (15 mL), hydrogen chloride-1,4-dioxane solution (about 4 mol/L) (10 mL) was added and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure to obtain the title compound (1 g).
^1H -NMR (DMSO- _d6 ) δ 13.27 (br.s, 1H), 12.80 (br.s, 1H), 8.16 (br.s, 1H), 8.00 (s, 1H), 7.76 (br.s, 2H), 7.68 (dd, J = 1.6, 2.8 Hz, 1H), 6.68 (s, 1H), 3.22 - 3.13 (m, 1H), 2.33 (s, 3H), 1.13 - 1.01 (m, 2H), 0.83 - 0.76 (m, 2H); LC-MS(m/z): 357.09 [M+H] ⁺ .

　５－（４－アセチル－１Ｈ－ピロール－２－イル）－２－［シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ］チアゾール－４－カルボキサミド（参考例１０）（１．８５ｇ，５．１９１ｍｍｏｌ）と３－フルオロ－４－ヨードピリジン（１．７３ｇ，７．７９ｍｍｏｌ）の１，４－ジオキサン（４０ｍＬ）溶液に、炭酸カリウム（２．１５ｇ，１５．５８ｍｍｏｌ）とヨウ化銅（Ｉ）（０．１９７ｇ，１．０２ｍｍｏｌ）と（１Ｒ，２Ｒ）－Ｎ１，Ｎ２－ジメチルシクロヘキサン－１，２－ジアミン（０．２９５ｇ，２．０８ｍｍｏｌ）を加え、混合物を窒素気流下、１３０℃で一晩攪拌した。反応混合物を室温まで冷却後、セライトを用いて固形物をろ過し、ろ液を減圧濃縮した。残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、標記化合物（０．７ｇ）を得た。
¹H-NMR (DMSO-d6) δ13.27 (s, 1H), 8.79 (d, J = 3.7 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 5.3 Hz, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.96 (dd, J = 7.0, 5.3 Hz, 1H), 7.87 (s, 1H), 7.72 (dd, J = 3.1, 1.6 Hz, 1H), 6.77 (dd, J = 2.3, 1.6 Hz, 1H), 2.57 (p, J = 1.9 Hz, 1H), 2.35 (s, 3H), 1.26 - 1.17 (m, 2H), 0.97 - 0.90 (m, 2H); LC-MS (m/z): 452.2 [M+H]⁺. Example 1
Preparation of 5-(4-acetyl-1H-pyrrol-2-yl)-2-{cyclopropyl[1-(3-fluoropyridin-4-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxamide

To a solution of 5-(4-acetyl-1H-pyrrol-2-yl)-2-[cyclopropyl(1H-pyrazol-4-yl)amino]thiazole-4-carboxamide (Reference Example 10) (1.85 g, 5.191 mmol) and 3-fluoro-4-iodopyridine (1.73 g, 7.79 mmol) in 1,4-dioxane (40 mL), potassium carbonate (2.15 g, 15.58 mmol), copper (I) iodide (0.197 g, 1.02 mmol), and (1R, 2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.295 g, 2.08 mmol) were added, and the mixture was stirred overnight under a nitrogen stream at 130° C. After cooling the reaction mixture to room temperature, the solid matter was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (0.7 g).
^1H -NMR (DMSO-d6) δ13.27 (s, 1H), 8.79 (d, J = 3.7 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 5.3 Hz, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.96 (dd, J = 7.0, 5.3 Hz, 1H), 7.87 (s, 1H), 7.72 (dd, J = 3.1, 1.6 Hz, 1H), 6.77 (dd, J = 2.3, 1.6 Hz, 1H), 2.57 (p, J = 1.9 Hz, 1H), 2.35 (s, 3H), 1.26 - 1.17 (m, 2H), 0.97 - 0.90 (m, 2H); LC-MS (m/z): 452.2 [M+H] ⁺ .

　２－（シクロプロピル［１Ｈ－ピラゾール－４－イル］アミノ）－５－（４－［ジメチルカルバモイル］－１Ｈ－ピロール－２－イル）チアゾール－４－カルボキサミド（参考例７）（０．０８ｇ，０．２１ｍｏｌ）のジクロロメタン溶液（４ｍＬ）に（４－フルオロフェニルボロン酸（５８ｍｇ，０．４２ｍｏｌ）、ピリジン（１６４ｍｇ，２．０８ｍｏｌ）及び酢酸銅（ＩＩ）（７５ｍｇ，０．４２ｍｏｌ）を加え、混合液を酸素雰囲気下、室温で一晩攪拌した。溶媒を減圧留去して得られた残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、標記化合物（２３ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 13.08 (s, 1H), 8.80 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.95 - 7.88 (m, 3H), 7.42 - 7.32 (m, 3H), 6.62 (s, 1H), 3.20 (s, 1H), 3.06 (s, 6H), 1.21 - 1.14 (m, 2H), 0.92 - 0.89 (m, 2H); LC-MS (m/z): 480.3 [M+H]⁺. Example 2
Preparation of 2-{cyclopropyl[1-(4-fluorophenyl)-1H-pyrazol-4-yl]amino}-5-[4-(dimethylcarbamoyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide

4-Fluorophenylboronic acid (58 mg, 0.42 mol), pyridine (164 mg, 2.08 mol) and copper (II) acetate (75 mg, 0.42 mol) were added to a dichloromethane solution (4 mL) of 2-(cyclopropyl[1H-pyrazol-4-yl]amino)-5-(4-[dimethylcarbamoyl]-1H-pyrrol-2-yl)thiazole-4-carboxamide (Reference Example 7) (0.08 g, 0.21 mol), and the mixture was stirred overnight at room temperature under an oxygen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (23 mg).
^1H -NMR (DMSO-d6) δ 13.08 (s, 1H), 8.80 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.95 - 7.88 (m, 3H), 7.42 - 7.32 (m, 3H), 6.62 (s, 1H), 3.20 (s, 1H), 3.06 (s, 6H), 1.21 - 1.14 (m, 2H), 0.92 - 0.89 (m, 2H); LC-MS (m/z): 480.3 [M+H] ⁺ .

（第１工程）
５－（４－カルバモイル－２－｛シクロプロピル［１－（４－フルオロ－２－メトキシフェニル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－５－イル）－１Ｈ－ピロール－３－カルボン酸メチル

　５－｛４－カルバモイル－２－［シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ］チアゾール－５－イル｝－１Ｈ－ピロール－３－カルボン酸メチル（参考例５）（１ｇ，２．６９ｍｏｌ）のジクロロメタン溶液（１０ｍＬ）に４－フルオロ－２－メトキシフェニルボロン酸（０．９ｇ，５．３８ｍｏｌ）、ピリジン（６．４ｇ，８０．６４ｍｏｌ）及び酢酸銅（ＩＩ）（０．２４３ｇ，１．３４ｍｏｌ）を加え、混合液を酸素雰囲気下、室温で一晩攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、標記化合物（０．８ｇ）を得た。
¹H-NMR (DMSO-d₆) δ 13.25 (br.s, 1H), 8.54 (s, 1H), 8.08 - 8.03 (m, 2H), 7.77 (br.s, 1H), 7.64 - 7.61 (m, 2H), 7.20 (dd, J = 2.5, 11.0 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.70 (t, J = 1.9 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 3H), 3.22 - 3.17 (m, 1H), 1.20 - 1.12 (m, 2H), 0.91 - 0.87 (m, 2H); LC-MS (M/Z): 497.4 [M+H]⁺. Example 3
Preparation of 2-{cyclopropyl[1-(4-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl]amino}-5-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]-1H-pyrrol-2-yl}thiazole-4-carboxamide

(First step)
5-(4-carbamoyl-2-{cyclopropyl[1-(4-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl]amino}thiazol-5-yl)-1H-pyrrole-3-carboxylate methyl

4-Fluoro-2-methoxyphenylboronic acid (0.9 g, 5.38 mol), pyridine (6.4 g, 80.64 mol) and copper (II) acetate (0.243 g, 1.34 mol) were added to a dichloromethane solution (10 mL) of 5-{4-carbamoyl-2-[cyclopropyl(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-methyl carboxylate (Reference Example 5) (1 g, 2.69 mol), and the mixture was stirred overnight at room temperature under an oxygen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.8 g).
^1H -NMR (DMSO- _d6 ) δ 13.25 (br.s, 1H), 8.54 (s, 1H), 8.08 - 8.03 (m, 2H), 7.77 (br.s, 1H), 7.64 - 7.61 (m, 2H), 7.20 (dd, J = 2.5, 11.0 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.70 (t, J = 1.9 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 3H), 3.22 - 3.17 (m, 1H), 1.20 - 1.12 (m, 2H), 0.91 - 0.87 (m, 2H); LC-MS (M/Z): 497.4 [M+H] ⁺ .

