WO2013162061A1 - Bicyclic pyrimidine compound - Google Patents

Abstract

Provided is a novel compound which inhibits Axl, and is useful in the treatment of diseases caused by Axl hyperfunction, the treatment of diseases related to Axl hyperfunction, and/or the treatment of diseases which accompany Axl hyperfunction. The bicyclic pyrimidine compound provided comprises various substituents and is represented by formula (1) (in formula (1) R¹, R², R³, R⁴, R⁵, R⁶, R⁷, A, W, X, Y, and n are each as defined in the description).

Description

Bicyclic pyrimidine compounds

The present invention relates to a bicyclic pyrimidine compound having Axl inhibitory activity or a salt thereof.

Axl is a receptor tyrosine kinase belonging to the Tyro3-Axl-Mer (TAM) receptor tyrosine kinase family with a growth arrest specific gene 6 (Gas6) protein as a ligand, and was initially identified as a transforming gene in chronic myeloid leukemia (Non-Patent Document 1).
The Gas6 / Axl signaling system regulates various cellular responses such as cell survival, cell division, autophagy, cell migration, angiogenesis, platelet aggregation, NK cell differentiation, etc. (Non-patent document 2), primary colon cancer (non-patent document 3), stomach cancer (non-patent document 4), esophageal cancer (non-patent document 5), melanoma (non-patent document 6), Many overexpressions in cancer tissues such as ovarian cancer (Non-patent document 7), kidney cancer (Non-patent document 8), endometrial cancer (Non-patent document 9), thyroid cancer (Non-patent document 10) have been reported. . It has also been shown that the presence of Axl is greatly related to lymph node status and stage in lung cancer and ER expression in breast cancer (Non-Patent Document 11). Furthermore, Axl is immune (non-patent document 12), platelet function (non-patent document 13), spermatogenesis (non-patent document 14), vascular calcification (non-patent document 15), thrombin-induced vascular smooth muscle cells (VSMC). It has also been shown to have a role in proliferation (Non-Patent Document 16) and various kidney diseases such as acute and chronic glomerulonephritis, diabetic nephropathy and chronic allograft rejection (Non-Patent Document 17). Inhibitors include but are not limited to cancer (including solid tumors such as carcinomas, sarcomas and leukemias and lymphoid malignancies), as well as vascular diseases (including thrombosis, atherosclerosis and restenosis). ), Kidney disease (including but not limited to acute and chronic glomerulonephritis, diabetic nephropathy and transplant rejection), and disordered angiogenesis are critical Expected to be beneficial in the treatment of a number of diseases, including but not limited to diabetic retinopathy, retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangiomas Has been.
Examples of compounds that inhibit Axl include compounds having a sulfonamide structure (Patent Document 3), compounds having a pyrrolopyrimidine structure (Patent Documents 4 and 5), compounds having a pyridine and pyrazine structure (Patent Document 6), and pyrazine. A compound having a structure (Patent Document 7), a compound having a pyrazinylbenzimidazole structure (Patent Document 8), a compound having an indolinone structure (Patent Document 9), a compound having a triazolopyridine and a triazolopyrimidine structure (Patent Document) 10), a compound having an imidazole structure (Patent Document 11), a compound having a triazole structure (Patent Document 12, Patent Document 13, Patent Document 14, Patent Document 15, Patent Document 16, Patent Document 17, Patent Document 20, Patent Document) 24, Patent Document 25, Patent Document 26, Patent Document 27, Patent 28), compounds having a pyrimidinediamine structure (Patent Document 18), compounds having a pyrimidine structure (Patent Document 19, Non-Patent Document 18, Non-Patent Document 22), compounds having a quinolinyloxyphenylsulfonamide structure (Patent Document 19) 21), compounds having a quinoline structure (Patent Document 22, Patent Document 30, Non-Patent Document 21), compounds having a pyridine structure (Patent Document 23, Non-Patent Document 19), compounds having a urea structure (Patent Document 29) , A compound having a 2,4-disubstituted arylamide structure (Non-Patent Document 20), a compound having a secosteroid structure (Non-Patent Document 23), and a compound having a bicyclic pyrimidine structure (Patent Document 31 and Patent Document 32) Nitrogen-containing heterocyclic-2-carboxamide derivatives (Patent Document 33) and the like have been reported.

International Publication No. 2008/025820 International Publication No. 2008/074997 International Publication No. 2008/128072 US Patent Application Publication No. 20110422221 International Publication No. 2010/090764 International Publication No. 2009/053737 International Publication No. 2009/007390 International Publication No. 2009/024825 International Publication No. 2007/057399 International Publication No. 2009/047514 International Publication No. 2009/058801 International Publication No. 2008/083367 International Publication No. 2008/083353 International Publication No. 2010/005879 International Publication No. 2008/083357 International Publication No. 2008/083356 International Publication No. 2008/083354 International Publication No. 2008/045978 International Publication No. 2007/070872 International Publication No. 2007/030680 International Publication No. 2011/045084 International Publication No. 2009/127417 International Publication No. 2007/066187 International Publication No. 2009/054864 International Publication No. 2010/005876 International Publication No. 2009/054864 US Patent Application Publication No. 20090111816 US Patent Application Publication No. 2013018416 International Publication No. 2009/138799 US Patent Application Publication No. 20090274693 US Patent Application Publication No. 20120006369 US Patent Application Publication No. 20070142402 European Patent Publication No. 2423208

The present invention provides a novel Axl inhibitory compound. The present invention also provides a therapeutic agent for a disease caused by hyperfunction of Axl, a therapeutic agent for a disease associated with hyperfunction of Axl, and / or treatment of a disease associated with hyperfunction of Axl, comprising an Axl inhibitory compound. An agent such as an anticancer agent is provided.

As a result of intensive studies, the present inventors have found that a compound having a structure represented by the following general formula (1) or a salt thereof has strong Axl inhibitory activity, and completed the present invention.
That is, the present invention relates to the following [1] to [25].
[1] General formula (1)

[In Formula (1),
A represents a phenylene group or a 6-membered heteroarylene group, and the relative configuration of the amino group and nitrogen-containing heterocycle bonded to A is a para configuration;
W represents a carbon atom or a nitrogen atom (provided that when W is a nitrogen atom, R ⁴ does not exist);
X represents CH or a nitrogen atom,
Y represents a carbon atom or a nitrogen atom (provided that when Y is a nitrogen atom, R ⁶ does not exist);
R ¹ is a cycloalkyl group optionally having one or more substituents selected from group 1, an aryl group optionally having one or more substituents selected from group 1, group 1 represents a heteroaryl group optionally having one or more substituents selected from 1;
R ² is a C ₁ -C ₆ alkyl group optionally having one or more substituents selected from Group 2, —OR ^C (where R ^C is a C ₁ -C ₆ alkoxy group, A C ₁ -C ₆ alkyl group optionally having one or more substituents selected from a halogen atom and a hydroxyl group, or a hydrogen atom), one or more substituents selected from Group 2; C ₁ -C ₆ alkylthio group which may have, NR ^A R ^B (wherein R ^A and R ^B each independently represents a C ₁ -C ₆ alkyl group, a hydrogen atom, or R ^A and R ^B are taken together they may form a heterocycloalkyl group of 3 to 7-membered together with the nitrogen atom to be replaced.), have one or more substituents selected from the group 1 May represent a cycloalkyl group or a hydrogen atom,
R ³ is a substituent on A (n is an integer of 0 to 4, and R ³ when n is 2 or more may be the same or different from each other), and is selected from Group 2 C ₁ -C ₆ alkoxy optionally having one or more substituents selected from a C ₁ -C ₆ alkyl group optionally having one or more substituents, a halogen atom and a hydroxyl group A C ₁ -C ₆ alkylthio group, a halogen atom or a hydroxyl group which may have one or more substituents selected from a group, a halogen atom and a hydroxyl group;
R ⁴ is a substituent on W in the case where W is a carbon atom, and is a C ₁ -C ₆ alkyl group optionally having one or more substituents selected from Group 2, C _1- C ₁ -C ₆ alkoxy group optionally having one or more substituents selected from a C ₆ alkoxy group, a heterocycloalkyl group, a halogen atom and a hydroxyl group, one or more substituents selected from Group 3 A cycloalkyl group that may have a group, a cycloalkenyl group that may have one or more substituents selected from group 3, and one or more substituents selected from group 3 An optionally substituted heterocycloalkyl group, a heterocycloalkenyl group optionally having one or more substituents selected from group 3, and one or more substituents selected from group 3 Good alley A heteroaryl group, a cyano group, a halogen atom or a hydrogen atom which may have one or more substituents selected from
R ⁵ is a C ₁ -C ₆ alkyl group optionally having one or more substituents selected from Group 2, —OR ^C (where R ^C is a C ₁ -C ₆ alkoxy group, One or more substituents selected from a C ₁ to C ₆ alkyl group, a halogen atom, a C ₁ to C ₆ alkyl group and a hydroxyl group, which may have one or more substituents selected from a halogen atom and a hydroxyl group A 3- to 7-membered heterocycloalkyl group which may have a group, or a hydrogen atom), or a hydrogen atom,
R ⁶ is a substituent on Y in the case where Y is a carbon atom, and is a C ₁ -C ₆ alkyl group which may have one or more substituents selected from Group 2 or a hydrogen atom. Show
R ⁷ represents a hydrogen atom or a C ₁ to C ₆ alkyl group optionally having one or more substituents selected from Group 2. ]
Or a salt thereof.
Group 1: a C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy group, oxo group, hydroxyl group and halogen atom which may have one or more substituents selected from a halogen atom and a hydroxyl group.
Group 2:
A halogen atom,
An oxo group,
-NR ^A R ^B , -CONR ^A R ^B (wherein R ^A and R ^B each independently have one or more substituents selected from a halogen atom, a C ₁ -C ₆ alkoxy group and a hydroxyl group) or show was good C ₁ ~ C ₆ alkyl group optionally or a hydrogen atom, together with the nitrogen atom to replace them together is R ^a and R ^B, a halogen atom, C ₁ ~ C ₆ alkyl groups, C _{A 1} to C ₆ alkoxy group and a 3- to 7-membered heterocycloalkyl group which may have one or more substituents selected from a hydroxyl group may be formed).
-OR ^C (wherein, ^{R C} is, _{C 1} ~ _{C 6} alkoxy group, one or a plurality of which may have a substituent _{C 1} ~ _{C 6} alkyl group selected from a halogen atom and a hydroxyl group, a halogen atom shows a C ₁ ~ C ₆ alkyl group and one or a plurality of substituents may be 3-7 membered heterocycloalkyl group selected from a hydroxyl group or a hydrogen atom.),
One or more selected from a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, an oxo group and a halogen atom, which may have one or more substituents selected from a halogen atom and a hydroxyl group An aryl group which may have a substituent,
One or more selected from a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, an oxo group, a hydroxyl group and a halogen atom, which may have one or more substituents selected from a halogen atom and a hydroxyl group Heteroaryl group optionally having 1 substituent,
One or more selected from a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, an oxo group, a hydroxyl group and a halogen atom, which may have one or more substituents selected from a halogen atom and a hydroxyl group 3 to 7-membered cycloalkyl group optionally having one substituent,
One or more selected from a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, an oxo group, a hydroxyl group and a halogen atom, which may have one or more substituents selected from a halogen atom and a hydroxyl group 3- to 7-membered heterocycloalkyl group which may have one substituent: C ₁ -C ₆ alkyl group which may have one or more substituents selected from group 2; A C ₁ -C ₆ acyl group optionally having one or more substituents selected from Group 2;
A C ₁ -C ₆ alkylthio group optionally having one or more substituents selected from a halogen atom and a hydroxyl group,
—CONR ^A R ^B (wherein R ^A and R ^B are each independently a C atom optionally having one or more substituents selected from a halogen atom, a C ₁ -C ₆ alkoxy group and a hydroxyl group) ₁ ~ _{C 6} alkyl group or a hydrogen atom, together with the nitrogen atom ^{to which R a} and ^{R B} are substituted they are taken together, a halogen atom, _{C 1} ~ _{C 6} alkyl group, _{C 1} ~ _{C 6} alkoxy group And a 3- to 7-membered heterocycloalkyl group which may have one or more substituents selected from a hydroxyl group).
—OR ^C (wherein R ^C may have one or more substituents selected from a C ₁ -C ₆ alkoxy group, a halogen atom, a 3- to 7-membered heterocycloalkyl group, and a hydroxyl group. A C ₁ to C ₆ alkyl group, a halogen atom, a C ₁ to C ₆ alkyl group and a 3- to 7-membered heterocycloalkyl group optionally having one or more substituents selected from a hydroxyl group, or a hydrogen atom ),
The compound or salt thereof according to [1], wherein heterocycloalkyl group [2] A optionally having one or more substituents selected from group 2 is a phenylene group.
[3] The compound or salt thereof according to [1] or [2], wherein W is a carbon atom.
[4] The compound or salt thereof according to any one of [1] to [3], wherein X and Y are nitrogen atoms.
[5] The compound or salt thereof according to any one of [1] to [4], wherein n is 0.
[6] The compound or salt thereof according to any one of [1] to [5], wherein R ⁵ is a hydrogen atom.
[7] Any one compound or salt thereof selected from the following group.