　５－（４－カルバモイル－２－（シクロプロピル（１－（４－フルオロ－２－メトキシフェニル）－１Ｈ－ピラゾール－４－イル）アミノ）チアゾール－５－イル）－１Ｈ－ピロール－３－カルボン酸メチル（０．８ｇ，１．６１ｍｏｌ）の１，４－ジオキサン／メタノールの混合液（６ｍＬ／６ｍＬ）に、３Ｍ水酸化ナトリウム水溶液（３ｍＬ）を加え７０℃で５時間攪拌した。溶媒を減圧留去して得られた残渣に１０％クエン酸水溶液を加え、析出した固体をろ取し、標記化合物（０．６ｇ）を得た。
¹H-NMR (DMSO-d₆) δ 13.17 (br.s, 1H), 11.98 (br.s, 1H), 8.54 (s, 1H), 8.08 - 8.03 (m, 2H), 7.77 (br.s, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.53 (br.s, 1H), 7.22 - 7.19 (m, 1H), 6.96 - 6.89 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.22 - 3.17 (m, 1H), 1.19 - 1.11 (m, 2H), 0.92 - 0.84 (m, 2H); LC-MS (M/Z): 483.2 [M+H]⁺. (Second step)
5-(4-carbamoyl-2-{cyclopropyl[1-(4-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl]amino}thiazol-5-yl)-1H-pyrrole-3-carboxylic acid

A 3M aqueous solution of sodium hydroxide (3 mL) was added to a mixture (6 mL/6 mL) of 5-(4-carbamoyl-2-(cyclopropyl(1-(4-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl)amino)thiazol-5-yl)-1H-pyrrole-3-methyl carboxylate (0.8 g, 1.61 mol) in 1,4-dioxane/methanol, and the mixture was stirred at 70° C. for 5 hours. The solvent was distilled off under reduced pressure, and a 10% aqueous solution of citric acid was added to the resulting residue. The precipitated solid was collected by filtration to obtain the title compound (0.6 g).
^1H -NMR (DMSO- _d6 ) δ 13.17 (br.s, 1H), 11.98 (br.s, 1H), 8.54 (s, 1H), 8.08 - 8.03 (m, 2H), 7.77 (br.s, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.53 (br.s, 1H), 7.22 - 7.19 (m, 1H), 6.96 - 6.89 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.22 - 3.17 (m, 1H), 1.19 - 1.11 (m, 2H), 0.92 - 0.84 (m, 2H); LC-MS (M/Z): 483.2 [M+H] ⁺ .

(Third process)
Preparation of 2-{cyclopropyl[1-(4-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl]amino}-5-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]-1H-pyrrol-2-yl}thiazole-4-carboxamide 1-(oxetan-3-yl)piperazine (0.035 g, 0.25 mol), HATU (0.094 g, 0.25 mol) and DIPEA (0.04 mL, 0.25 mol) were added to a DMF solution (3 mL) of 5-(4-carbamoyl-2-(cyclopropyl(1-(4-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl)amino)thiazol-5-yl)-1H-pyrrole-3-carboxylic acid (0.06 g, 0.12 mol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified using a HPLC preparative chromatography system to obtain the title compound (21 mg).
^1H -NMR (500 MHz, DMSO-d6) δ 13.08 (br.s, 1H), 8.53 (s, 1H), 8.02 (br.s, 2H), 7.72 (br.s, 1H), 7.62 (dd, J = 6.4, 8.9 Hz, 1H), 7.29 (s, 1H), 7.19 (dd, J = 3.0, 11.0 Hz, 1H), 6.93 (dt, J = 2.6, 8.5 Hz, 1H), 6.53 (s, 1H), 4.54 (t, J = 6.6 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 3.87 (s, 3H), 3.65 - 3.62 (m, 4H), 3.45 - 3.40 (m, 1H), 3.21 - 3.17 (m, 1H), 2.30 - 2.24 (m, 4H), 1.17 - 1.11 (m, 2H), 0.91 - 0.85 (m, 2H); LC-MS (m/z): 607.4 [M+H] ⁺ .

　２－（シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ）－５－（４－（モルホリン－４－カルボニル）－１Ｈ－ピロール－２－イル）チアゾール－４－カルボキサミド（参考例８）（０．０４ｇ，０．０９４ｍｏｌ）のジクロロメタン溶液（２ｍＬ）に５－フルオロ－２－メトキシフェニルボロン酸（３２ｍｇ，０．１８７ｍｏｌ）、ピリジン（７４ｍｇ，０．９３６ｍｏｌ）及び酢酸銅（ＩＩ）（３４ｍｇ，０．１８７ｍｏｌ）を加え、混合物を酸素雰囲気下、室温で一晩攪拌した。溶媒を減圧留去して得られた残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、標記化合物（１９．２ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 13.25 - 13.00 (m, 1H), 8.68 (d, J = 0.8 Hz, 1H), 8.10 (s, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.54 (dd, J = 9.5, 3.1 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.31 - 7.20 (m, 2H), 6.58 (dd, J = 2.3, 1.6 Hz, 1H), 3.88 (s, 3H), 3.65 - 3.57 (m, 8H), 3.22 (tt, J = 6.8, 3.7 Hz, 1H), 1.19 - 1.14 (m, 2H), 0.93 - 0.87 (m, 2H); LC-MS (m/z): 552.3 [M+H]⁺. Example 4
Preparation of 2-{cyclopropyl[1-(5-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl]amino}-5-[4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide

5-Fluoro-2-methoxyphenylboronic acid (32 mg, 0.187 mol), pyridine (74 mg, 0.936 mol) and copper (II) acetate (34 mg, 0.187 mol) were added to a dichloromethane solution (2 mL) of 2-(cyclopropyl(1H-pyrazol-4-yl)amino)-5-(4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl)thiazole-4-carboxamide (Reference Example 8) (0.04 g, 0.094 mol), and the mixture was stirred overnight at room temperature under an oxygen atmosphere. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (19.2 mg).
^1H -NMR (DMSO-d6) δ 13.25 - 13.00 (m, 1H), 8.68 (d, J = 0.8 Hz, 1H), 8.10 (s, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.54 (dd, J = 9.5, 3.1 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.31 - 7.20 (m, 2H), 6.58 (dd, J = 2.3, 1.6 Hz, 1H), 3.88 (s, 3H), 3.65 - 3.57 (m, 8H), 3.22 (tt, J = 6.8, 3.7 Hz, 1H), 1.19 - 1.14 (m, 2H), 0.93 - 0.87 (m, 2H); LC-MS (m/z): 552.3 [M+H] ⁺ .

　２－（シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ）－５－（４－（ジメチルカルバモイル）－１Ｈ－ピロール－２－イル）チアゾール－４－カルボキサミド（参考例７）（０．０５ｇ，０．１３ｍｏｌ）のジクロロメタン溶液（３ｍＬ）に、３，４－ジフルオロフェニルボロン酸（４４ｍｇ，０．２６ｍｏｌ）、ピリジン（１０３ｍｇ，１．３ｍｏｌ）及び酢酸銅（ＩＩ）（４７ｍｇ，０．２６ｍｏｌ）を加え、混合液を酸素雰囲気下、室温で一晩攪拌した。溶媒を減圧留去して得られた残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、標記化合物（９ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 13.10 (s, 1H), 8.86 (d, J = 0.7 Hz, 1H), 8.17 (s, 1H), 8.04 - 8.00 (m, 2H), 7.98 (s, 1H), 7.66 - 7.58 (m, 2H), 7.36 (dd, J = 2.9, 1.6 Hz, 1H), 6.63 (dd, J = 2.4, 1.6 Hz, 1H), 3.24 - 3.16 (m, 1H), 3.06 (m, 6H), 1.22 - 1.12 (m, 2H), 0.95 - 0.84 (m, 2H); LC-MS (m/z): 498.2 [M+H]⁺. Example 5
Preparation of 2-{cyclopropyl[1-(3,4-difluorophenyl)-1H-pyrazol-4-yl]amino}-5-(4-(dimethylcarbamoyl)-1H-pyrrol-2-yl)thiazole-4-carboxamide

3,4-Difluorophenylboronic acid (44 mg, 0.26 mol), pyridine (103 mg, 1.3 mol) and copper(II) acetate (47 mg, 0.26 mol) were added to a dichloromethane solution (3 mL) of 2-(cyclopropyl(1H-pyrazol-4-yl)amino)-5-(4-(dimethylcarbamoyl)-1H-pyrrol-2-yl)thiazole-4-carboxamide (Reference Example 7) (0.05 g, 0.13 mol), and the mixture was stirred overnight at room temperature under an oxygen atmosphere. The solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (9 mg).
^1H -NMR (DMSO-d6) δ 13.10 (s, 1H), 8.86 (d, J = 0.7 Hz, 1H), 8.17 (s, 1H), 8.04 - 8.00 (m, 2H), 7.98 (s, 1H), 7.66 - 7.58 (m, 2H), 7.36 (dd, J = 2.9, 1.6 Hz, 1H), 6.63 (dd, J = 2.4, 1.6 Hz, 1H), 3.24 - 3.16 (m, 1H), 3.06 (m, 6H), 1.22 - 1.12 (m, 2H), 0.95 - 0.84 (m, 2H); LC-MS (m/z): 498.2 [M+H] ⁺ .

　２－（シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ）－５－（４－（ジメチルカルバモイル）－１Ｈ－ピロール－２－イル）チアゾール－４－カルボキサミド（参考例７）（０．０５ｇ，０．１３ｍｏｌ）のジクロロメタン溶液（３ｍＬ）に、（４－フルオロ－３－メトキシフェニル）ボロン酸（４４ｍｇ，０．２６ｍｏｌ）、ピリジン（１０３ｍｇ，１．３ｍｏｌ）及び酢酸銅（ＩＩ）（４７ｍｇ，０．２６ｍｏｌ）を加え、混合物を酸素雰囲気下、室温で一晩攪拌した。溶媒を減圧留去して得られた残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、標記化合物（１０．５ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 13.08 (s, 1H), 8.77 (d, J = 0.7 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.84 - 7.79 (m, 1H), 7.71 (m, 2H), 7.35 (dd, J = 2.9, 1.6 Hz, 1H), 7.29 (t, J = 9.1 Hz, 1H), 6.62 (dd, J = 2.3, 1.6 Hz, 1H), 3.23 - 3.16 (m, 1H), 2.97 (m, 6H), 2.32 (s, 3H), 1.20 - 1.13 (m, 2H), 0.90 - 0.87 (m, 2H); LC-MS (m/z): 494.1 [M+H]⁺. Example 6
Preparation of 2-{cyclopropyl[1-(4-fluoro-3-methylphenyl)-1H-pyrazol-4-yl]amino}-5-[4-(dimethylcarbamoyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide

To a dichloromethane solution (3 mL) of 2-(cyclopropyl(1H-pyrazol-4-yl)amino)-5-(4-(dimethylcarbamoyl)-1H-pyrrol-2-yl)thiazole-4-carboxamide (Reference Example 7) (0.05 g, 0.13 mol), (4-fluoro-3-methoxyphenyl)boronic acid (44 mg, 0.26 mol), pyridine (103 mg, 1.3 mol) and copper(II) acetate (47 mg, 0.26 mol) were added, and the mixture was stirred overnight at room temperature under an oxygen atmosphere. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (10.5 mg).
^1H -NMR (DMSO-d6) δ 13.08 (s, 1H), 8.77 (d, J = 0.7 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.84 - 7.79 (m, 1H), 7.71 (m, 2H), 7.35 (dd, J = 2.9, 1.6 Hz, 1H), 7.29 (t, J = 9.1 Hz, 1H), 6.62 (dd, J = 2.3, 1.6 Hz, 1H), 3.23 - 3.16 (m, 1H), 2.97 (m, 6H), 2.32 (s, 3H), 1.20 - 1.13 (m, 2H), 0.90 - 0.87 (m, 2H); LC-MS (m/z): 494.1 [M+H] ⁺ .

　２－（シクロプロピル［１Ｈ－ピラゾール－４－イル］アミノ）－５－（４－［ジメチルカルバモイル］－１Ｈ－ピロール－２－イル）チアゾール－４－カルボキサミド（参考例７）（０．０５ｇ，０．１３ｍｏｌ）のジクロロメタン溶液（３ｍＬ）に５－フルオロ－２－メトキシフェニルボロン酸（４４ｍｇ，０．２６ｍｏｌ）、ピリジン（１０３ｍｇ，１．３ｍｏｌ）及び酢酸銅（ＩＩ）（４７ｍｇ，０．２６ｍｏｌ）を加え、混合液を酸素雰囲気下、室温で一晩攪拌した。溶媒を減圧留去して得られた残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、標記化合物（７．６ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 13.07 (s, 1H), 8.68 (d, J = 0.7 Hz, 1H), 8.11 (d, J = 0.7 Hz, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.54 (dd, J = 9.4, 3.1 Hz, 1H), 7.36 (dd, J = 2.9, 1.6 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.25 - 7.21 (m, 1H), 6.62 (dd, J = 2.4, 1.6 Hz, 1H), 3.88 (s, 3H), 3.24 - 3.16 (m, 1H), 2.99 (d, J = 12.0 Hz, 6H), 1.19 - 1.15 (m, 2H), 0.93 - 0.88 (m, 2H); LC-MS (m/z): 510.1 [M+H]⁺. Example 7
Preparation of 2-{cyclopropyl[1-(5-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl]amino}-5-[4-(dimethylcarbamoyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide

5-Fluoro-2-methoxyphenylboronic acid (44 mg, 0.26 mol), pyridine (103 mg, 1.3 mol) and copper (II) acetate (47 mg, 0.26 mol) were added to a dichloromethane solution (3 mL) of 2-(cyclopropyl[1H-pyrazol-4-yl]amino)-5-(4-[dimethylcarbamoyl]-1H-pyrrol-2-yl)thiazole-4-carboxamide (Reference Example 7) (0.05 g, 0.13 mol), and the mixture was stirred overnight at room temperature under an oxygen atmosphere. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (7.6 mg).
^1H -NMR (DMSO-d6) δ 13.07 (s, 1H), 8.68 (d, J = 0.7 Hz, 1H), 8.11 (d, J = 0.7 Hz, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.54 (dd, J = 9.4, 3.1 Hz, 1H), 7.36 (dd, J = 2.9, 1.6 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.25 - 7.21 (m, 1H), 6.62 (dd, J = 2.4, 1.6 Hz, 1H), 3.88 (s, 3H), 3.24 - 3.16 (m, 1H), 2.99 (d, J = 12.0 Hz, 6H), 1.19 - 1.15 (m, 2H), 0.93 - 0.88 (m, 2H); LC-MS (m/z): 510.1 [M+H] ⁺ .