[8] An Axl inhibitor comprising the compound according to any one of [1] to [7] or a salt thereof.
[9] A medicament comprising the compound or salt thereof according to any one of [1] to [7] as an active ingredient.
[10] A disease caused by increased Axl kinase function, a disease associated with increased Axl kinase function, and / or Axl kinase, comprising the compound or salt thereof according to any one of [1] to [7] as an active ingredient A medicament for the treatment of diseases associated with hyperfunction.
[11] A medicament for the treatment of a hyperproliferative disease comprising the compound according to any one of [1] to [7] or a salt thereof as an active ingredient.
[12] A medicament for treating cancer comprising the compound according to any one of [1] to [7] or a salt thereof as an active ingredient.
[13] A medicament for preventing cancer metastasis comprising the compound or salt thereof according to any one of [1] to [7] as an active ingredient.
[14] A medicament for releasing drug resistance comprising the compound or salt thereof according to any one of [1] to [7] as an active ingredient.
[15] Cancer is breast cancer, colon cancer, prostate cancer, lung cancer, stomach cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, uterine cancer, esophageal cancer, squamous cell carcinoma, leukemia, osteosarcoma [12] or [13], wherein the medicament is selected from melanoma, glioblastoma, and neuroblastoma.
[16] A pharmaceutical composition comprising the compound according to any one of [1] to [7] or a salt thereof, and a pharmaceutically acceptable carrier.
[17] Use of the compound or salt thereof according to any one of [1] to [7], a disease caused by an increased Axl kinase function, a disease associated with an increased Axl kinase function, and / or A method for treating a disease associated with hyperfunction of Axl kinase.
[18] A method for treating a hyperproliferative disease, comprising using the compound according to any one of [1] to [7] or a salt thereof.
[19] A method for treating cancer, comprising using the compound according to any one of [1] to [7] or a salt thereof.
[20] A method for preventing cancer metastasis, comprising using the compound or salt thereof according to any one of [1] to [7].
[21] A method for releasing drug resistance, comprising using the compound or salt thereof according to any one of [1] to [7].
[22] Cancer is breast cancer, colon cancer, prostate cancer, lung cancer, stomach cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, uterine cancer, esophageal cancer, squamous cell carcinoma, leukemia, osteosarcoma [19] or [20], wherein the method is selected from melanoma, glioblastoma and neuroblastoma.
[23] Use of the compound according to any one of [1] to [7] or a salt thereof for producing a medicament.
[24] Use of the compound or salt thereof according to any one of [1] to [7] for the treatment of cancer.
[25] Use of the compound or salt thereof according to any one of [1] to [7] for preventing metastasis of cancer.

The present invention provides a novel bicyclic pyrimidine derivative represented by the above formula (1) having Axl inhibitory activity. Such novel compounds are useful as therapeutic agents, for example, anticancer agents, for diseases caused by increased Axl function, diseases associated with increased Axl function, and / or diseases associated with increased Axl function.

In the present invention, Axl refers to a protein encoded by the Axl gene. “Axl” includes an Axl protein encoded by a full-length Axl gene or an Axl protein encoded by an Axl gene mutant (including a deletion mutant, a substitution mutant, or an additional mutant). In the present invention, “Axl” includes homologs derived from various animal species.
In the present invention, “Axl inhibitor” refers to an inhibitor of the function of Axl as a tyrosine kinase.
In the present invention, the terms “tumor” and “cancer” are used interchangeably. In the present invention, a tumor, a malignant tumor, a cancer, a malignant neoplasm, a carcinoma, a sarcoma, etc. may be collectively referred to as “tumor” or “cancer”.
In the present invention,
“C ₁ ~ C ₆ “Alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. “C ₁ ~ C ₆ Examples of the “alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group and the like.
“C ₁ ~ C ₆ The term “alkoxy group” means an alkoxy group having a linear or branched alkyl group having 1 to 6 carbon atoms. “C ₁ ~ C ₆ Examples of the “alkoxy group” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The “oxo group” means a group represented by “═O” unless otherwise specified.
The “cycloalkyl group” means a cyclic alkyl group having 3 to 8 carbon atoms unless otherwise specified, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
The “heterocycloalkyl group” means a monovalent saturated heterocyclic group, and includes a saturated heterocyclic group having a nitrogen atom in the ring, a saturated heterocyclic group having an oxygen atom in the ring, and the like, for example, pyrrolidine, And monovalent groups derived from imidazoline, piperidine, piperazine, azetidine, morpholine, dioxane, oxetane, tetrahydropyran, and quinuclidine.
Examples of the “cycloalkenyl group” include those having an unsaturated bond such as one or more double bonds in the above “cycloalkyl group”, and examples thereof include a cyclopentenyl group and a cyclohexenyl group.
Examples of the “heterocycloalkenyl group” include those having an unsaturated bond such as one or more double bonds in the above “heterocycloalkyl group”, and examples thereof include a tetrahydropyridyl group and a dihydropyranyl group. .
The “aryl group” means a monovalent substituent derived from an aromatic hydrocarbon, and examples of the aryl group include a phenyl group, an indenyl group, a naphthyl group, a fluorenyl group, an anthranyl group, and a phenanthrenyl group. .
`` Heteroaryl group '' means a monovalent aromatic heterocyclic group, pyrrolyl group, pyrazolyl group, triazolyl group, oxazolyl group, oxadiazolyl group, thiophenyl group, thiazolyl group, thiadiazolyl group, pyridinyl group, pyrimidyl group, Examples include a pyridazyl group, a pyrazinyl group, a benzimidazolyl group, a benzotriazolyl group, a benzofuranyl group, a benzothiophenyl group, a quinolyl group, a carbazolyl group, and a dibenzofuranyl group.
The “heteroarylene group” means a divalent aromatic heterocyclic group, and examples thereof include a divalent group derived from pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like.
Below, each substituent in Formula (1) is demonstrated.
In the following general formula (1),