（第１工程）
５－（４－カルバモイル－２－｛シクロプロピル［１－（２，４－ジメトキシフェニル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－５－イル）－１Ｈ－ピロール－３－カルボン酸メチル

　５－｛４－カルバモイル－２－［シクロプロピル（１Ｈ－ピラゾール－４－イル）アミノ］チアゾール－５－イル｝－１Ｈ－ピロール－３－カルボン酸メチル（参考例５）（２ｇ，５．３８ｍｏｌ）のジクロロメタン溶液（６０ｍＬ）に、２，４－ジメトキシフェニルボロン酸（１．９５ｇ，１０．７５ｍｏｌ）、ピリジン（１３ｍＬ）及び酢酸銅（ＩＩ）（０．１９５ｇ，１．０７ｍｏｌ）を加え、混合物を酸素雰囲気下、室温で一晩攪拌した。溶媒を減圧留去して得られた残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、標記化合物（０．８ｇ）を得た。
1H NMR (400 MHz, DMSO-d6) δ 13.17 (br. s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.97 (m, 1H), 7.73 (s, 1H), 7.56 - 7.46 (m, 2H), 6.78 (d, J = 2.5 Hz, 1H), 6.68 - 6.62 (m, 2H), 3.84 (s, 6H), 3.72 (s, 3H), 3.23 - 3.14 (m, 1H), 1.16 - 1.13 (m, 2H), 0.92 - 0.85 (m, 2H).LC-MS (M/Z): 509.3 [M+H]⁺. Example 8
Preparation of 2-{cyclopropyl[1-(2,4-dimethoxyphenyl)-1H-pyrazol-4-yl]amino}-5-{4-[4-(oxetan-3-yl)piperazine-1-carbonyl]-1H-pyrrol-2-yl}thiazole-4-carboxamide

(First step)
5-(4-carbamoyl-2-{cyclopropyl[1-(2,4-dimethoxyphenyl)-1H-pyrazol-4-yl]amino}thiazol-5-yl)-1H-pyrrole-3-carboxylate methyl

2,4-Dimethoxyphenylboronic acid (1.95 g, 10.75 mol), pyridine (13 mL) and copper(II) acetate (0.195 g, 1.07 mol) were added to a dichloromethane solution (60 mL) of 5-{4-carbamoyl-2-[cyclopropyl(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-methyl carboxylate (Reference Example 5) (2 g, 5.38 mol), and the mixture was stirred overnight at room temperature under an oxygen atmosphere. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (0.8 g).
1H NMR (400 MHz, DMSO-d6) δ 13.17 (br. s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.97 (m, 1H), 7.73 (s, 1H), 7.56 - 7.46 (m, 2H), 6.78 (d, J = 2.5 Hz, 1H), 6.68 - 6.62 (m, 2H), 3.84 (s, 6H), 3.72 (s, 3H), 3.23 - 3.14 (m, 1H), 1.16 - 1.13 (m, 2H), 0.92 - 0.85 (m, 2H).LC-MS (M/Z): 509.3 [M+H] ⁺ .

　５－（４－カルバモイル－２－（シクロプロピル（１－（２，４－ジメトキシフェニル）－１Ｈ－ピラゾール－４－イル）アミノ）チアゾール－５－イル）－１Ｈ－ピロール－３－カルボン酸メチル（０．８ｇ，１．５７ｍｏｌ）の１，４－ジオキサン／メタノールの混合液（４０ｍＬ／４０ｍＬ）に、３Ｍ水酸化ナトリウム水溶液（１．６ｍＬ，４．７２ｍｍｏｌ）を加え８０℃で１６時間攪拌した。溶媒を減圧留去して得られた残渣に１０％クエン酸水溶液を加え、析出した固体をろ取し、標記化合物（０．７ｇ）を得た。
¹H-NMR (400 MHz, DMSO-d6) δ 13.17 (br.s, 1H), 11.99 (br.s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.97 (m, 1H), 7.73 (s, 1H), 7.56 - 7.46 (m, 2H), 6.78 (d, J = 2.5 Hz, 1H), 6.68 - 6.62 (m, 2H), 3.84 (s, 6H), 3.23 - 3.14 (m, 1H), 1.16 - 1.13 (m, 2H), 0.92 - 0.85 (m, 2H); LC-MS (M/Z): 495.2 [M+H]⁺. (Second step)
5-(4-carbamoyl-2-{cyclopropyl[1-(2,4-dimethoxyphenyl)-1H-pyrazol-4-yl]amino}thiazol-5-yl)-1H-pyrrole-3-carboxylic acid

A 3M aqueous solution of sodium hydroxide (1.6 mL, 4.72 mmol) was added to a mixture (40 mL/40 mL) of 5-(4-carbamoyl-2-(cyclopropyl(1-(2,4-dimethoxyphenyl)-1H-pyrazol-4-yl)amino)thiazol-5-yl)-1H-pyrrole-3-methyl carboxylate (0.8 g, 1.57 mol) in 1,4-dioxane/methanol, and the mixture was stirred at 80° C. for 16 hours. The solvent was distilled off under reduced pressure, and a 10% aqueous solution of citric acid was added to the resulting residue. The precipitated solid was collected by filtration to obtain the title compound (0.7 g).
^1H -NMR (400 MHz, DMSO-d6) δ 13.17 (br.s, 1H), 11.99 (br.s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.97 (m, 1H), 7.73 (s, 1H), 7.56 - 7.46 (m, 2H), 6.78 (d, J = 2.5 Hz, 1H), 6.68 - 6.62 (m, 2H), 3.84 (s, 6H), 3.23 - 3.14 (m, 1H), 1.16 - 1.13 (m, 2H), 0.92 - 0.85 (m, 2H); LC-MS (M/Z): 495.2 [M+H] ⁺ .

(Third process)
2-(cyclopropyl(1-(2,4-dimethoxyphenyl)-1H-pyrazol-4-yl)amino)-5-(4-(4-(oxetan-3-yl)piperazine-1-carbonyl)-1H-pyrrol-2-yl)thiazole-4-carboxamide 5-(4-carbamoyl-2-(cyclopropyl(1-(2,4-dimethoxyphenyl)-1H-pyrazol-4-yl)amino)thiazole-5-yl)-1H-pyrrole-3-carboxylic acid (0.07 g, 0.14 mol) in THF solution (7 mL) was added with 1-(oxetan-3-yl)piperazine (0.04 g, 0.28 mol), HATU (0.108 g, 0.28 mol) and DIPEA (0.049 mL, 0.28 mol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified using a HPLC preparative chromatography system to obtain the title compound (21.3 mg).
^1H -NMR (DMSO-d6) δ 13.08 (br.s, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 7.71 (br.s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.29 (br.s, 1H), 6.78 (br.s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.52 (br.s, 1H), 4.54 (t, J = 6.0 Hz, 2H), 4.45 (t, J = 5.6 Hz, 2H), 3.83 (d, J = 5.1 Hz, 6H), 3.71 - 3.60 (m, 4H), 3.44 - 3.39 (m, 1H), 3.21 - 3.13 (m, 1H), 2.33 - 2.27 (m, 4H), 1.16 - 1.09 (m, 2H), 0.88 - 0.84 (m, 2H); LC-MS (m/z): 619.4 [M+H] ⁺ .

Examples 9 to 183
The following example compounds [Table 1] were produced using the corresponding raw materials (commercially available products, or compounds derived from commercially available compounds by known methods or methods similar thereto) according to the methods described in the above examples, and, if necessary, by appropriately combining methods commonly used in organic synthetic chemistry. The physicochemical data of each compound is shown in [Table 2].

[Table 1]

[Table 2]

（第１工程）
２－｛（シクロプロピルメチル）［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボン酸エチル

　２－｛［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボン酸エチル（参考例１第２工程の化合物）（１．５ｇ，４．７ｍｍｏｌ）の１，４－ジオキサン溶液（２５ｍＬ）に（ブロモメチル）シクロプロパン（１．９ｇ，１４ｍｍｏｌ）および炭酸カリウム（１．９ｇ，１４ｍｍｏｌ）を室温で加え、混合物を１００℃で１６時間撹拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲル、石油エーテル／酢酸エチル）で精製し、標記化合物（１．５ｇ）を得た。
¹H-NMR (500 MHz, Chloroform-d) δ 7.81 (d, J = 0.8 Hz, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.33 (s, 1H), 5.42 - 5.33 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.10 - 4.02 (m, 2H), 3.82 - 3.72 (m, 3H), 2.11 (m, 2H), 2.07 - 2.00 (m, 1H), 1.71 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.12 (m, 1H), 0.54 - 0.46 (m, 2H), 0.29 - 0.22 (m, 2H); LC-MS (m/z): 377.33 [M+H]⁺. Example 184
Preparation of 2-{[1-(but-2-yn-1-yl)-1H-pyrazol-4-yl](cyclopropylmethyl)amino}-5-[4-(dimethylcarbamoyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide

(First step)
2-{(cyclopropylmethyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate ethyl

To a solution (25 mL) of ethyl 2-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate (compound from Step 2 of Reference Example 1) (1.5 g, 4.7 mmol) in 1,4-dioxane, (bromomethyl)cyclopropane (1.9 g, 14 mmol) and potassium carbonate (1.9 g, 14 mmol) were added at room temperature, and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give the title compound (1.5 g).
^1H -NMR (500 MHz, Chloroform-d) δ 7.81 (d, J = 0.8 Hz, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.33 (s, 1H), 5.42 - 5.33 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.10 - 4.02 (m, 2H), 3.82 - 3.72 (m, 3H), 2.11 (m, 2H), 2.07 - 2.00 (m, 1H), 1.71 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.12 (m, 1H), 0.54 - 0.46 (m, 2H), 0.29 - 0.22 (m, 2H); LC-MS (m/z): 377.33 [M+H] ⁺ .

　２－｛（シクロプロピルメチル）［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボン酸エチル（１．５ｇ，３．９ｍｍｏｌ）のジクロロメタン溶液（２０ｍＬ）に、０℃でＮＢＳ（６３７ｍｇ，３．６ｍｍｏｌ）を加え、混合物を室温で３時間撹拌した。反応混合物に氷水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、標記化合物（１．４ｇ）を得た。
¹H-NMR (Chloroform-d) δ 7.78 (s, 1H), 7.57 (s, 1H), 5.38 (dd, J = 8.5, 3.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.07 (d, J = 12.3 Hz, 1H), 3.81 - 3.61 (m, 3H), 2.17 - 1.98 (m, 3H), 1.68 (m, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.09 (m, 1H), 0.55 - 0.42 (m, 2H), 0.26 (t, J = 5.1 Hz, 2H).; LC-MS (m/z): 455.12 ([M+H]⁺. (Second step)
5-Bromo-2-{(cyclopropylmethyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate ethyl

NBS (637 mg, 3.6 mmol) was added to a dichloromethane solution (20 mL) of ethyl 2-{(cyclopropylmethyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylate (1.5 g, 3.9 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.4 g).
^1H -NMR (Chloroform-d) δ 7.78 (s, 1H), 7.57 (s, 1H), 5.38 (dd, J = 8.5, 3.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.07 (d, J = 12.3 Hz, 1H), 3.81 - 3.61 (m, 3H), 2.17 - 1.98 (m, 3H), 1.68 (m, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.09 (m, 1H), 0.55 - 0.42 (m, 2H), 0.26 (t, J = 5.1 Hz, 2H).; LC-MS (m/z): 455.12 ([M+H] ⁺ .

　５－ブロモ－２－｛（シクロプロピルメチル）［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボン酸エチル（１．４ｇ，３．１ｍｍｏｌ）の１，４－ジオキサン／メタノールの混合液（１：１，１０ｍＬ）に、４Ｍ水酸化ナトリウム水溶液（５ｍＬ）を加え、室温で１６時間攪拌した。反応混合物に塩酸を加えて中和した後、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、標記化合物（１．２ｇ）を得た。
LC-MS (m/z): 427.06 [M+H]⁺. (Third process)
5-Bromo-2-{(cyclopropylmethyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylic acid

A 4M aqueous sodium hydroxide solution (5 mL) was added to a mixture of 5-bromo-2-{(cyclopropylmethyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-ethyl carboxylate (1.4 g, 3.1 mmol) in 1,4-dioxane/methanol (1:1, 10 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with hydrochloric acid, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (1.2 g).
LC-MS (m/z): 427.06 [M+H] ⁺ .

　５－ブロモ－２－｛（シクロプロピルメチル）［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボン酸（１．２ｇ，２．８ｍｍｏｌ）のＴＨＦ溶液（１０ｍＬ）に１，１’－カルボニルジイミダゾール（０．９ｇ，５．６ｍｍｏｌ）を加え、室温で２時間撹拌した後、アンモニア水（５ｍＬ）を加えて、さらに室温で１時間撹拌した。析出物をろ取し、乾燥させて標記化合物（１．０ｇ）を得た。
LC-MS (m/z): 426.14 ([M+H]⁺. (Fourth step)
5-Bromo-2-{(cyclopropylmethyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxamide

1,1'-carbonyldiimidazole (0.9 g, 5.6 mmol) was added to a THF solution (10 mL) of 5-bromo-2-{(cyclopropylmethyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxylic acid (1.2 g, 2.8 mmol), and the mixture was stirred at room temperature for 2 hours, and then aqueous ammonia (5 mL) was added and the mixture was further stirred at room temperature for 1 hour. The precipitate was collected by filtration and dried to obtain the title compound (1.0 g).
LC-MS (m/z): 426.14 ([M+H] ⁺ .

　５－ブロモ－２－｛（シクロプロピルメチル）［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル］アミノ｝チアゾール－４－カルボキサミド（１．０ｇ，２．４ｍｍｏｌ）と５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－１Ｈ－ピロール－３－カルボン酸メチル（参考例３）（８８５ｍｇ，３．５ｍｍｏｌ）の１，４－ジオキサン／水の混合液（１５ｍＬ／１．５ｍＬ）に、テトラキス（トリフェニルホスフィン）パラジウム（０）（２７．２ｍｇ，０．２ｍｍｏｌ）と炭酸カリウム（９７５ｍｇ，７．１ｍｍｏｌ）を加え、混合物を１００℃で２時間攪拌した。反応混合物に氷水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（シリカゲル、酢酸エチル）で精製し、標記化合物（８００ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 13.27 (s, 1H), 8.24 (d, J = 0.8 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 0.8 Hz, 1H), 7.61 - 7.59 (m, 1H), 6.47 (dd, J = 2.3, 1.6 Hz, 1H), 5.42 (dd, J = 10.1, 2.1 Hz, 1H), 3.96 (d, J = 11.9 Hz, 1H), 3.92 (s, 1H), 3.76 (d, J = 7.1 Hz, 2H), 3.68 (m, 5H), 2.12 (dt, J = 11.9, 9.4 Hz, 1H), 1.98 - 1.91 (m, 2H), 1.59 - 1.48 (m, 2H), 0.50 - 0.40 (m, 2H), 0.30 - 0.21 (m, 2H); LC-MS (m/z): 471.26 [M+H]⁺. (Fifth step)
5-[4-carbamoyl-2-{(cyclopropylmethyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino}thiazol-5-yl]-1H-pyrrole-3-carboxylate methyl

Tetrakis(triphenylphosphine)palladium(0) (27.2 mg, 0.2 mmol) and potassium carbonate (975 mg, 7.1 mmol) were added to a mixture (15 mL/1.5 mL) of 5-bromo-2-{(cyclopropylmethyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]amino}thiazole-4-carboxamide (1.0 g, 2.4 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-methyl carboxylate (Reference Example 3) (885 mg, 3.5 mmol) in 1,4-dioxane/water, and the mixture was stirred at 100° C. for 2 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to obtain the title compound (800 mg).
^1H -NMR (DMSO-d6) δ 13.27 (s, 1H), 8.24 (d, J = 0.8 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 0.8 Hz, 1H), 7.61 - 7.59 (m, 1H), 6.47 (dd, J = 2.3, 1.6 Hz, 1H), 5.42 (dd, J = 10.1, 2.1 Hz, 1H), 3.96 (d, J = 11.9 Hz, 1H), 3.92 (s, 1H), 3.76 (d, J = 7.1 Hz, 2H), 3.68 (m, 5H), 2.12 (dt, J = 11.9, 9.4 Hz, 1H), 1.98 - 1.91 (m, 2H), 1.59 - 1.48 (m, 2H), 0.50 - 0.40 (m, 2H), 0.30 - 0.21 (m, 2H); LC-MS (m/z): 471.26 [M+H] ⁺ .