A represents a phenylene group or a 6-membered heteroarylene group. The relative arrangement of the amino group bonded to ring A and the nitrogen-containing heterocycle is a para arrangement.
When A is a heteroarylene group, A is preferably a group containing a nitrogen atom, particularly preferably a group derived from pyridine. The position of elements other than carbon in the ring of A is not particularly limited.
A is more preferably a phenylene group.
W represents a carbon atom or a nitrogen atom (provided that when W is a nitrogen atom, R ⁴ Does not exist. ), More preferably a carbon atom.
X represents CH or a nitrogen atom, and more preferably a nitrogen atom.
Y represents a carbon atom or a nitrogen atom (provided that when Y is a nitrogen atom, R ⁶ Does not exist. ), More preferably a nitrogen atom.
R ¹ Is a cycloalkyl group optionally having one or more substituents selected from Group 1 above, an aryl group optionally having one or more substituents selected from Group 1 above, 1 represents a heteroaryl group optionally having one or more substituents selected from Group 1.
Here, “R may optionally have one or more substituents selected from the above group 1” ¹ When “is a cycloalkyl group”, the “cycloalkyl group” is preferably a cyclopentyl group or a cyclohexyl group, where R ¹ Is preferably an unsubstituted cyclohexyl group.
R ¹ However, in the case of “an aryl group optionally having one or more substituents selected from the group 1”, the “aryl group” is preferably a phenyl group. As the substituent of the phenyl group, it may have 1 to 3 substituents selected from fluorine atom, chlorine atom and hydroxyl group. ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ One to three groups selected from an alkoxy group, a hydroxyl group, a fluorine atom or a chlorine atom are preferred.
R ¹ Is a “heteroaryl group” in which it is a “heteroaryl group optionally having one or more substituents selected from group 1” above, a heteroaryl group containing a nitrogen atom is preferred, and pyridinyl Group, pyrimidinyl group, pyridazinyl group or pyrazinyl group is more preferable, and pyridyl group is particularly preferable. The substituent for the heteroaryl group may have 1 to 3 substituents selected from a fluorine atom, a chlorine atom and a hydroxyl group. ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ One to three groups selected from an alkoxy group, a hydroxyl group, a fluorine atom or a chlorine atom are preferred.
R ¹ As an unsubstituted phenyl group, 1 to 3 halogen atoms may be substituted. ₁ ~ C ₆ A phenyl group substituted with 1 to 3 groups selected from an alkyl group and a halogen atom, an unsubstituted pyridinyl group, and 1 to 3 halogen atoms optionally substituted with C ₁ ~ C ₆ More preferred is a pyridinyl group substituted with 1 to 3 groups selected from an alkyl group and a halogen atom.
R ² May have one or more substituents selected from Group 2 above ₁ ~ C ₆ Alkyl group, -OR ^C (Where R ^C Is C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group ₁ ~ C ₆ An alkyl group or a hydrogen atom is shown. ), Optionally having one or more substituents selected from group 2 above ₁ ~ C ₆ Alkylthio group, -NR ^A R ^B (Where R ^A And R ^B Are independently C ₁ ~ C ₆ Represents an alkyl group, or a hydrogen atom, or R ^A And R ^B Together with the nitrogen atom with which they are substituted may form a 3-7 membered heterocycloalkyl group. ), A cycloalkyl group or a hydrogen atom which may have one or more substituents selected from the above group 1.
Where R ² "C optionally having one or more substituents selected from group 2 above" ₁ ~ C ₆ C in the case of “alkyl group” ₁ ~ C ₆ As the alkyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group is preferable.
R ² "C optionally having one or more substituents selected from group 2 above" ₁ ~ C ₆ C in the case of “alkyl group” ₁ ~ C ₆ The halogen atom as a substituent of the alkyl group is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably a fluorine atom. C ₁ ~ C ₆ A plurality of the same or different halogen atoms may be substituted on the alkyl group, and the number of substitution is preferably 1 to 3 in the case of substitution.
R ² "C optionally having one or more substituents selected from group 2 above" ₁ ~ C ₆ C in the case of “alkyl group” ₁ ~ C ₆ -OR as a substituent of an alkyl group ^C (Where R ^C Is C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group ₁ ~ C ₆ An alkyl group is shown. ) Is R ^C Is C ₁ ~ C ₆ C optionally having an alkoxy group ₁ ~ C ₆ An alkyl group is preferred.
R ² Is "-OR ^C (Where R ^C Is C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group ₁ ~ C ₆ An alkyl group or a hydrogen atom is shown. ) "If R ^C The preferred range of C is C ₁ ~ C ₆ Alkoxy group and halogen atom may be substituted C ₁ ~ C ₆ An alkyl group is preferred, R ^C Is C ₁ ~ C ₃ Alkoxy group and fluorine atom may be substituted C ₁ ~ C ₃ More preferably, it is an alkyl group.
R ² Is "C which may have one or a plurality of substituents selected from Group 2 above" ₁ ~ C ₆ A preferred range in the case of “alkylthio group” is an unsubstituted C ₁ ~ C ₆ C substituted with an alkyl group ₁ ~ C ₆ Alkylthio groups are preferred and unsubstituted C ₁ ~ C ₆ An alkylthio group is more preferred.
R ² Is "-NR ^A R ^B (Where R ^A And R ^B Are independently C ₁ ~ C ₆ Represents an alkyl group, or a hydrogen atom, or R ^A And R ^B Together with the nitrogen atom with which they are substituted may form a 3-7 membered heterocycloalkyl group. ) ", R ^A And R ^B Each independently represents an unsubstituted C ₁ ~ C ₆ An alkyl group or a hydrogen atom, or R ^A And R ^B Together with the nitrogen atom with which they are substituted, a halogen atom, C ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ It is preferable to form a 3- to 6-membered heterocycloalkyl group which may have one or more substituents selected from an alkoxy group and a hydroxyl group, wherein “3- to 6-membered heterocycloalkyl group” "Is preferably a pyrrolidinyl group or an azetidinyl group.
R ² Is a “cycloalkyl group” in which it is a “cycloalkyl group optionally having one or more substituents selected from group 1” above, a 3- to 7-membered cycloalkyl group is preferred, A propyl group and a cyclobutyl group are more preferable.
R ² As for C, one to three halogen atoms may be substituted. ₁ ~ C ₆ Alkyl group, C which may be substituted with 1 to 3 halogen atoms ₁ ~ C ₆ An alkoxy group or a hydrogen atom is more preferable.
R ³ Is a substituent on A (wherein n represents an integer of 0 to 4 and n is 2 or more, R ³ May be the same as or different from each other. ), C optionally having one or more substituents selected from group 2 ₁ ~ C ₆ C may have one or more substituents selected from an alkyl group, a halogen atom and a hydroxyl group ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group ₁ ~ C ₆ An alkylthio group, a halogen atom or a hydroxyl group is shown.
R ³ Is "C which may have one or a plurality of substituents selected from Group 2 above" ₁ ~ C ₆ The preferred range in the case of “alkyl group” is the above R ² "C optionally having one or more substituents selected from group 2 above" ₁ ~ C ₆ Synonymous with "alkyl group" but R ³ "C optionally having one or more substituents selected from group 2 above" ₁ ~ C ₆ In the case of an “alkyl group”, it may be substituted with 1 to 3 fluorine atoms, chlorine atoms, bromine atoms or hydroxyl groups. ₁ ~ C ₆ It is preferably an alkyl group, and unsubstituted C ₁ ~ C ₆ More preferably, it is an alkyl group.
R ³ Is "C optionally having one or more substituents selected from a halogen atom and a hydroxyl group" ₁ ~ C ₆ In the case of “alkoxy group”, C may be substituted with 1 to 3 fluorine atoms, chlorine atoms, bromine atoms or hydroxyl groups. ₁ ~ C ₃ It is preferably an alkoxy group, and unsubstituted C ₁ ~ C ₃ More preferably, it is an alkoxy group.
R ³ Is "C optionally having one or more substituents selected from a halogen atom and a hydroxyl group" ₁ ~ C ₆ In the case of an alkylthio group, it may be substituted with 1 to 3 fluorine atoms, chlorine atoms, bromine atoms or hydroxyl groups. ₁ ~ C ₃ It is preferably an alkylthio group, and unsubstituted C ₁ ~ C ₃ More preferably, it is an alkylthio group.
R ³ Is a “halogen atom”, it is preferably a fluorine atom, a chlorine atom or a bromine atom.
R ³ N is preferably 0 to 3, more preferably n is 0 or 1, and when n is 1 to 3, ³ Is a fluorine atom, a chlorine atom, a bromine atom, C ₁ ~ C ₆ Alkyl group or C ₁ ~ C ₆ More preferably, it is an alkoxy group.
R ⁴ Is a substituent on W when W is a carbon atom, and may have one or more substituents selected from Group 2 above. ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ C may have one or more substituents selected from an alkoxy group, a cycloheteroalkyl group, a halogen atom and a hydroxyl group ₁ ~ C ₆ An alkoxy group, a cycloalkyl group optionally having one or more substituents selected from Group 3 above, a cycloalkenyl group optionally having one or more substituents selected from Group 3; A heterocycloalkyl group optionally having one or more substituents selected from group 3, a heterocycloalkenyl group optionally having one or more substituents selected from group 3 above, An aryl group optionally having one or more substituents selected from group 3 or a heteroaryl group optionally having one or more substituents selected from group 3; a cyano group; Indicates an atom or a hydrogen atom.
R ⁴ Is "C which may have one or a plurality of substituents selected from Group 2 above" ₁ ~ C ₆ The preferred range in the case of “alkyl group” is the above R ² "C optionally having one or more substituents selected from group 2 above" ₁ ~ C ₆ Synonymous with “alkyl group”, but unsubstituted C ₁ ~ C ₆ Alkyl group, C substituted with 1 to 3 halogen atoms ₁ ~ C ₆ Alkyl groups are preferred and unsubstituted C ₁ ~ C ₆ An alkyl group is more preferred.
R ⁴ Is "C ₁ ~ C ₆ Optionally having one or more substituents selected from an alkoxy group, a heterocycloalkyl group, a halogen atom and a hydroxyl group ₁ ~ C ₆ In the case of “alkoxy group”, unsubstituted C ₁ ~ C ₆ C substituted with an alkoxy group or 1 to 3 halogen atoms ₁ ~ C ₆ Alkoxy groups are preferred and unsubstituted C ₁ ~ C ₆ An alkoxy group is more preferable.
R ⁴ Is a “cycloalkyl group” in the case of “a cycloalkyl group optionally having one or more substituents selected from the group 3”, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. Group is preferred, R ⁴ Is a cyclopentenyl group or a cyclohexenyl group, preferably “cycloalkenyl group optionally having one or more substituents selected from group 3” above. ⁴ Is a “heterocycloalkyl group” in the case of “heterocycloalkyl group optionally having one or more substituents selected from group 3” as azetidinyl group, pyrrolidinyl group, piperidinyl group, A piperazinyl group or a morpholinyl group is preferred, and R ⁴ Is a “heterocycloalkenyl group that may have one or more substituents selected from the above group 3”, the “heterocycloalkenyl group” includes a tetrahydropyridyl group or a dihydropyranyl group. Preferably R ⁴ Is a phenyl group as the aryl group, preferably an aryl group optionally having one or more substituents selected from Group 3 above, ⁴ Is a “heteroaryl group” in the case of “a heteroaryl group optionally having one or more substituents selected from the above group 3”, a pyridinyl group, pyrazinyl group, pyrimidinyl group, pyrazolyl group An imidazolyl group, a thiophenyl group, a thiazolyl group, an isothiazolyl group, a furanyl group, an oxazolyl group or a triazolyl group is preferred.
The number of substituents substituted on the cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group is preferably 0 to 3.
The substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group may be “which may have one or more substituents selected from the above group 2. Good C ₁ ~ C ₆ C in the case of “alkyl group” ₁ ~ C ₆ As the alkyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group is preferable.
The substituent of the cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group may have “one or more substituents selected from the above group 2”. C ₁ ~ C ₆ A preferable range in the case of “alkyl group” includes a halogen atom, C ₁ ~ C ₆ Alkyl group, -NR ^A R ^B And -CONR ^A R ^B (Where R ^A And R ^B Each independently represents a halogen atom, C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group and a hydroxyl group ₁ ~ C ₆ Represents an alkyl group, or a hydrogen atom, or R ^A And R ^B Together with the nitrogen atom with which they are substituted, a halogen atom, C ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ A 3- to 7-membered heterocycloalkyl group which may have one or a plurality of substituents selected from an alkoxy group and a hydroxyl group may be formed. ), -OR ^C (Where R ^C Is C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group ₁ ~ C ₆ Alkyl group, halogen atom, C ₁ ~ C ₆ 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom. ) Or C which may be substituted with an optionally substituted heterocycloalkyl group ₁ ~ C ₆ An alkyl group is preferred.
Where C ₁ ~ C ₆ The halogen atom as the substituent of the alkyl group is preferably a fluorine atom, a chlorine atom or a bromine atom, and C ₁ ~ C ₆ A plurality of the same or different halogen atoms may be substituted on the alkyl group, and the number of substitution is preferably 1 to 3 in the case of substitution.
Where C ₁ ~ C ₆ —NR as a substituent of an alkyl group ^A R ^B And -CONR ^A R ^B (Where R ^A And R ^B Each independently represents a halogen atom, C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group and a hydroxyl group ₁ ~ C ₆ Represents an alkyl group, or a hydrogen atom, or R ^A And R ^B Together with the nitrogen atom with which they are substituted, a halogen atom, C ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ A 3- to 7-membered heterocycloalkyl group which may have one or a plurality of substituents selected from an alkoxy group and a hydroxyl group may be formed. ) Is R ^A And R ^B Together, a halogen atom, C ₁ ~ C ₆ An amino group or R which forms a 3- to 7-membered heterocycloalkyl group which may have one or more substituents selected from an alkoxy group and a hydroxyl group; ^A And R ^B Together, a halogen atom, C ₁ ~ C ₆ A carbamoyl group forming a 3- to 7-membered heterocycloalkyl group which may have one or a plurality of substituents selected from an alkoxy group and a hydroxyl group is preferable. It is more preferably a carbamoyl group forming a 3- to 7-membered heterocycloalkyl group optionally having an amino group or a hydroxyl group forming a 3- to 7-membered heterocycloalkyl group. Particularly preferred are amino groups forming a substituted azetidinyl group, pyrrolidinyl group, piperidinyl group.
Where C ₁ ~ C ₆ -OR as a substituent of an alkyl group ^C (Where R ^C May have one or more substituents selected from a halogen atom and a hydroxyl group. ₁ ~ C ₆ An alkyl group or a hydrogen atom is shown. ) Is R ^C Is C ₁ ~ C ₆ It is preferably an alkyl group or a hydrogen atom, and the number of substitutions for substitution is preferably 1 to 3.
Where C ₁ ~ C ₆ The heterocycloalkyl group which may have a substituent as a substituent of the alkyl group may have one or more substituents selected from a halogen atom and a hydroxyl group. ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ It is preferably a 3- to 7-membered heterocycloalkyl group which may have one or more substituents selected from an alkoxy group, an oxo group, a hydroxyl group and a halogen atom,
Unsubstituted or C ₁ ~ C ₆ A 3- to 7-membered heterocycloalkyl group substituted with an alkyl group is more preferred. Here, the “3- to 7-membered heterocycloalkyl group” includes a tetrahydropyranyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, an imidazolidinyl group, and a pyrazolidinyl group. Group, piperidino group, morpholino group, dioxanyl group and oxetanyl group are preferable, and pyrrolidinyl group and dioxanyl group are more preferable. C of each heterocycloalkyl group ₁ ~ C ₆ The bonding position to the alkyl group is not limited, but in the case of a dioxanyl group, it is preferably bonded at the 2-position, and in the case of a pyrrolidinyl group, it is preferably bonded at the 2-position.
The substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group may be “which may have one or more substituents selected from the above group 2. Good C ₁ ~ C ₆ A preferable range in the case of “acyl group” is C ₁ ~ C ₆ Alkyl group, -OR ^C (Where R ^C Is C ₁ ~ C ₆ An alkyl group or a hydrogen atom is shown. C) optionally substituted with ₁ ~ C ₆ An acyl group is preferred. Hydroxyl group or C ₁ ~ C ₃ C in which the alkyl group may be substituted ₁ ~ C ₃ More preferably, it is an acyl group.
The substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group is “having one or more substituents selected from a halogen atom and a hydroxyl group. Moyo C ₁ ~ C ₆ In the case of “alkylthio group”, unsubstituted C ₁ ~ C ₆ An alkylthio group is preferred, and “—CONR ^A R ^B (Where R ^A And R ^B Each independently represents a halogen atom, C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group and a hydroxyl group ₁ ~ C ₆ Represents an alkyl group, or a hydrogen atom, or R ^A And R ^B Together with the nitrogen atom with which they are substituted, a halogen atom, C ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ A 3- to 7-membered heterocycloalkyl group which may have one or a plurality of substituents selected from an alkoxy group and a hydroxyl group may be formed. ) ", R ^A And R ^B Each independently represents an unsubstituted C ₁ ~ C ₆ An alkyl group or a hydrogen atom, or R ^A And R ^B Together with the nitrogen atom with which they are substituted, a halogen atom, C ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ It is preferable to form a 3- to 6-membered heterocycloalkyl group which may have one or more substituents selected from an alkoxy group and a hydroxyl group, wherein “3- to 6-membered heterocycloalkyl group” "Is preferably a pyrrolidinyl group, a morpholino group, an azetidinyl group or a piperidinyl group.
The substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group is represented by "-OR ^C (Where R ^C Is C ₁ ~ C ₆ Optionally having one or more substituents selected from an alkoxy group, a halogen atom, a 3- to 7-membered heterocycloalkyl group and a hydroxyl group ₁ ~ C ₆ Alkyl group, halogen atom, C ₁ ~ C ₆ 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom. ) "," R " ^C Is C ₁ ~ C ₆ Optionally having one or more substituents selected from an alkoxy group, a halogen atom, a 3- to 7-membered heterocycloalkyl group and a hydroxyl group ₁ ~ C ₆ An alkyl group or a hydrogen atom is preferred, and C ₁ ~ C ₆ C substituted with an alkoxy group or a 3-7 membered heterocycloalkyl group ₁ ~ C ₆ An alkyl group is more preferred. Here, the 3- to 7-membered heterocycloalkyl group is preferably a pyrrolidyl group, imidazolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, tetrahydropyranyl group, dioxanyl group or tetrahydrofuranyl group. "R ^C "Is particularly preferably a methyl group, an ethyl group, a methyl group substituted with a dioxanyl group, an ethyl group substituted with a dioxanyl group, a methyl group substituted with a methoxy group, or an ethyl group substituted with a methoxy group. In addition, "-OR ^C Are substituted on the cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group, “-OR ^C May be combined with each other to form a saturated oxygen-containing saturated heterocyclic ring. Multiple "-OR ^C ”May be substituted on the same atom or different atoms on the cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group.
The substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group may have “one or more substituents selected from Group 1”. In the case of “heterocycloalkyl”, C ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ An alkoxy group, an oxo group, a hydroxyl group or a heterocycloalkyl group optionally substituted with a halogen atom is preferred, and C ₁ ~ C ₆ A heterocycloalkyl group substituted with an alkyl group, a halogen atom or an oxo group or an unsubstituted heterocycloalkyl group is more preferred.
R ⁴ Is a “halogen atom”, it is preferably a fluorine atom, a chlorine atom or a bromine atom.
R ⁴ 1 to 3 C ₁ ~ C ₆ Phenyl group substituted with alkoxy group, 1 to 3 C ₁ ~ C ₆ 5- or 6-membered nitrogen-containing heteroaryl group substituted with an alkyl group or the following group

It is preferable that it is either group represented by these. Here, the nitrogen-containing heteroaryl group is preferably a pyridinyl group or a pyrazolyl group.
R ⁵ May have one or more substituents selected from Group 1 above. ₁ ~ C ₆ Alkyl group, -OR ^C (Where R ^C Is C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group ₁ ~ C ₆ Alkyl group, halogen atom, C ₁ ~ C ₆ 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom. ) Or a hydrogen atom.
R ⁵ "C optionally having one or more substituents selected from the above group 1 ₁ ~ C ₆ The preferred range in the case of “alkyl group” is the above R ² "C optionally having one or more substituents selected from the above group 1" ₁ ~ C ₆ Synonymous with “alkyl group”, but unsubstituted C ₁ ~ C ₆ Alkyl group, C substituted with 1 to 3 halogen atoms ₁ ~ C ₆ Alkyl groups are preferred and unsubstituted C ₁ ~ C ₆ An alkyl group is more preferred.
R ⁵ Is "-OR ^C (Where R ^C Is C ₁ ~ C ₆ C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group ₁ ~ C ₆ Alkyl group, halogen atom, C ₁ ~ C ₆ 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom. ) ", Hydrogen atom, unsubstituted C ₁ ~ C ₆ C substituted with an alkoxy group or 1 to 3 halogen atoms ₁ ~ C ₆ Alkoxy groups are preferred and unsubstituted C ₁ ~ C ₆ An alkoxy group is more preferable.
R ⁵ As C ₁ ~ C ₆ Alkyl group, C ₁ ~ C ₆ An alkoxy group or a hydrogen atom is preferable, and a methoxy group, an ethoxy group, a trifluoromethoxy group, a difluoromethoxy group, or a hydrogen atom is more preferable.
R ⁶ Is a substituent on Y in the case where Y is a carbon atom, and may have one or more substituents selected from Group 1 above. ₁ ~ C ₆ An alkyl group or a hydrogen atom is shown.
R ⁶ Is "C which may have one or a plurality of substituents selected from Group 1 above" ₁ ~ C ₆ The preferred range in the case of “alkyl group” is the above R ² "C optionally having one or more substituents selected from the above group 1" ₁ ~ C ₆ Synonymous with “alkyl group”, but unsubstituted C ₁ ~ C ₆ C substituted with an alkyl group or 1 to 3 halogen atoms ₁ ~ C ₆ Alkyl groups are preferred and unsubstituted C ₁ ~ C ₆ An alkyl group is more preferred.
R when Y is a carbon atom ⁶ As C ₁ ~ C ₆ An alkyl group or a hydrogen atom is preferred, and a methyl group, ethyl group, propyl group, butyl group or hydrogen atom is more preferred.
R ⁷ As C ₁ ~ C ₆ An alkyl group or a hydrogen atom is preferred, and a methyl group, ethyl group, propyl group, butyl group or hydrogen atom is more preferred.
The compound represented by the general formula (1) of the present invention is preferably 1 compound selected from the following group.