　５－［４－カルバモイル－２－｛（シクロプロピルメチル）（１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－４－イル）アミノ｝チアゾール－５－イル］－１Ｈ－ピロール－３－カルボン酸メチル（８００ｍｇ，１．７ｍｍｏｌ）の１，４－ジオキサン／メタノールの混合液（１：１，１４ｍＬ）に４Ｍ水酸化ナトリウム水溶液（５ｍＬ）を加え、混合物を７０℃で１時間攪拌した。反応混合物に濃塩酸を加えて酸性にし、析出した固体をろ取し、標記化合物（２２０ｍｇ）を得た。
¹H-NMR (DMSO-d6) δ 13.17 (m, 2H), 7.90 (q, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.43 (dd, J = 3.0, 1.6 Hz, 1H), 7.29 (dt, J = 3.3, 1.8 Hz, 1H), 6.73 (q, J = 2.4 Hz, 1H), 6.36 (t, J = 1.9 Hz, 1H), 3.71 (d, J = 7.0 Hz, 2H), 1.05 (tt, J = 7.6, 5.2 Hz, 1H), 0.44 - 0.38 (m, 2H), 0.25 - 0.17 (m, 2H); LC-MS (m/z): 373.16 [M+H]⁺. (Sixth step)
5-{4-carbamoyl-2-[(cyclopropylmethyl)(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-carboxylic acid

A 4M aqueous sodium hydroxide solution (5 mL) was added to a mixture of 5-[4-carbamoyl-2-{(cyclopropylmethyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)amino}thiazol-5-yl]-1H-pyrrole-3-methyl carboxylate (800 mg, 1.7 mmol) in 1,4-dioxane/methanol (1:1, 14 mL), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration to obtain the title compound (220 mg).
^1H -NMR (DMSO-d6) δ 13.17 (m, 2H), 7.90 (q, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.43 (dd, J = 3.0, 1.6 Hz, 1H), 7.29 (dt, J = 3.3, 1.8 Hz, 1H), 6.73 (q, J = 2.4 Hz, 1H), 6.36 (t, J = 1.9 Hz, 1H), 3.71 (d, J = 7.0 Hz, 2H), 1.05 (tt, J = 7.6, 5.2 Hz, 1H), 0.44 - 0.38 (m, 2H), 0.25 - 0.17 (m, 2H); LC-MS (m/z): 373.16 [M+H] ⁺ .

　５－｛4－カルバモイル－２－［（シクロプロピルメチル）（１Ｈ－ピラゾール－４－イル）アミノ］チアゾール－５－イル｝－１Ｈ－ピロール－３－カルボン酸（２００ｍｇ，０．５ｍｏｌ）のＤＭＦ溶液（３ｍＬ）に、ジメチルアミン塩酸塩（２０３ｍｇ，１．１ｍｏｌ）及びＥＤＣ・ＨＣｌ（２０４ｍｇ，１．１ｍｏｌ）を加え、室温で３時間攪拌した。反応混合物を水で希釈し、析出した固体をろ取し、標記化合物（１７０ｍｇ）を得た。
LC-MS (m/z): 400.22 [M+H]⁺. (Seventh step)
2-[(cyclopropylmethyl)(1H-pyrazol-4-yl)amino]-5-[4-(dimethylcarbamoyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide

Dimethylamine hydrochloride (203 mg, 1.1 mol) and EDC.HCl (204 mg, 1.1 mol) were added to a DMF solution (3 mL) of 5-{4-carbamoyl-2-[(cyclopropylmethyl)(1H-pyrazol-4-yl)amino]thiazol-5-yl}-1H-pyrrole-3-carboxylic acid (200 mg, 0.5 mol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the precipitated solid was collected by filtration to obtain the title compound (170 mg).
LC-MS (m/z): 400.22 [M+H] ⁺ .

(Step 8)
Preparation of 2-[(1-(but-2-yn-1-yl)-1H-pyrazol-4-yl)(cyclopropylmethyl)amino)-5-[4-(dimethylcarbamoyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide Potassium carbonate (103 mg, 0.75 mmol) was added to a solution of 2-[(cyclopropylmethyl)(1H-pyrazol-4-yl)amino]-5-[4-(dimethylcarbamoyl)-1H-pyrrol-2-yl]thiazole-4-carboxamide (150 mg, 0.38 mmol) and 1-bromo-2-butyne (103 mg, 0.75 mmol) in DMF (3 mL), and the mixture was reacted at 120° C. for 1 hour using a microwave synthesis apparatus. After cooling the reaction mixture to room temperature, solids were filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform/methanol) to obtain the title compound (30 mg).
^1H -NMR (DMSO-d6) δ 13.10 (s, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.99 - 7.84 (m, 2H), 7.69 (d, J = 0.8 Hz, 1H), 7.29 (dd, J = 2.8, 1.6 Hz, 1H), 6.42 - 6.39 (m, 1H), 5.00 (q, J = 2.5 Hz, 2H), 3.74 (d, J = 7.1 Hz, 2H), 2.97 (d, J = 34.5 Hz, 6H), 1.85 (t, J = 2.5 Hz, 3H), 1.15 - 1.04 (m, 1H), 0.48 - 0.44 (m, 2H), 0.27 (dd, J = 4.8, 1.8 Hz, 2H); LC-MS (m/z): 452.2 [M+H] ⁺ .

Examples 185 to 226
The following example compounds [Table 3] were produced using the corresponding raw materials (commercially available products, or compounds derived from commercially available compounds by known methods or methods similar thereto) according to the methods described in the above examples, and, if necessary, by appropriately combining methods commonly used in organic synthetic chemistry. The physicochemical data of each compound is shown in [Table 4].

[Table 3]

[Table 4]

Test Example 1
ALK5 activity inhibition test (TR-FRET method)
Kinase activity was measured by time-resolved fluorescence resonance energy transfer (TR-FRET) using a QuickScout Screening Assist™ TR-FRET Assay Kit (GST-TGFβR1; Karna Biosciences, Catalog No. 09-141TR).
A 10 mM DMSO solution of the test compound was further diluted with DMSO to 10 concentrations (0.00003 mM, 0.0001 mM, 0.0003 mM, 0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, 1 mM), and each was diluted 25-fold with assay buffer to prepare a drug solution (4% DMSO solution).
Drug or control solution (5 μL), substrate mixture (5 μL), and enzyme solution (10 μL) were mixed in wells of a 384-well black plate and reacted at room temperature for 1 hour. After stopping the reaction by adding 60 μL of detection solution [15 mM Tris-HCl (pH 7.5), 0.01% Tween 20, 20 mM EDTA, 0.53 nM Eu-labeled anti-phosphorylated TopoIIa antibody (PerkinElmer)], the TR-FRET signal was measured using a multimode plate reader (EnVision, PerkinElmer) according to the protocol attached to the kit.
(Method of evaluating inhibitory activity)
As a blank, an assay buffer was added instead of the enzyme solution to measure.
The inhibition rate (%) of the test compound was calculated according to the following formula.
Inhibition rate (%) = (1 - (C - A) / (B - A)) x 100
Here, A, B, and C respectively indicate the TR-FRET signal of a blank well, the TR-FRET signal of a control solution well, and the TR-FRET signal of a compound-added well.
The IC ₅₀ value was calculated by regression analysis of the inhibition rate and the test compound concentration (logarithm).

(Evaluation results)
The inhibitory activity against ALK5 of representative compounds of the present invention is shown in Table 5. As kinase activity inhibitory action, _IC50 values of less than 0.05 μM are indicated by ***, 0.05 μM or more and less than 0.5 μM are indicated by **, and 0.5 μM or more and less than 5 μM are indicated by *.

　この結果は、本発明の化合物（Ｉ）が、強いＡＬＫ５阻害活性を有することを示している。 [Table 5]

This result indicates that compound (I) of the present invention has strong ALK5 inhibitory activity.