The compound represented by the formula (1) of the present invention may have stereoisomers or optical isomers derived from asymmetric carbon atoms. These stereoisomers, optical isomers, and mixtures thereof Any of these are included in the present invention.
When the compound represented by the general formula (1) of the present invention has a basic group such as an amino group, a pharmaceutically acceptable salt can be obtained as desired. Examples of such salts include hydrohalates such as hydrochloride and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; methanesulfonate and trifluoromethanesulfone. Lower alkane sulfonate such as acid salt and ethane sulfonate; aryl sulfonate such as benzene sulfonate and p-toluene sulfonate; formic acid, acetic acid, malic acid, fumarate, succinate, citric acid Organic acid salts such as acid salts, tartrate salts, oxalate salts, maleates; and amino acid salts such as ornithates, glutamates, aspartates; and the like. preferable.
When the compound represented by the general formula (1) of the present invention has an acidic group such as a carboxy group, it is generally possible to form a base addition salt. Examples of the pharmaceutically acceptable salt include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt , Morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl And organic amine salts such as -N- (2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl) aminomethane salt.
The compound represented by the general formula (1) or a salt thereof of the present invention may exist as a free form or a solvate. It may exist as a hydrate by absorbing moisture in the air. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specifically, a hydrate, an ethanolate, and the like are preferable. Further, when a nitrogen atom is present in the compound of the present invention represented by the general formula (1), it may be an N-oxide, and these solvates and N-oxides are also within the scope of the present invention. included.
The compound represented by the general formula (1) of the present invention may be a geometric isomer such as a cis isomer or a trans isomer, a tautomer, an optical isomer such as a d isomer, or an l isomer depending on the type or combination of substituents. The compounds of the present invention include all isomers, stereoisomers, and any ratios of these isomers and stereoisomer mixtures, unless otherwise specified. It is.
The compound represented by the general formula (1) of the present invention may contain an unnatural proportion of atomic isotopes at one or more of the constituent atoms. As an atomic isotope, for example, deuterium ( ² H), tritium ( ³ H), iodine-125, ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variants of the compound represented by general formula (1) are included within the scope of the present invention, whether radioactive or not.
The present invention also relates to a compound that is converted into the compound (1) which is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, A compound that is converted to compound (1) by hydrolysis or the like, or a “pharmaceutically acceptable prodrug compound” that is converted to compound (1) by hydrolysis or the like by gastric acid or the like is also encompassed in the present invention. .
As the prodrug, when an amino group is present in the compound (1), a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated, alanylated, pentylamino Carbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc. In the case where the compound (1) has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, the hydroxyl group is acetylated, palmitoyl). , Propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbo Le reduction has been a compound.), And the like. In addition, when a carboxy group is present in compound (I), a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylamino Methyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation, or methylamidated compounds).
Prodrugs of the compounds of the present invention can be produced from compound (1) by known methods. In addition, the prodrug of the compound of the present invention is a compound that changes to compound (1) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. Is also included.
Next, a typical method for producing the compound represented by the general formula (1) will be described. The compound of the present invention can be produced by various production methods, and the production methods shown below are merely examples, and the present invention should not be construed as being limited thereto. In the reaction, if necessary, the substituent can be protected with an appropriate protecting group, and the kind of the protecting group is not particularly limited.
[Production Method 1]
[Wherein A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y, W, and n are as defined above. Where M ¹ ~ M ⁴ Represents boronic acid, boronic acid ester or alkyl tin. R, G ¹ , G ² Represents a corresponding suitable alkyl group. L ¹ ~ L ⁴ Represents a leaving group such as a halogen atom. ]
Among the compounds represented by the formula (1), the compound 1a shown below can be produced by, for example, the following reaction formula.

(1) Conversion from compound 2 to compound 4
Conversion from compound 2 to compound 4 is carried out by a coupling reaction using a known organic chemical technique between compound 2 and a compound having a partial structure containing A (for example, compound 3).
The reaction is carried out with respect to compound 2 in the presence of a suitable organic boronic acid, organic tin, organic zinc, or organic magnesium derivative (for example, compound 3) and a suitable transition metal catalyst (for example, a palladium compound) as necessary. Adding a base or an inorganic base (for example, sodium carbonate, potassium carbonate, tripotassium phosphate, diisopropylethylamine), a ligand (for example, triphenylphosphine) and a known reaction promoting additive (for example, lithium chloride or copper iodide) Do.
In the above coupling reaction, the solvent is a suitable solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, water, etc.) or a mixed solvent thereof, and the reaction The temperature is preferably from 0 ° C. to 300 ° C., more preferably from room temperature to 200 ° C. (the optimum temperature is from 80 ° C. to 100 ° C.). The above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation. The organic boronic acid and the like and the base are preferably used in an excess molar equivalent of 1 to 1 with respect to the compound 2, the organic boronic acid and the like are preferably used in an amount of 1 to 1.5 molar equivalents, and the base is preferably used in an amount of 1 to 5 molar equivalents . The reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
(2) Conversion from compound 4 to compound 6
Conversion from compound 4 to compound 6 is carried out by subjecting compound 4 to an amidation reaction using a known organic chemical technique. From −30 ° C. to the boiling point of the solvent used in the reaction in an appropriate solvent that does not adversely influence the reaction (eg, benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, etc.) or a mixed solvent thereof. N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy, preferably at 0 ° C. to 50 ° C. ) Dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), N, N, N ′, N′-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU), etc. In the presence of a condensing agent Carried out by reacting separately synthesized carboxylic acid compound 5.
The condensing agent may be used in an excess molar equivalent, preferably 1 to 5 molar equivalents relative to compound 4. Further, a base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) may be added as necessary. As the amount of the base, a catalytic amount or an excess amount can be used.
The reaction time is preferably 10 minutes to 72 hours, more preferably 30 minutes to 24 hours. Moreover, it reacts using a well-known reaction promotion additive (1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, etc.) as needed. As the amount of the reaction promoting additive, an excess amount from a catalyst amount can be used.
In addition, the reaction is performed from −30 ° C. in an appropriate solvent (for example, benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, etc.) or a mixed solvent thereof that does not adversely affect the reaction with respect to compound 4. Carboxylic acid derived from carboxylic acid compound 5 in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.) up to the boiling point of the solvent used in It can also be carried out by reacting a halide. As the amount of the base, a catalytic amount or an excess amount can be used.
The reaction time is preferably 10 minutes to 72 hours, more preferably 30 minutes to 24 hours.
Alternatively, the reaction can be carried out by reacting compound 4 with carboxylic acid compound 5 in an acidic solvent (for example, polyphosphoric acid or the like) from 0 ° C. to the boiling point of the solvent used for the reaction, preferably 10 ° C. to 120 ° C. The reaction time is preferably 10 minutes to 72 hours, more preferably 30 minutes to 24 hours.
(3) Conversion from compound 6 to compound 1a
The conversion of compound 6 to compound 1a involves conversion of compound 6 and R ⁴ It is carried out by a coupling reaction using a known organic chemical technique with a compound having a partial structure containing A general coupling reaction similar to the coupling reaction described in (1) can be applied.
For example, the reaction may be carried out for compound 6 in the presence of a suitable organoboronic acid, organotin, organozinc, or organomagnesium derivative (such as compound 7) and a suitable transition metal catalyst (such as a palladium compound) as necessary. An organic base or an inorganic base (for example, sodium carbonate, potassium carbonate, tripotassium phosphate, diisopropylethylamine, etc.), a ligand (for example, triphenylphosphine), and a known reaction promoting additive (for example, lithium chloride or copper iodide). In addition.
In the above coupling reaction, the solvent is a suitable solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, water, etc.) or a mixed solvent thereof, and the reaction The temperature is preferably from 0 ° C to 300 ° C, more preferably from room temperature to 200 ° C (optimum temperature is from 80 ° C to 120 ° C). The above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation. The organic boronic acid and the like and the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to compound 6. The reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
[Production Method 2]

The compound 1a can also be obtained by reacting the compound 4 of [Production Method 1] with the order of the amidation reaction (2) and the coupling reaction (3) reversed.
(1) Conversion from compound 4 to compound 8
Conversion from compound 4 to compound 8 can be carried out by a general coupling reaction similar to the method described in (1) of [Production Method 1] above.
(2) Conversion from compound 8 to compound 1a
The conversion from compound 8 and compound 5 to compound 1a can be carried out by the usual amidation reaction similar to the method described in the above [Production Method 1].
[Production Method 3]

A compound 9 having a partial structure containing A is synthesized in advance, and the compound 1a can also be obtained by a route via a coupling reaction between the compound 9 and the compound 2.
(1) Conversion from compound 3 to compound 9
Conversion from compound 3 and compound 5 to compound 9 is carried out by subjecting compound 3 to an amidation reaction using a known organic chemical technique. Details of the reaction are the same as in Method (2) (ordinary amidation reaction) described in [Production Method 1].
(2) Conversion from compound 9 to compound 6
Conversion from Compound 2 and Compound 9 to Compound 6 is performed by a coupling reaction using a known organic chemical reaction between Compound 2 and Compound 9 having a partial structure containing A. The details of the reaction are the same as those in the method (1) (general coupling reaction) described in [Production Method 1].
(3) Conversion from compound 6 to compound 1a
The conversion from compound 6 to compound 1a is as shown in [Production Method 1].
[Production Method 4]

Compound 1a can also be produced using Compound 10.
Details of the reaction are the same as in Production Methods 1 and 2, and the order in which Compound 3 and Compound 7 are used in each step may be changed.
Compound 8 of [Production Method 4] can also be produced, for example, according to the following reaction formula.
[Production Method 5]

(1) Conversion from compound 11 to compound 12
In the conversion from the compound 11 to the compound 12, a halogen-metal exchange reaction is performed on the compound 11 using a known organic chemical method. For example, for compound 11, an organic or inorganic base (for example, potassium acetate, sodium carbonate, or diisopropylethylamine) in the presence of a suitable diboronic acid ester, an alkyltin compound, and the like and a suitable transition metal catalyst (for example, a palladium compound). Etc.), a ligand (such as triphenylphosphine) and a known reaction promoting additive (such as lithium chloride or copper iodide).
In the above coupling reaction, the solvent is a suitable solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, water, etc.) or a mixed solvent thereof, and the reaction The temperature is preferably from 0 ° C to 300 ° C, more preferably from room temperature to 200 ° C. The above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation. The diboronic acid ester and the like and the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to compound 11. The reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
(2) Conversion from compound 12 to compound 8
Conversion from compound 12 to compound 8 is performed by a coupling reaction of compound 12 and compound 13 using a known organic chemical technique.
For example, for compound 12, in the presence of compound 13, an appropriate transition metal catalyst (such as a palladium compound), an organic or inorganic base (such as sodium carbonate, potassium carbonate, tripotassium phosphate, diisopropylethylamine, etc.) A ligand (for example, triphenylphosphine) and a known reaction promoting additive (for example, lithium chloride or copper iodide) are added.
In the above coupling reaction, the solvent is a suitable solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, water, etc.) or a mixed solvent thereof, and the reaction The temperature is preferably from 0 ° C. to 300 ° C., more preferably from room temperature to 200 ° C. (the optimum temperature is from 80 ° C. to 100 ° C.). The above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation. The compound 13 and the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound 12, respectively. The reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
Compound 1a can also be produced via Compound 14 that can be synthesized from Compound 5 and Compound 13 and Compound 12 described above.
[Production Method 6]

Details of the reaction are the same as in Production Method 5.
Among the compounds represented by formula (1), compound 1b in which W is N or CH can be produced by the following [Production Method 7].
[Production Method 7]

Conversion from compound 15 to compound 16 can be carried out by the same procedure as in the general coupling reaction described in [Production Method 1].
Conversion from compound 16 to compound 1b can be carried out by the same procedure as in the ordinary amidation reaction described in [Production Method 1].
As described below, compound 1b can be produced even if the order of the reaction of [Production Method 7] is changed.
[Production Method 8]

The details of the reaction are the same as those described in [Production Method 7].
[Production Method 9]
Compound 5 can be produced using intermediate 18 that can be synthesized with reference to commercially available or reported reports. Hereinafter, L ³ Represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group.

(1) Conversion from compound 18 to compound 20
Conversion from compound 18 to compound 20 may be carried out by subjecting compound 18 to an alkylation reaction using a known organic chemical technique. For example, an organic or inorganic base (potassium carbonate, cesium carbonate, potassium) in a suitable solvent (for example, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile) or a mixed solvent thereof that does not adversely influence the reaction of compound 18 in the presence of tert-butoxide or triethylamine) at −30 ° C. to 300 ° C., preferably 0 ° C. to 100 ° C. ¹ , R ⁷ It is carried out by treatment with a compound 19 having a partial structure containing, for example, an alkyl halide compound or a methanesulfonyloxyalkyl compound, a trifluoromethanesulfonyloxyalkyl compound, a p-toluenesulfonyloxyalkyl compound, or the like. Compound 19 and the base may each be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to Compound 18. The reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
(2) Conversion from compound 20 to compound 5
The conversion from the compound 20 to the compound 5 may be performed by a normal hydrolysis reaction. For example, the reaction temperature is 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C. in an appropriate solvent (for example, methanol, ethanol, propanol, or water) or a mixed solvent thereof that does not adversely influence the compound 20 In the above, it is carried out by treating with an appropriate acid (for example, sulfuric acid, hydrochloric acid, etc.) or alkali (for example, sodium hydroxide, potassium carbonate, etc.). Suitable acids or alkalis use from 1 to excess molar equivalents relative to compound 20. The reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
In addition, the conversion from compound 20 to compound 5 is carried out in an appropriate solvent that does not adversely influence the reaction (for example, pyridine, quinoline, N, N-dimethylformamide, acetonitrile, etc.) or a mixed solvent thereof from 1 to an excess molar equivalent. It can also be performed by treating with lithium iodide. The reaction temperature is from room temperature to 300 ° C, preferably from room temperature to 150 ° C. The reaction time is preferably 1 minute to 72 hours, more preferably 1 hour to 48 hours.
[Production method 10]
The compound 18a shown below among the compounds 18 in [Production Method 9] can be produced from an aminotriazole compound 21 and diethyl ethoxymethylenemalonate 22 which can be synthesized on the basis of commercially available or known or reported reports.

Conversion of compound 21 to compound 18a is R ² In the absence of a solvent or a suitable solvent that does not adversely influence the reaction (for example, ethanol, toluene, xylene, diphenyl ether, N, N-dimethylformamide, acetic acid, etc.) or a mixed solvent thereof, It is carried out by treatment with diethyl ethoxymethylenemalonate from ℃ to 300 ℃, preferably from room temperature to 150 ℃. Diethyl ethoxymethylenemalonate may be used in an amount of 1 to an excess molar equivalent relative to compound 21. The reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
[Production Method 11]
Compound 21 in [Production Method 10] can be produced from commercially available carboxylic acid compound 23 and aminoguanidine 24 as shown below.

Conversion of compound 23 to compound 21 is R ² 0 to 300 ° C., preferably 0 to 300 ° C. in the absence of a solvent or a suitable solvent that does not adversely influence the reaction (for example, toluene, xylene, bromobenzene, water, etc.) or a mixed solvent thereof. The treatment is carried out at room temperature to 200 ° C. by treatment with a salt of aminoguanidine 24 (sulfate, nitrate, hydrochloride, etc.), or aminoguanidine 24 and an acid (nitric acid, sulfuric acid, hydrochloric acid, polyphosphoric acid, etc.). Compound 23 may be used in an amount of 1 to excess molar equivalents relative to Compound 24. The reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
[Production method 12]
Compound 21 in [Production Method 10] can also be produced from commercially available carboxylic acid ester 25 and aminoguanidine 24 as shown below.

Conversion of compound 25 to compound 21 is R ² In a suitable solvent (for example, methanol, ethanol, tetrahydrofuran, etc.) that does not adversely influence the reaction, or a mixed solvent thereof, the compound 25 having a partial structure containing is at 0 ° C. to 300 ° C., preferably at room temperature to 100 ° C. It is carried out by treatment with aminoguanidine 24 or a salt of aminoguanidine 24. The reaction can be carried out by adding a base (sodium methoxide, sodium ethoxide, potassium tert-butoxide, pyridine, etc.) as necessary. Aminoguanidine 24 or a salt thereof may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to compound 25. The reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
[Production method 13]
OG in compound 21 in [Production Method 11] ¹ The compound 21a having the formula: Helvetica Chimica Acta, 1983, 66, 1129; Heterocyclic Chem. , 1984, 21, 61, etc., can be produced from commercially available alcohol 26 and dimethyl cyanocarbonodithioimidate 27.

Conversion of compound 26 to compound 21a is OG ¹ In a suitable solvent (for example, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc.) or a mixed solvent thereof that does not adversely affect the reaction of the compound 26 having a partial structure containing, a base (sodium hydride, In the presence of potassium tert-butoxide, etc.) at −30 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 72 hours, preferably 5 minutes to 24 hours, and reacted with dimethyl cyanocarbonodithioimidate 26 Later, it is carried out by treatment with hydrazine at −30 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C. for 1 minute to 72 hours, preferably 5 minutes to 24 hours. Compound 26 may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to Compound 27. The base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 2 molar equivalents, relative to compound 27. Hydrazine may be used in an amount of 1 to excess molar equivalents, preferably 1 to 1.5 molar equivalents, relative to compound 27.
[Production Method 14]
The compound 7a shown below among the compounds 7 can manufacture more commercially available or well-known boronic acid ester 28. Hereinafter, L ⁴ Represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group. Ar-H represents a phenyl group having a hydroxyl group or a pyrazolyl group in which one nitrogen atom of a pyrazole ring is substituted with a hydrogen atom.

Conversion from compound 28 to compound 7a may be carried out by subjecting compound 28 to an alkylation reaction using a known organic chemical technique. For example, an organic or inorganic base (potassium carbonate, cesium carbonate, potassium) in a suitable solvent (for example, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile) or a mixed solvent thereof that does not adversely influence the compound 28. tert-butoxide or triethylamine) in the presence of -30 ° C to 300 ° C, preferably 0 ° C to 100 ° C. ² It is carried out by treating with a compound 29 (for example, an alkyl halide compound or a methanesulfonyloxyalkyl compound, a trifluoromethanesulfonyloxyalkyl compound, a p-toluenesulfonyloxyalkyl compound, etc.) having a partial structure containing Compound 29 and the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to Compound 28, respectively. The reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
Production raw materials 2, 10 or 15 are commercially available or can be synthesized according to known methods.
Production raw materials 3 and 28 are commercially available or can be synthesized according to a method described in the literature (Bioorg. Med. Chem. Lett., 2007.17.5406-5409, etc.).
Production raw materials 7, 18, and 21 are commercially available or publicly known, or can be synthesized according to the methods described in the examples.
Production raw materials 13, 19, 23, 25, 26 and 29 are commercially available or can be synthesized according to known methods.
As described above, the Gas6 / Axl signal transduction system has various cellularity such as cell survival, cell division, autophagy, cell migration, angiogenesis, platelet aggregation, and NK cell differentiation. Since it has been reported that the response is regulated (Non-Patent Document 2), Axl inhibitors are diseases caused by Axl kinase hyperfunction, diseases associated with Axl kinase hyperfunction, and / or Axl kinase. Useful for the treatment of diseases with hyperfunction.
Diseases caused by increased Axl kinase function, diseases associated with increased Axl kinase function, diseases associated with increased Axl kinase function include diseases having tissues in which overexpression of Axl gene and / or protein is observed, Axl phosphorus Examples include diseases having tissues in which an increase in oxidative activity is observed.
Examples of the above diseases include, for example, hyperproliferative diseases. Examples of hyperproliferative diseases include endometrial hyperplasia, thrombin-induced vascular smooth muscle cell (VSMC) proliferative benign tumor, malignant tumor (cancer). Include, but are not limited to, acute and chronic glomerulonephritis, diabetic nephropathy, and the like.
Furthermore, Axl is immune (Non-patent document 12), platelet function (Non-patent document 13), spermatogenesis (Non-patent document 14), vascular calcification (Non-patent document 15), (Non-patent document 16) and various It has also been shown to have a role in kidney disease, chronic allograft rejection (Non-Patent Document 17) and Axl inhibitors include but are not limited to vascular diseases (including but not limited to thrombosis, atherosclerosis and restenosis). And diseases in which disordered angiogenesis is critical (including but not limited to diabetic retinopathy, retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma). ) And the like.
Since the compounds of the present invention inhibit Axl, they are useful for the treatment of the diseases described above.
More preferably, the compounds of the invention are useful for the treatment of various cancers. Examples of cancer include breast cancer, colon cancer, prostate cancer, lung cancer, stomach cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, esophageal cancer, squamous cell carcinoma , Leukemia, osteosarcoma, melanoma, glioblastoma, neuroblastoma, ovarian cancer, head and neck cancer, testicular tumor, colon cancer, blood cancer, retinoblastoma, pancreatic cancer, etc. It is not limited to.
Regarding the relationship between cancer and Axl, various reports have been made from the viewpoints of inhibition of growth, inhibition of metastasis / movement / invasion, and release of drug resistance.
Dominant negative mutants of Axl have been reported to inhibit brain tumor growth (Vajkoczy et al., PNAS 2006, 103, 5799). It has been reported that when Axl expression or Axl / Gas6 co-expression is observed in a tissue derived from a glioblastoma patient, tumor growth proceeds significantly faster and patient survival is short (Hutterer et al., Clin Cancer Res 2008). , 14, 130). Axl shRNA has been reported to suppress the growth of breast cancer cells (Yi-Xiang et al., Cancer Res 2008, 68, 1905). From these reports it is clear that Axl inhibitors are useful for inhibiting cell growth in cancer.
On the other hand, dominant negative mutants of Axl have been reported to inhibit cell migration and invasion (Zhang et al., Cancer Res 2008 68 68, 1905, Vajkoczy et al., PNAS 2006). , 103, 5799, Holland et al., Cancer Res 2005, 65, 9294). It has been reported that Axl-shRNA suppressed metastasis in vivo (Li et al., Oncogene 2009, 28, 3442). It has been reported that anti-Axl antibody and siRNA suppressed tumor growth and metastasis in a mouse model (Li et al., Oncogene 2009 28, 3442, Ye et al., Oncogene 2010, 29, 5254). Axl has been reported to promote cell invasion (Tai et al., Oncogene 2008, 27, 4044). It has been reported that R-428, an Axl inhibitor, inhibited a diffusion model of metastatic breast cancer (Holland et al., Cancer Res 2010, 70, 1544). It has been reported that Axl antibody, Axl shRNA and Axl inhibitor NA80x1 inhibited breast cancer cell migration and invasion (Yi-Xiang et al., Cancer Res 2008, 68 1905). In addition, it has been reported that Axl is involved in metastasis and malignancy of prostate cancer, spleen cancer, metastatic ovarian cancer, thymic cancer and the like. From these reports, it is clear that Axl inhibitors are useful for cancer metastasis, cell migration, inhibition of invasion, treatment, prevention and the like.
In addition, it has been reported that an Axl inhibitor has released imatinib resistance in gastric cancer (Mahadevan et al., Oncogene 2007, 26, 3909). Axl is shown to be induced in acute myeloid leukemia in resistance to chemotherapeutic agents such as doxorubicin, VP16, cisplatin (Hong et al., Cancer Letters 2008, 268, 314). It has been reported that Axl activation is seen in lapatinib resistance in HER-2 positive breast cancer cells (Liu et al., Cancer Res 2009, 69, 6871). Axl has been reported to be involved in the PLX4032 (vemurafenib) resistance mechanism (Johannessen et al., Nature 2010, 468, 968). In addition, it has been reported that Axl is involved in resistance to temozolomode, carboplatin, and vincristine (AK Keating et al., Mol Cancer Ther 2010, 9 (5), 1298). From these reports, it is clear that Axl inhibitors are useful for releasing drug resistance, for example, releasing resistance to various anticancer agents.
Furthermore, Axl has been reported to be involved in renal fibrosis such as kidney fibrosis and diabetic nephropathy (Japanese translations of publication 2005-517412), and the Axl inhibitor is the above-mentioned renal disease and other idiopathic pulmonary fibrosis. It is clear that it is useful for the treatment of fibrotic diseases such as
The Axl inhibitory activity of a compound can be measured by, for example, the method described in Test Examples of the present application, but is not limited thereto.
Cell growth inhibitory activity can be examined using a growth inhibition test method commonly used by those skilled in the art. Cell growth inhibitory activity can be performed by comparing the extent of cell (eg, tumor cell) growth in the presence or absence of the test compound. The degree of proliferation can be examined, for example, using a test system that measures live cells. As a method for measuring living cells, for example, [ ³ H] -thymidine incorporation test, BrdU method, MTT assay and the like.
Moreover, the antitumor activity in vivo can be investigated using the antitumor test method normally used by those skilled in the art. For example, various tumor cells are transplanted into mice, rats, etc., and after the engraftment of the transplanted cells is confirmed, the compound of the present invention is administered orally, intravenously, etc. The in vivo antitumor activity of the present invention can be confirmed by comparing the tumor growth in and the compound administration group.
In addition, with regard to metastasis suppression activity, invasion inhibition activity, movement inhibition activity, and drug resistance release activity, the relationship between Axl and each activity is reported as described in the literature cited above. It can be measured by a test method.
The pharmaceutical composition of the present invention comprises the compound of the present invention and a pharmaceutically acceptable carrier, and is used as various injections such as intravenous injection, intramuscular injection, subcutaneous injection, or oral administration or transdermal administration. Administration can be by a variety of methods. A pharmaceutically acceptable carrier is a pharmaceutically acceptable material involved in transporting a compound of the present invention or a composition comprising a compound of the present invention from one organ or organ to another. (For example, excipient, diluent, additive, solvent, etc.).
As a preparation method of the preparation, an appropriate preparation (for example, oral preparation or injection) is selected according to the administration method, and the preparation can be prepared by various preparation preparations which are usually used. Examples of oral preparations include tablets, powders, granules, capsules, pills, troches, solutions, syrups, elixirs, emulsions, and oily or aqueous suspensions. In the case of oral administration, it may be in the free form or in the salt form. Aqueous preparations can be prepared by forming an acid adduct with a pharmaceutically acceptable acid or by forming an alkali metal salt such as sodium. In the case of injections, stabilizers, preservatives or solubilizers can be used in the preparation. A solution that may contain these adjuvants and the like may be stored in a container and then prepared as a solid preparation by lyophilization or the like. Moreover, the single dose may be stored in one container, and the multiple doses may be stored in one container.
Examples of solid preparations include tablets, powders, granules, capsules, pills, or lozenges. These solid preparations may contain pharmaceutically acceptable additives together with the compound of the present invention. Examples of the additive include fillers, extenders, binders, disintegrants, dissolution accelerators, wetting agents, and lubricants, which are selected and mixed as necessary. And can be formulated.
Examples of the liquid preparation include solutions, syrups, elixirs, emulsions, and suspensions. These liquid formulations may contain pharmaceutically acceptable additives along with the compounds of the present invention. Examples of the additive include a suspending agent or an emulsifier, and these can be selected and mixed as necessary to prepare a formulation.
The compounds of the present invention can be used for the treatment of cancer in mammals, particularly humans. The dose and administration interval can be appropriately selected according to the judgment of the doctor according to the location of the disease, the height, weight, sex, or medical history of the patient. When the compound of the present invention is administered to humans, the dosage range is about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 100 mg / kg body weight per day. It is. When administered to humans, it is preferably administered once a day or divided into 2 to 4 times and repeated at appropriate intervals. In addition, the daily amount may exceed the above amount depending on the judgment of the doctor.
The compound of the present invention may be used in combination with other antitumor agents. For example, antitumor antibiotics, antitumor plant components, BRM (biological response control substances), hormones, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents and the like can be mentioned.
More specifically, examples of the alkylating agent include an alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambutyl, an aziridine alkylating agent such as carbocon or thiotepa, dibromomannitol or dibromodarsi Examples thereof include epoxide-based alkylating agents such as Toll, carmustine, lomustine, semustine, nimustine hydrochloride, nitrosourea-based alkylating agents such as streptozocin, chlorozotocin or ranimustine, busulfan, improsulfan tosylate or dacarbazine.
Examples of various antimetabolites include, for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine, and pyrimidine metabolism antagonists such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine And antifolate inhibitors such as methotrexate or trimethrexate.
Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin or epirubicin, chromomycin A3 Or actinomycin D etc. are mentioned.
Examples of the antitumor plant component include vinca alkaloids such as vindesine, vincristine or vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide or teniposide.
Examples of BRM include tumor necrosis factor or indomethacin.
Examples of the hormone include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, phosfestol, ethinyl estradiol, chlormadinone or medroxyprogesterone.
Examples of vitamins include vitamin C and vitamin A.
Anti-tumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, dalatinib, satinib
Examples of other antitumor agents include cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocartinostatin, Examples include hydroxyurea, ubenimex, and krestin.
The present invention also includes a method for preventing and / or treating cancer, which comprises administering the compound of the present invention or a salt thereof.
Furthermore, the present invention includes the use of the compound of the present invention, a salt thereof or a solvate thereof for producing the medicament.
The present invention will be specifically described with reference to the following examples. However, the present invention is not limited to these examples, and is not construed as being limited in any way. In addition, in this specification, reagents, solvents and starting materials not particularly described are readily available from commercially available sources.
The present invention will be specifically described with reference to the following examples. However, the present invention is not limited to these examples, and is not construed as being limited in any way. Also, reagents, solvents and starting materials not specifically mentioned herein are known in the report or are readily available from commercial sources.