Test Example 2
Inhibition test of Smad3 phosphorylation by intracellular ALK5 (culture of cells used)
A549 cells (ATCC No. CCL-185) were cultured in a T75 flask at 37°C in a 5% CO2 incubator using D-MEM medium (Nacalai, #08459-64) (hereinafter referred to as growth medium) supplemented with 10% fetal bovine serum (hereinafter referred to as FBS) (AusGene) and 1% penicillin-streptomycin (Nacalai). The cultured A549 cells were diluted with growth medium to a cell density of 3.3 x 105 cells/mL, and the resulting cell suspension was seeded in a 24-well culture plate (Falcon, 353226) at 3.3 x 105 cells/mL/well, and cultured overnight at 37°C in a 5% _CO2 incubator. The next day, the growth medium was removed with an aspirator and immediately washed with FBS-free D-MEM medium (hereinafter referred to as medium) kept at 37°C. The cell plate was prepared by adding 0.989 mL of medium to each well.
(Addition of Test Compound and Stimulation with TGFβ)
1 μL of a DMSO solution of the test compound (1000-3 μM) was added to each well of the cell plate (1 μL of DMSO alone was added to the control well), and the plate was incubated for 1 hour at 37° C. in a 5% CO ₂ incubator. 10 μL of TGFβ1 (Peprotec, PEP-100-21-10) adjusted to 200 ng/mL in culture medium was added to each well of the cell plate (10 μL of culture medium alone was added to the control well), and the plate was further incubated for 30 minutes at 37° C. in a 5% CO ₂ incubator.

(Protein Extraction)
The medium was removed from the cell plate with an aspirator, washed twice with PBS (-), and then 100 μL of lysis buffer [RIPA Buffer (×1) (Cell Signaling Technology) to which 1% Phosphatase inhibitor Cacktail 3 (Sigma, No. P0044), 1% Phosphatase inhibitor Cacktail (Nacalai, No. 07575) and 1 mM phenylmethylsulfonyl fluoride (PMSF) were added] was added, gently stirred, and then allowed to stand for 10 minutes. The supernatant was collected by centrifugation (15,000 rpm, 15 minutes), and the protein amount was quantified. The mixture was mixed with SDS-sample buffer and reacted at 95°C for 5 minutes to denature the proteins, and a sample solution was prepared. 5 μg/12 μL of the sample solution was applied to each well of a 5-20% gradient acrylamide gel (Nacalai, No. 13064-04) and electrophoresis was performed. The proteins in the gel were then transferred to a PVDF membrane using a Transblot Turbo transfer system (Bio-Rad).
(Detection of phosphorylated Smad3)
The transferred PVDF membrane was subjected to blocking treatment with 2% ECL prime blocking agent (GE Healthcare), and then reacted overnight at 4° C. with rabbit anti-phosphorylated Smad3 antibody (Abeam, ab51451) or mouse anti-β-actin antibody (Abeam, ab6276) as the primary antibody. After washing off the unreacted primary antibody with TBST buffer (10 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.1% Tween 20), the sections were reacted with HRP-labeled goat anti-rabbit IgG antibody (Cell Signaling Technology, No. 7074) or HRP-labeled goat anti-mouse IgG antibody (Cell Signaling Technology, No. 7076) as the secondary antibody at room temperature for 1 hour in TBST buffer supplemented with 2% ECL prime blocking agent. After washing off unreacted secondary antibody with TBST buffer, the antibody was reacted with Chemiluminescent One Super (Nacalai) according to the attached protocol, and each band was detected by chemiluminescence using a CCD camera (GE Healthcare, ImageQuant LAS500).

（阻害活性の評価方法）
　検出されたバンドをデンシトメトリー（ＩｍａｇｅＱｕａｎｔ　ＴＬ解析ソフトウェア）により数値化し、化合物非添加かつＴＧＦβ刺激群のリン酸化Ｓｍａｄ３のバンドの発光を１００％、化合物非添加かつＴＧＦβ無刺激群のリン酸化Ｓｍａｄ３のバンドの発光を０％として、各群におけるバンドの強度から阻害率を算出した。なお、それぞれのリン酸化Ｓｍａｄ３のバンドは、βアクチンにより補正を行なった。
　被験化合物のＳｍａｄ３リン酸化の阻害率（％）は、次の式に従って算出した。
阻害率（％）＝（１－（Ｃ－Ａ）／（Ｂ－Ａ））×１００
ただし、Ａ、Ｂ、Ｃは、それぞれ化合物非添加かつＴＧＦβ無刺激群のリン酸化Ｓｍａｄ３のバンドの発光、化合物非添加かつＴＧＦβによる刺激群のリン酸化Ｓｍａｄ３のバンドの発光、化合物添加かつＴＧＦβによる刺激群のリン酸化Ｓｍａｄ３のバンドの発光を示す。
また、ＩＣ_５０値は、阻害率と被験化合物濃度（対数）の回帰分析により算出した。
　本発明の代表化合物の細胞内Ｓｍａｄ３リン酸化阻害活性を、表７に示す。細胞内Ｓｍａｄ３リン酸化阻害活性としてＩＣ_５０値が、０．１μＭ未満を＊＊＊印、０．１μＭ以上０．３μＭ未満を＊＊印、０．３μＭ以上を＊印で示した。 The combinations and dilution concentrations of the primary and secondary antibodies used in this test are as follows.

(Method of evaluating inhibitory activity)
The detected bands were quantified by densitometry (ImageQuant TL analysis software), and the inhibition rate was calculated from the band intensity in each group, taking the luminescence of the phosphorylated Smad3 band in the compound-free and TGFβ-stimulated group as 100% and the luminescence of the phosphorylated Smad3 band in the compound-free and TGFβ-unstimulated group as 0%. Each phosphorylated Smad3 band was corrected with β-actin.
The inhibition rate (%) of Smad3 phosphorylation by the test compound was calculated according to the following formula.
Inhibition rate (%) = (1 - (C - A) / (B - A)) x 100
Here, A, B, and C respectively show the luminescence of the phosphorylated Smad3 band in the group without addition of compound and without stimulation with TGFβ, the group without addition of compound and stimulation with TGFβ, and the group with addition of compound and stimulation with TGFβ.
The IC ₅₀ value was calculated by regression analysis of the inhibition rate and the test compound concentration (logarithm).
The inhibitory activity of intracellular Smad3 phosphorylation of representative compounds of the present invention is shown in Table 7. As the inhibitory activity of intracellular Smad3 phosphorylation, _IC50 values of less than 0.1 μM are indicated by ***, those of 0.1 μM or more and less than 0.3 μM are indicated by **, and those of 0.3 μM or more are indicated by *.

　本試験において、表７に示すとおり、本発明化合物（Ｉ）は細胞内においてＡＬＫ５のＳｍａｄ３リン酸化を強く阻害した。
　試験例２の結果は、本発明の化合物（Ｉ）が、“細胞内ＡＬＫ５のＳｍａｄ３リン酸化作用”についても、強い阻害作用を有することを示している。 [Table 7]

In this test, as shown in Table 7, compound (I) of the present invention strongly inhibited Smad3 phosphorylation of ALK5 in cells.
The results of Test Example 2 show that compound (I) of the present invention also has a strong inhibitory effect on the "Smad3 phosphorylation effect of intracellular ALK5."

Test Example 3
Inhibition test of regulatory T cell (Treg) differentiation induction by TGF-β stimulation Spleens were collected from mice (BALB/cCrSlc, female, 7 weeks old), and mouse lymphocytes were separated from a suspension of splenocytes (FBS-free IMDM medium) prepared using a cell strainer using HISTOPAQUE-1083 (Sigma).
CD4 positive T cells were isolated from these mouse lymphocytes using EasySep Mouse Naive CD4+ T Cell Isolation Kit (manufactured by STEMCELL technologies) according to the protocol attached to the kit.
After coating a 96-well plate with anti-CD3ε antibody (manufactured by BioXCell), 30 μL of a compound solution prepared by diluting a DMSO solution of a test compound 100-fold with IMDM medium supplemented with IL-2-containing FBS was added to each well. CD4-positive T cells were suspended in IMDM medium supplemented with IL-2-containing FBS (2×10 ⁵ cells/mL), 0.1 mL of the solution was added to each well, and the mixture was incubated for 1 hour in a CO ₂ incubator. 30 μL of anti-CD28 antibody (manufactured by BioXCell) and TGF-β1 (manufactured by Gibco) diluted with IMDM medium supplemented with IL-2-containing FBS were added to each well, and 110 μL of IMDM medium supplemented with IL-2-containing FBS was added, followed by incubation for 5 days in a CO ₂ incubator.
The cells were collected from each well, stained with FITC anti-mouse CD4 Antibody (BioLegend), APC anti-mouse CD25 Antibody (BioLegend), and FOXP3 Monoclonal Antibody (FJK-16s) PE (eBioscience), and the proportion of the Treg fraction (CD4+/CD25+/Foxp3+) was measured using a flow cytometer. As a control, IMDM medium supplemented with IL-2-containing FBS was used instead of TGF-β1. The IC ₅₀ value was calculated by regression analysis of the change in the proportion of the Treg fraction and the test compound concentration (logarithm).