Abbreviation
DMF: N, N-dimethylformamide
THF: tetrahydrofuran
TFA: trifluoroacetic acid
EDC · HCl: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
HOBt: 1-hydroxybenzotriazole
PLC: preparative thin layer chromatography
HPLC: High performance liquid chromatography
Example 1
[Step 1] 3- (4-Aminophenyl) -5-bromopyridin-2-amine

To a solution of 5-bromo-3-iodopyridin-2-amine (2.99 g) in dioxane (40 ml) and water (10 ml) was added tetrakis (triphenylphosphine) palladium (1.16 g), 4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (2.48 g) and potassium carbonate (4.15 g) were added at room temperature. The reaction mixture was stirred at 100 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [chloroform: methanol = 9: 1 (v / v)] to obtain 2.48 g of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.80 (2H, br s), 4.58 (2H, br s), 6.76 (2H, dt, J = 8.9, 2.3 Hz), 7.22 (2H, dt, J = 8.9, 2.3 Hz), 7.43 (1H, d, J = 2.3 Hz), 8.05 (1H, d, J = 2.3 Hz).
MS (ESI) m / z: 264 (M + H) +.
[Step 2] 3- (4-Aminophenyl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine

Compound (1110 mg) obtained in Step 1 above, 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (874 mg) in dioxane To the (50 ml) solution, water (5 ml), potassium carbonate (1742 mg), and tetrakis (triphenylphosphine) palladium (242 mg) were added and stirred at 100 ° C. for 5 hours. The mixture was allowed to cool, diluted with chloroform, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 96: 4 (v / v)] to obtain 638 mg of the title compound as a solid.
MS (ESI) m / z: 266 (M + H)⁺.
[Step 3] 4- (4-Fluorobenzyl) -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 7-oxo-4,7-dihydropyrazole [1,5-a] pyrimidine-6-carboxylate (100 mg) was suspended in DMF (2 ml), potassium carbonate (167 mg), 4-fluorobenzyl bromide (71 μl). Were sequentially added and stirred at 50 ° C. for 13 hours. Water was added to the reaction solution, followed by stirring at 80 ° C. for 9 hours. 1N Hydrochloric acid aqueous solution was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the crude title compound.
MS (ESI) m / z: 288 (M + H)⁺.
[Step 4] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl) -7-oxo -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxamide

To the crude carboxylic acid obtained in Step 3 above and the compound obtained in Step 2 of Example 1 (128 mg) and HOBt (67 mg) in DMF (2 ml), EDC · HCl (139 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give 121 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.94 (3H, s), 4.60 (2H, s), 5.22-5.28 (2H, m), 6.17-6.20 (1H, m), 7.09 −7.17 (2H, m), 7.23 to 7.58 (6H, m), 7.67 to 7.86 (3H, m), 7.97 to 8.02 (1H, m), 8 .18-8.23 (1H, m), 8.77 (1H, s), 11.19 (1H, s).
MS (ESI) m / z: 535 (M + H)⁺.
Example 2
[Step 1] 4-Benzyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (75 mg) is suspended in DMF (1 ml), potassium carbonate (65 mg), benzyl Bromide (53 μl) was sequentially added and stirred at 50 ° C. for 14 hours. 1N Aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 4 hr. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 79 mg of the title compound.
MS (ESI) m / z: 271 (M + H)⁺.
[Step 2] N- {4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4-benzyl-7-oxo-4,7- Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To the compound (79 mg) obtained in Step 1 above and the DMF (2 ml) solution of the compound (63 mg) and HOBt (33 mg) in Step 2 of Example 1, EDC · HCl (69 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give 62 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.94 (3H, s), 4.56 (2H, s), 5.47-5.53 (2H, m), 7.40-7.57 (9H, m), 7.67 -7.71 (1H, m), 7.77-7.83 (2H, m), 8.19-8.25 (2H, m), 8.85 (1H, s), 10.92 (1H , S).
MS (ESI) m / z: 518 (M + H)⁺.
Example 3
[Step 1] 4- (4-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyridine-6-carboxylate (100 mg) was suspended in DMF (1 ml) and potassium carbonate (86 mg), 4 -Fluorobenzyl bromide (71 μl) was sequentially added and stirred at 50 ° C. for 10 hours. Ethanol (2 ml) was added to the reaction solution, 1N aqueous sodium hydroxide solution (1 ml) was added at room temperature, and the mixture was stirred at 80 ° C. for 12 hr. A 1N aqueous hydrochloric acid solution was added, and the precipitated solid was collected by filtration to obtain 72 mg of the title compound.
MS (ESI) m / z: 289 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 (101 mg) and the compound obtained in Step 2 of Example 1 (93 mg) and HOBt (48 mg) in DMF (2 ml), EDC · HCl (101 mg) was added at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried using dioxane to give 80 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.94 (3H, s), 4.58 (2H, s), 5.42-5.49 (2H, m), 7.08-7.15 (2H, m), 7.41 -7.58 (6H, m), 7.66-7.70 (1H, m), 7.77-7.82 (2H, m), 8.18-8.25 (2H, m), 8 .89 (1H, s), 10.90 (1H, s).
MS (ESI) m / z: 536 (M + H)⁺.
Example 4
[Step 1] 4-Benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (100 mg) was suspended in DMF (1 ml) and potassium carbonate ( 81 mg) and benzyl bromide (64 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 3 hours. Ethanol (2 ml) was added to the reaction solution, 1N aqueous sodium hydroxide solution (1 ml) was added at room temperature, and the mixture was stirred at 80 ° C. for 4 hr. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 60 mg of the title compound as a crude product.
MS (ESI) m / z: 285 (M + H)⁺.
[Step 2] N- {4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4-benzyl-2-methyl-7-oxo- 4,7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 above (60 mg) and the compound obtained in Step 2 of Example 1 (68 mg) and HOBt (29 mg) in DMF (2 ml), EDC · HCl (61 mg) was added at room temperature. After stirring at 50 ° C. for 63 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give 37 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 2.59 (3H, s), 3.94 (3H, s), 4.57 (2H, s), 5.44-5.47 (2H, m), 7.39-7.57 (9H, m), 7.67-7.71 (1H, m), 7.77-7.82 (2H, m), 8.19-8.22 (1H, m), 8.79 (1H , S), 10.98 (1H, s).
MS (ESI) m / z: 532 (M + H)⁺.
Example 5
[Step 1] 4- (4-Fluorobenzyl) -2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (75 mg) was suspended in DMF (1 ml) and potassium carbonate ( 61 mg) and 4-fluorobenzyl bromide (50 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 14 hours. 1N Aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 4 hr. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 86 mg of the title compound.
MS (ESI) m / z: 303 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl) -2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 above (86 mg) and the compound obtained in Step 2 of Example 1 (75 mg) and HOBt (39 mg) in DMF (2 ml), EDC · HCl (82 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried using dioxane to give 70 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 2.59 (3H, s), 3.94 (3H, s), 4.57 (2H, s), 5.41-5.45 (2H, m), 7.08-7.16 (2H, m), 7.43-7.57 (6H, m), 7.68-7.70 (1H, m), 7.77-7.82 (2H, m), 8.19-8 .23 (1H, m), 8.79 (1H, s), 10.97 (1H, s).
MS (ESI) m / z: 550 (M + H)⁺.
Example 6
[Step 1] Ethyl 2-ethyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

5-ethyl-4H-1,2,4-triazol-3-amine (50 mg) and diethyl ethoxymethylenemalonate (90 μl) were added to acetic acid (1 ml), and the mixture was heated to reflux for 5 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 72 mg of the title compound.
MS (ESI) m / z: 237 (M + H)⁺.
[Step 2] 2-Ethyl-4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

The compound (72 mg) obtained in the above Step 1 was suspended in DMF (1 ml), potassium carbonate (105 mg) and 4-fluorobenzyl bromide (45 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 9 hours. Water (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 2 hours. 1N Hydrochloric acid aqueous solution was added, and the precipitated solid was filtered and washed with water to give 59 mg of the title compound.
MS (ESI) m / z: 317 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -2-ethyl-4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 2 (59 mg) and the compound obtained in Step 2 of Example 1 (50 mg) and HOBt (26 mg) in DMF (2 ml), EDC · HCl (54 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give the title compound 1 .9 mg was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 1.41-1.46 (3H, m), 2.90-2.97 (2H, m), 3.94 (3H, s), 4.58 (2H, s), 5.41 -5.45 (2H, m), 7.08-7.20 (2H, m), 7.44-7.82 (9H, m), 8.19-8.22 (1H, m), 8 .79 (1H, s), 11.00 (1H, s).
MS (ESI) m / z: 564 (M + H)⁺.
Example 7
[Step 1] Ethyl 7-oxo-2- (propan-2-yl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

5-Isopropyl-4H-1,2,4-triazol-3-amine (50 mg) and diethyl ethoxymethylenemalonate (80 μl) were added to acetic acid (1 ml), and the mixture was heated to reflux for 19 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 63 mg of the title compound.
MS (ESI) m / z: 251 (M + H)⁺.
[Step 2] 4- (4-Fluorobenzyl) -7-oxo-2- (propan-2-yl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6 -Carboxylic acid

The compound (63 mg) obtained in the above Step 1 was suspended in DMF (1 ml), potassium carbonate (86 mg) and 4-fluorobenzyl bromide (37 μl) were successively added, and the mixture was stirred at 50 ° C. for 9 hours. Water (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 2 hours. A 1N aqueous hydrochloric acid solution was added, and the precipitated solid was filtered and washed with water to obtain 68 mg of the title compound.
MS (ESI) m / z: 331 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl) -7-oxo 2- (propan-2-yl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 2 above (68 mg) and the compound obtained in Step 2 of Example 1 (55 mg) and HOBt (28 mg) in DMF (2 ml), EDC · HCl (59 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to 55 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 1.39-1.47 (6H, m), 3.18-3.30 (1H, m), 3.94 (3H, s), 4.58 (2H, s), 5.41 -5.46 (2H, m), 7.08-7.16 (2H, m), 7.44-7.82 (9H, m), 8.19-8.22 (1H, m), 8 79 (1H, s), 11.03 (1H, s).
MS (ESI) m / z: 578 (M + H)⁺.
Example 8
[Step 1] Ethyl 2- (methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

Aminoguanidine bicarbonate (1.0 g) and methoxyacetic acid (0.61 ml) were heated to reflux in bromobenzene (1 ml) for 3 days. Thereafter, the concentrated residue and diethyl ethoxymethylenemalonate (1.48 ml) were added to acetic acid (10 ml), and the mixture was heated to reflux for 19 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 1.18 g of the title compound.
MS (ESI) m / z: 253 (M + H)⁺.
[Step 2] 4-Benzyl-2- (methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid
The compound (100 mg) obtained in the above Step 1 was suspended in DMF (2 ml), potassium carbonate (72 mg) and 4-fluorobenzyl bromide (57 μl) were successively added, and the mixture was stirred at 50 ° C. for 14 hours. 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 4 hours. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 121 mg of the title compound.
[Step 3] N- {4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4-benzyl-2- (methoxymethyl) -7 -Oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 2 above (60 mg) and the compound obtained in Step 2 of Example 1 (51 mg) and HOBt (27 mg) in DMF (2 ml), EDC · HCl (55 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried using dioxane to give 34 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.54 (3H, s), 3.94 (3H, s), 4.56 (2H, s), 4.70-4.73 (2H, m), 5.50-5.53 (2H, m), 7.38-7.51 (8H, m), 7.54-7.56 (1H, m), 7.68-7.70 (1H, m), 7.77-7 .81 (2H, m), 8.19-8.21 (1H, m), 8.82 (1H, s), 10.91 (1H, s).
MS (ESI) m / z: 562 (M + H)⁺.
Example 9
[Step 1] 4- (4-Fluorobenzyl) -2- (methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

The compound (50 mg) obtained in Step 1 of Example 8 was suspended in DMF (1 ml), potassium carbonate (36 mg) and 4-fluorobenzyl bromide (29 μl) were successively added, and the mixture was stirred at 50 ° C. for 5 hours. 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 9 hours. A 1N aqueous hydrochloric acid solution was added, and the precipitated solid was filtered and washed with water to obtain 52 mg of the title compound.
MS (ESI) m / z: 333 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl) -2- ( Methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 above (52 mg) and the compound obtained in Step 2 of Example 1 (42 mg) and HOBt (22 mg) in DMF (2 ml), EDC · HCl (45 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried using dioxane to give 26 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.54 (3H, s), 3.94 (3H, s), 4.57 (2H, s), 4.69-4.72 (2H, m), 5.47-5.50 (2H, m), 7.08-7.15 (2H, m), 7.41-7.82 (9H, m), 8.19-8.22 (1H, m), 8.82 (1H , S), 10.90 (1H, s).
MS (ESI) m / z: 580 (M + H)⁺.
Example 10
[Step 1] Ethyl [2-cyclopropyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

5-cyclopropyl-4H-1,2,4-triazol-3-amine (50 mg) and diethyl ethoxymethylenemalonate (81 μl) were added to acetic acid (1 ml), and the mixture was heated to reflux for 5 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 74 mg of the title compound.
MS (ESI) m / z: 249 (M + H)⁺.
[Step 2] 2-Cyclopropyl-4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

The compound (74 mg) obtained in the above Step 1 was suspended in DMF (1 ml), potassium carbonate (103 mg) and 4-fluorobenzyl bromide (44 μl) were successively added, and the mixture was stirred at 50 ° C. for 9 hours. Water (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 2 hours. 1N hydrochloric acid aqueous solution was added, and the precipitated solid was filtered and washed with water to obtain 74 mg of the title compound.
MS (ESI) m / z: 329 (M + H)⁺.
[Step 3] N- {4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -2-cyclopropyl-4- (4-fluorobenzyl ) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 (74 mg) and the compound obtained in Step 2 of Example 1 (60 mg) and HOBt (31 mg) in DMF (2 ml), EDC · HCl (65 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried with dioxane to give 45 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃): 1.10-1.20 (4H, m), 2.19-2.27 (1H, m), 3.94 (3H, s), 4.57 (2H, s), 5.37 -5.40 (2H, m), 7.08-7.15 (2H, m), 7.42-7.81 (9H, m), 8.19-8.22 (1H, m), 8 .75 (1H, s), 11.02 (1H, s).
MS (ESI) m / z: 576 (M + H)⁺.
Example 11
[Step 1] Ethyl 2-cyclobutyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

5-cyclobutyl-4H-1,2,4-triazol-3-amine (50 mg) and diethyl ethoxymethylenemalonate (73 μl) were added to acetic acid (1 ml), and the mixture was heated to reflux for 19 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 68 mg of the title compound.
MS (ESI) m / z: 263 (M + H)⁺.
[Step 2] 2-Cyclobutyl-4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

The compound obtained in 1 above (68 mg) was suspended in DMF (1 ml), potassium carbonate (47 mg) and 4-fluorobenzyl bromide (38 μl) were successively added, and the mixture was stirred at 50 ° C. for 5 hours. 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 9 hours. 1N hydrochloric acid aqueous solution was added, and the precipitated solid was filtered and washed with water to obtain 75 mg of the title compound.
MS (ESI) m / z: 343 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -2-cyclobutyl-4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 2 above (75 mg) and the compound obtained in Step 2 of Example 1 (58 mg) and HOBt (30 mg) in DMF (2 ml), EDC · HCl (63 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and lyophilized using dioxane to give 75 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 2.01-2.22 (2H, m), 2.39-2.59 (4H, m), 3.74-3.86 (1H, m), 3.94 (3H, s) , 4.57 (2H, s), 5.42-5.48 (2H, m), 7.09-7.16 (2H, m), 7.44-7.82 (9H, m), 8 19-8.22 (1H, m), 8.78 (1H, s), 11.02 (1H, s).
MS (ESI) m / z: 590 (M + H)⁺.
Example 12
[Step 1] Ethyl 2- (methylsulfanyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

Hydrazine monohydrate (25 μl) was added to ethanol (1 ml) of dimethyl cyanocarbonodithioimidate (50 mg), and the mixture was heated to reflux for 2 hours. Diethyl ethoxymethylenemalonate (104 μl) and acetic acid (2 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was refluxed for 13 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 28 mg of the title compound.
[Step 2] 4- (4-Fluorobenzyl) -2- (methylsulfanyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

The compound (28 mg) obtained in the above Step 1 was suspended in DMF (1 ml), potassium carbonate (20 mg) and 4-fluorobenzyl bromide (16 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 1.5 hours. A 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 26 mg of the title compound.
[Step 3] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl) -2- ( Methylsulfanyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 2 (26 mg) and the compound obtained in Step 2 of Example 1 (21 mg) and HOBt (11 mg) in DMF (2 ml), EDC · HCl (22 mg) was added at room temperature. After stirring at 50 ° C. for 5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give the title compound 6 0.0 mg was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 2.74 (3H, s), 3.94 (3H, s), 4.61 (2H, s), 5.38-5.43 (2H, m), 7.06-7.20 (2H, m), 7.41-7.59 (6H, m), 7.67-7.72 (1H, m), 7.75-7.83 (2H, m), 8.18-8 .23 (1H, m), 8.75 (1H, s), 11.00 (1H, s).
MS (ESI) m / z: 582 (M + H)⁺.
Example 13
[Step 1] Ethyl 2- (dimethylamino) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

To a THF solution (1 ml) of dimethyl cyanocarbonodithioimidate (200 mg) was added 2N dimethylamine tetrahydrofuran solution, and the mixture was stirred at room temperature for 3 hours. Thereafter, ethanol (1 ml) and hydrazine monohydrate (100 μl) were added, and the mixture was heated to reflux for 5 hours. Diethyl ethoxymethylenemalonate (416 μl) and acetic acid (2 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was heated to reflux for 13 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 212 mg of the title compound.
MS (ESI) m / z: 252 (M + H)⁺.
[Step 2] 2- (Dimethylamino) -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

The compound (50 mg) obtained in the above Step 1 was suspended in DMF (1 ml), potassium carbonate (36 mg) and 4-fluorobenzyl bromide (29 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 8 hours. A 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 49 mg of the title compound.
MS (ESI) m / z: 332 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -2- (dimethylamino) -4- (4- Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 2 (49 mg) and the compound obtained in Step 2 of Example 1 (40 mg) and HOBt (21 mg) in DMF (2 ml), EDC · HCl (43 mg) was added at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried using dioxane to give 17 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.17 (6H, s), 3.94 (3H, s), 4.57 (2H, s), 5.34-5.37 (2H, m), 7.07-7.15 (2H, m), 7.42-7.57 (6H, m), 7.67-7.71 (1H, m), 7.75-7.81 (2H, m), 8.19-8 .22 (1H, m), 8.61 (1H, s), 11.28 (1H, s).
MS (ESI) m / z: 579 (M + H)⁺.
Example 14
[Step 1] 4- (2-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) suspended in DMF (1 ml), potassium carbonate (43 mg), 2 -Fluorobenzyl bromide (35 μl) was sequentially added and stirred at 50 ° C. for 8 and a half hours. A 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a crude product.
MS (ESI) m / z: 289 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (2-fluorobenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To the crude product obtained in Step 1 above and the compound obtained in Step 2 of Example 1 (64 mg) and HOBt (33 mg) in DMF (2 ml), EDC · HCl (69 mg) was added at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained compound was recrystallized from dichloromethane and diisopropyl ether to obtain 86 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.95 (3H, s), 4.56 (2H, s), 5.53-5.58 (2H, m), 7.14-7.32 (2H, m), 7.40 -7.62 (6H, m), 7.68-7.71 (1H, m), 7.78-7.84 (2H, m), 8.19-8.24 (2H, m), 8 97 (1H, s), 10.92 (1H, s).
MS (ESI) m / z: 536 (M + H)⁺.
Example 15
[Step 1] 4- (2-Methylbenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) suspended in DMF (1 ml), potassium carbonate (43 mg), 1 -(Bromomethyl) -2-methylbenzene (39 μl) was sequentially added, and the mixture was stirred at 50 ° C. for 8 and a half hours. A 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a crude product.
MS (ESI) m / z: 285 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (2-methylbenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To the crude product obtained in Step 1 above and the compound obtained in Step 2 of Example 1 (63 mg) and HOBt (33 mg) in DMF (2 ml), EDC · HCl (69 mg) was added at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained compound was recrystallized from dichloromethane and diisopropyl ether to obtain 94 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.37 (3H, s), 3.94 (3H, s), 4.56 (2H, s), 5.51-5.55 (2H, m), 7.21-7.40 (4H, m), 7.44-7.57 (4H, m), 7.68-7.70 (1H, m), 7.76-7.81 (2H, m), 8.18-8 .28 (2H, m), 8.70 (1H, s), 10.93 (1H, s).
MS (ESI) m / z: 532 (M + H)⁺.
Example 16
[Step 1] 4- (2-Methoxybenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) suspended in DMF (1 ml), potassium carbonate (43 mg), 2 -Methoxybenzyl chloride (40 μl) was sequentially added and stirred at 50 ° C. for 8 and a half hours. A 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours. 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a crude product.
MS (ESI) m / z: 301 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (2-methoxybenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To the crude product obtained in Step 1 above and the compound obtained in Step 2 of Example 1 (63 mg) and HOBt (33 mg) in DMF (2 ml), EDC · HCl (69 mg) was added at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained compound was recrystallized from dichloromethane and diisopropyl ether to obtain 102 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.92 (3H, s), 3.95 (3H, s), 4.56 (2H, s), 5.47-5.50 (2H, m), 6.92-7.05 (2H, m), 7.37-7.60 (6H, m), 7.67-7.71 (1H, m), 7.77-7.85 (2H, m), 8.18-8 .24 (2H, m), 9.09 (1H, s), 10.97 (1H, s).
MS (ESI) m / z: 548 (M + H)⁺.
Example 17
[Step 1] 4- (2,4-Difluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (75 mg) is suspended in DMF (1 ml), potassium carbonate (65 mg), 2 , 4-Difluorobenzyl bromide (56 μl) was sequentially added and stirred at 50 ° C. for 13 hours. 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 5 hours. 1N Aqueous hydrochloric acid solution was added, extracted with dichloromethane, dried over sodium sulfate, filtered, and concentrated to give 80 mg of the title compound.
MS (ESI) m / z: 307 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (2,4-difluorobenzyl) -7 -Oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 above (80 mg) and the compound obtained in Step 2 of Example 1 (69 mg) and HOBt (36 mg) in DMF (2 ml), EDC · HCl (75 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give 68 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.94 (3H, s), 4.56 (2H, s), 5.49-5.53 (2H, m), 6.89-7.00 (2H, m), 7.44 -7.71 (6H, m), 7.79-7.84 (2H, m), 8.20-8.22 (2H, m), 8.96 (1H, s), 10.89 (1H , S).
MS (ESI) m / z: 554 (M + H)⁺.
Example 18
[Step 1] Ethyl 7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) is suspended in DMF (1 ml), potassium carbonate (83 mg), 2 -(Bromomethyl) pyridine hydrobromide (73 mg) was sequentially added, and the mixture was stirred at 50 ° C. for 13 hours. To the reaction solution was added saturated brine, and the mixture was extracted with [dichloromethane: methanol = 5: 1 (v / v)], dried by adding sodium sulfate, filtered and concentrated to obtain the title compound as a crude product. .
MS (ESI) m / z: 300 (M + H)⁺.
[Step 2] 7-Oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