　本試験において、表８に示すとおり、本発明化合物（Ｉ）はナイーブＴ細胞においてＴＧＦ－βシグナルを阻害し、ＴＧＦ－β刺激によるＴｒｅｇへの分化誘導を強く抑制した。
　試験例３の結果は、本発明の化合物（Ｉ）が、細胞内ＴＧＦ－βシグナルを阻害し、Ｔｒｅｇの分化誘導に対して強い抑制作用を有することを示している。 The inhibitory activity of representative compounds of the present invention in inducing Treg differentiation by TGF-β stimulation is shown in Table 8. As the inhibitory activity inducing Treg differentiation, _IC50 values of less than 0.1 μM are indicated by ***, 0.1 μM or more and less than 0.5 μM by **, and 0.5 μM or more by *.
[Table 8]

In this test, as shown in Table 8, compound (I) of the present invention inhibited TGF-β signaling in naive T cells and strongly suppressed the induction of differentiation into Treg by TGF-β stimulation.
The results of Test Example 3 show that compound (I) of the present invention inhibits intracellular TGF-β signaling and has a strong suppressive effect on the induction of Treg differentiation.

Test Example 4
Effect of Combination with Anti-PD-1 Antibody in an Allograft Mouse Model of Mouse Colon Cancer Cell Line CT26.WT The effect of combination with an immune checkpoint inhibitor in cancer immunotherapy was examined using a syngeneic mouse tumor model (subcutaneous transplant) of the mouse colon cancer cell line CT26.WT.
(Preparation of tumor-bearing model)
CT26.WT cells were adjusted to a cell density of 1 x ¹⁰⁷ cells/mL in HBSS(-) medium (manufactured by Nacalai) to prepare a cell preparation for transplantation. 0.1 mL of this cell preparation for transplantation was subcutaneously transplanted into the back of a BALB/cCrslc mouse (female, 7 weeks old, Japan SLC). Four days after the cancer cells were transplanted, the mice were divided into groups so that the average tumor volume (see the calculation formula below) of the cancer-bearing mice was close to each other.
(Preparation of sample solution for administration of test substance)
The test substance was suspended in an administration solvent (Solutol HS15 (BASF)/0.5 w/v % methylcellulose 400 solution (Fujifilm Wako Pure Chemical Industries, Ltd.) = 1:4) to a concentration of 10 mg/mL, and the suspension was sonicated for 30 minutes to prepare a sample solution for administration.
(Preparation of antibody solution)
Anti-PD-1 antibody (Bio X Cell, clone RMP1-14; catalog No. BE0146) was prepared with physiological saline to a concentration of 1 mg/mL immediately before administration.
(Antitumor effect test of test substance)
Each mouse (6 mice per group) transplanted with cancer cells was forced to orally administer 0.1 mL of the test substance (100 mg/kg) or the solvent per 10 g of body weight on the day once a day from the 4th to the 20th day after transplantation. Drugs were suspended on the 9th, 10th, 16th, and 17th days after transplantation. In addition, the antibody administration group and the drug combination group were intraperitoneally administered 0.1 mL of the antibody solution (10 mg/kg) per 10 g of body weight on the day twice a week (5 times in total), and saline was administered intraperitoneally to the other groups. After transplantation, the mice were observed until the 21st day, and the tumor diameter was measured several times a week to calculate the tumor volume of each mouse using the following formula to evaluate the antitumor effect.
Formula Tumor volume = major axis x minor axis x minor axis x 0.5
(Evaluation results)
Figure 1 shows the change in tumor volume over time in each group. As shown in Figure 1, the compounds of the present invention, Example 6 and Example 7, showed a significant tumor growth suppression/tumor regression effect when used in combination with an anti-PD-1 antibody. This confirmed that the compounds of the present invention showed an excellent antitumor effect when used in combination with an immune checkpoint inhibitor, and are useful in the treatment of cancer.

Test Example 5
Combination effect of anti-PD-1 antibody in allograft mouse model of mouse colon cancer cell line CT26.WT 2
(Preparation of tumor-bearing model)
CT26.WT cells were adjusted to a cell density of 1 x ¹⁰⁷ cells/mL with HBSS(-) medium to prepare a cell preparation for transplantation. 0.1 mL of this cell preparation for transplantation was subcutaneously transplanted into the back of a BALB/cCrslc mouse (female, 7 weeks old, Japan SLC). On the third day after the cancer cells were transplanted, the mice were divided into groups so that the average tumor volume (see the calculation formula in Test Example 4) of the cancer-bearing mice was close to each other.
(Preparation of sample solution for administration of test substance)
The test substance was dissolved in an administration solvent (DMSO/polyethylene glycol 400 solution/30% hydroxypropyl-β-cyclodextrin=1:4:15) to a concentration of 3 mg/mL to prepare a sample solution for administration.
(Antitumor effect test of test substance)
Each mouse transplanted with cancer cells (10 mice in the solvent group, 9 mice in the compound group of Example 184, 9 mice in the antibody PD-1 antibody group, and 8 mice in the compound of Example 184 and antibody PD-1 antibody combination group) was forcibly administered 0.1 mL of the test substance (30 mg/kg) or the solvent per 10 g of body weight on the day once a day from the 3rd to the 21st day after transplantation. Drugs were suspended on the 8th, 9th, 15th, and 16th days after transplantation. In addition, the antibody administration group and the drug combination group were intraperitoneally administered 0.1 mL of antibody solution (10 mg/kg) per 10 g of body weight on the day twice a week (6 times in total), and saline was intraperitoneally administered to the other groups. After transplantation, the mice were observed until the 21st day, and the tumor diameter was measured several times a week to calculate the tumor volume of each mouse using the formula in Test Example 4 to evaluate the antitumor effect.
(Evaluation results)
Figure 2 shows the change in tumor volume over time in each group. As shown in Figure 2, the compound of the present invention, Example 184, showed a significant tumor growth inhibitory and tumor regression effect when used alone or in combination with an anti-PD-1 antibody. This confirmed that the compound of the present invention showed an excellent antitumor effect when used in combination with an immune checkpoint inhibitor, and is useful in the treatment of cancer.

The compounds provided by the present invention are useful for treating diseases known to be associated with abnormal cell responses via the TGFβ signal pathway, particularly cancer, and are also useful for preventing tumor metastasis and recurrence by targeting cancer stem cells. Furthermore, when used in combination with immune checkpoint inhibitors, they are useful for expanding and enhancing the therapeutic effect in cancer immunotherapy. They are also useful for treating and preventing fibrotic diseases, etc. Furthermore, they are useful as experimental and research reagents as ALK5 inhibitors and TGFβ signal inhibitors.

Claims (4)

The following formula (I):

(wherein R ¹ represents an optionally substituted alkyl group, an optionally substituted saturated heterocyclic group or an optionally substituted amino group; R ² represents an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted alkynyl group; and Z represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted saturated heterocyclic group or an optionally substituted cycloalkyl group), or a pharmacy acceptable salt thereof. The thiazole derivative or a pharma- ceutically acceptable salt thereof according to claim 1, wherein ^R2 is an optionally substituted aryl group or an optionally substituted heteroaryl group. The thiazole derivative or a pharma- ceutically acceptable salt thereof according to claim 1, wherein ^R2 is an alkynyl group which may have a substituent. A thiazole derivative or a pharma- ceutically acceptable salt thereof selected from the group consisting of Examples 1 to 226.

Images