The crude product obtained in Step 1 above and lithium iodide (39 mg) were heated to reflux in pyridine (1 ml) for 20 hours. The reaction solution was concentrated to give the title compound as a crude product.
MS (ESI) m / z: 272 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -7-oxo-4- (pyridin-2-ylmethyl) ) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To the crude product obtained in Step 2 above and the compound obtained in Step 2 of Example 1 (64 mg) and HOBt (33 mg) in DMF (2 ml), EDC · HCl (69 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give 68 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.94 (3H, s), 4.57 (2H, 3), 5.58-5.61 (2H, m), 7.27-7.33 (1H, m), 7.46 -7.53 (4H, m), 7.54-7.58 (1H, m), 7.68-7.71 (1H, m), 7.72-7.78 (1H, m), 7 .80-7.86 (2H, m), 8.16-8.18 (1H, m), 8.19-8.23 (1H, m), 8.54-8.58 (1H, m) , 9.10 (1H, s), 10.96 (1H, s).
MS (ESI) m / z: 519 (M + H)⁺.
Example 19
[Step 1] 4-[(6-Methylpyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (100 mg) suspended in DMF (1 ml), potassium carbonate (86 mg), 2 -(Bromomethyl) -6-methylpyridine (107 mg) was sequentially added, and the mixture was stirred at 70 ° C for 9 and a half hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [ethyl acetate], and the solvent was distilled off under reduced pressure to obtain 130 mg of the title compound.
MS (ESI) m / z: 314 (M + H)⁺.
[Step 2] 4-[(6-Methylpyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethanol (1 ml) and 1N aqueous sodium hydroxide solution (0.5 ml) were added to the compound (75 mg) obtained in Step 1 above, and the mixture was stirred at room temperature for 2 hours. 1N Aqueous hydrochloric acid solution was added, and the solvent was evaporated under reduced pressure to give the title compound as a crude product.
[Step 3] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4-[(6-methylpyridin-2-yl) ) Methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To the crude product obtained in Step 2 above and the compound obtained in Step 2 of Example 1 (64 mg) and HOBt (33 mg) in DMF (2 ml), EDC · HCl (69 mg) was added at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried using dioxane to obtain 57 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 2.50 (3H, s), 3.95 (3H, s), 4.59 (2H, s), 5.52-5.58 (2H, m), 7.10-7.31 (2H, m), 7.43-7.73 (6H, m), 7.79-7.88 (2H, m), 8.15-8.25 (2H, m), 9.13 (1H , S), 10.98 (1H, s).
MS (ESI) m / z: 533 (M + H)⁺.
Example 20
[Step 1] Ethyl 7-oxo-4- (1H-pyrazol-1-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) is suspended in DMF (1 ml), potassium carbonate (83 mg), 1 -(Chloromethyl) -1H-pyrazole hydrochloride (44 mg) was sequentially added and stirred at 50 ° C. for 14 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [dichloromethane: methanol = 10: 1 (v / v)]. The solvent was distilled off under reduced pressure to obtain 61 mg of the title compound.
MS (ESI) m / z: 289 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -7-oxo-4- (1H-pyrazole-1 -Ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Lithium iodide (28 mg) was added to a pyridine (1 ml) solution of the compound obtained in the above Step 1 (69 mg) and heated under reflux for 19 hours, and then the solvent was distilled off under reduced pressure. To the obtained residue, EDC · HCl (61 mg) was added at room temperature to a DMF (2 ml) solution of the compound (56 mg) obtained in Step 2 of Example 1 and HOBt (29 mg). After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried with dioxane to give 3 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.95 (3H, s), 5.14 (2H, s), 6.33-6.37 (1H, m), 6.51-6.53 (2H, m), 7.10 -7.20 (1H, m), 7.46-7.89 (8H, m), 8.12-8.14 (1H, m), 8.23 (1H, s), 9.20 (1H , S), 10.81 (1H, s).
MS (ESI) m / z: 508 (M + H)⁺.
Example 21
N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -1-benzyl-4-oxo-1,4-dihydropyrimido [ 1,2-a] benzimidazole-3-carboxamide

Ethyl 4-oxo-1,4-dihydropyrimido [1,2-a] benzimidazole-3-carboxylate (30 mg) was suspended in DMF (1 ml), and potassium carbonate (21 mg) and benzyl bromide (17 μl) were suspended. Sequentially added and stirred at 80 ° C. for 15 hours. Ethanol (2 ml) and 1N aqueous sodium hydroxide solution (1 ml) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 8 hours. 1N hydrochloric acid was added to the reaction solution and filtered. To the obtained solid (36 mg), EDC · HCl (32 mg) was added at room temperature to a DMF (1 ml) solution of the compound (30 mg) obtained in Step 2 of Example 1 and HOBt (15 mg). After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 10: 10: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diethyl ether to obtain 27 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.94 (3H, s), 4.59 (2H, s), 5.58-5.60 (2H, m), 7.38-7.59 (11H, m), 7.68 -7.72 (1H, m), 7.80-7.87 (3H, m), 8.18-8.22 (1H, m), 8.54-8.59 (1H, m), 8 .82 (1H, s), 11.08 (1H, s).
MS (ESI) m / z: 567 (M + H)⁺.
Example 22
[Step 1] 3- (4-Aminophenyl) -5- {1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl} pyridin-2-amine

Compound (1 g) obtained in Step 1 of Example 1, 1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-4-pyrazole boronic acid pinacol ester (1.39 g), tetrakis ( Triphenylphosphine) palladium (0.23 g) and potassium carbonate (1.62 g) were suspended in dioxane (20 ml) and water (2 ml), and the mixture was heated to reflux at 100 ° C. for 61 hours. After allowing to cool, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: methanol = 10: 1 (v / v)] to obtain 1.49 g of the title compound as a liquid.
MS (ESI) m / z: 380 (M + H)⁺.
[Step 2] N- [4- (2-amino-5- {1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl} pyridin-3-yl) Phenyl] -4-benzyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 2 (78 mg) and the compound obtained in Step 1 above (109 mg) and HOBt (40 mg) in DMF (2 ml) was added EDC · HCl (83 mg) at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] to obtain 110 mg of the title compound.
MS (ESI) m / z: 632 (M + H)⁺.
[Step 3] N- (4- {2-amino-5- [1- (2-hydroxyethyl) -1H-pyrazol-4-yl] pyridin-3-yl} phenyl) -4-benzyl-7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

1N Hydrochloric acid (1 ml) was added to a THF (2 ml) solution of the compound (110 mg) obtained in Step 2 above at room temperature. After stirring at room temperature for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 2 (v / v)] and subjected to lyophilization using dioxane to give 65 mg of the title compound. Got.
¹H-NMR (CDCl₃): 4.01-4.08 (2H, m), 4.25-4.31 (2H, m), 4.56 (2H, s), 5.48-5.52 (2H, m) 7.40-7.53 (8H, m), 7.61-7.65 (1H, m), 7.73-7.75 (1H, m), 7.78-7.83 (2H, m), 8.20-8.25 (2H, m), 8.89 (1H, s), 10.93 (1H, s).
MS (ESI) m / z: 548 (M + H)⁺.
Example 23
[Step 1] N- [4- (2-amino-5- {1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl} pyridin-3-yl) Phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound (70 mg) obtained in Step 1 of Example 3 and the compound (92 mg) obtained in Step 1 of Example 22 and HOBt (34 mg) in DMF (2 ml), EDC · HCl (70 mg) was added at room temperature. It was. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] to obtain 92 mg of the title compound.
MS (ESI) m / z: 650 (M + H)⁺.
[Step 2] N- (4- {2-amino-5- [1- (2-hydroxyethyl) -1H-pyrazol-4-yl] pyridin-3-yl} phenyl) -4- (4-fluorobenzyl ) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

1N Hydrochloric acid (1 ml) was added to a THF (2 ml) solution of the compound obtained in Step 1 above (92 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 2 (v / v)] and subjected to lyophilization using dioxane to give 41 mg of the title compound. Got.
¹H-NMR (CDCl₃) Δ: 4.00-4.08 (2H, m), 4.25-4.31 (2H, m), 4.58 (2H, s), 5.45-5.49 (2H, m) , 7.08-7.84 (11H, m), 8.19-8.26 (2H, m), 8.89 (1H, s), 10.91 (1H, s).
MS (ESI) m / z: 566 (M + H)⁺.
Example 24
[Step 1] N- [4- (2-Amino-5-bromopyridin-3-yl) phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] Triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound (0.90 g) obtained in Step 1 of Example 1 and the compound (0.97 g) obtained in Step 1 of Example 4 in DMF (50 ml), EDC.HCl (0.85 g) and HOBt (0 .68 g) was added and stirred at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, the residue was diluted with water and extracted with chloroform, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)] to obtain 1.82 g of the title compound as a solid.
MS (ESI) m / z: 532 (M + H)⁺.
[Step 2] N- (4- {2-amino-5- [1- (2-hydroxypropyl) -1H-pyrazol-4-yl] pyridin-3-yl} phenyl) -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

The compound (100 mg) obtained in the above step 1 and 1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl] Water (0.5 ml), cesium carbonate (80 mg) and tetrakis (triphenylphosphine) palladium (22 mg) were added to a solution of propan-2-ol (52 mg) in ethylene glycol dimethyl ether (4 ml), and the mixture was heated to 100 ° C. under microwave irradiation. And stirred for 20 minutes. After cooling, the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 19: 1 (v / v)], and further silica gel column chromatography (NH) [chloroform: methanol = 99: 1 → 19: 1 (v / v)], and the resulting solid was washed with ethyl acetate to obtain 30 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆): 1.04-1.05 (3H, m), 2.45 (3H, s), 3.98-4.00 (2H, m), 4.92-4.93 (1H, m) , 5.56 (2H, br s), 5.59 (2H, s), 7.36-7.42 (3H, m), 7.48 (2H, d, J = 6.9 Hz), 7. 52 (2H, d, J = 8.6 Hz), 7.55 (1H, d, J = 2.3 Hz), 7.80-7.82 (3H, m), 8.05 (1H, s), 8.21 (1H, d, J = 2.3 Hz), 9.11 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 576 (M + H)⁺.
Example 25
N- (4- {2-amino-5- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl] pyridin-3-yl} phenyl) -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

The compound (100 mg) obtained in Step 1 of Example 24 and 2-methyl-1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -Pyrazol-1-yl] propan-2-ol (53 mg) was synthesized in the same manner as in Step 2 of Example 24 to obtain 40 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.08 (6H, s), 2.45 (3H, s), 4.00 (2H, s), 4.72 (1H, s), 5.57-5.59 (4H, m) ), 7.36-7.42 (3H, m), 7.47-7.56 (5H, m), 7.80-7.83 (3H, m), 8.02 (1H, s), 8.22 (1H, d, J = 2.3 Hz), 9.12 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 590 (M + H)⁺.
Example 26
[Step 1] N- [4- (2-amino-5- {1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl} pyridin-3-yl) Phenyl] -4-benzyl-2- (methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 2 of Example 8 (60 mg) and the compound obtained in Step 1 of Example 22 (73 mg) and HOBt (27 mg) in DMF (2 ml), EDC · HCl (55 mg) was added at room temperature. It was. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] to obtain 89 mg of the title compound.
MS (ESI) m / z: 676 (M + H)⁺.
[Step 2] N- (4- {2-amino-5- [1- (2-hydroxyethyl) -1H-pyrazol-4-yl] pyridin-3-yl} phenyl) -4-benzyl-2- ( Methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

1N Hydrochloric acid (1 ml) was added to a THF (2 ml) solution of the above compound (89 mg) obtained in the above Step 1 at room temperature. After stirring at room temperature for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 2 (v / v)] and freeze-dried using dioxane to give 44 mg of the title compound. Got.
¹H-NMR (CDCl₃) Δ: 3.54 (3H, s), 4.01-4.07 (2H, m), 4.26-4.30 (2H, m), 4.57 (2H, s), 4.70 -4.73 (2H, m), 5.50-5.54 (2H, m), 7.39-7.52 (8H, m), 7.62-7.64 (1H, m), 7 .72-7.74 (1H, m), 7.77-7.81 (2H, m), 8.19-8.21 (1H, m), 8.82 (1H, s), 10.91 (1H, s).
MS (ESI) m / z: 592 (M + H)⁺.
Example 27
[Step 1] 3- (4-Aminophenyl) -5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-2-amine

4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (10 g) was added to a suspension of cesium carbonate (75.6 g) in dioxane (200 ml). (2R) -1,4-dioxan-2-ylmethyl methanesulfonate (12.1 g) and tetra-n-butylammonium iodide (0.95 g) were added and stirred for 6 hours at 100 ° C. did. After the reaction solution was cooled to room temperature, the compound (10.9 g) obtained in Step 1 of Example 1 and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (2. 1 g) was added and stirred at 100 ° C. for 1 hour. The reaction solution was returned to room temperature, ethyl acetate was added, and insoluble material was removed by filtration. The obtained organic layer was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 19: 1 (v / v)] to obtain 10.3 g of the title compound as a solid.
¹H-NMR (CDCl₃): 3.28-3.33 (1H, m), 3.55-3.83 (7H, m), 3.95-4.01 (1H, m), 4.16 (1H, s) , 4.17 (1H, s), 4.56 (2H, br s), 6.77-6.79 (2H, m), 7.26-7.29 (2H, m), 7.43 ( 1H, d, J = 2.3 Hz), 7.63 (1H, s), 7.70-7.70 (1 H, m), 8.17 (1 H, d, J = 2.3 Hz).
MS (ESI) m / z: 352 (M + H)⁺.
[Step 2] N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl ] -4-Benzyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) was suspended in DMF (1 ml), potassium carbonate (43 mg), benzyl Bromide (34 μl) was sequentially added and stirred at 50 ° C. for 5 hours. A 1N aqueous sodium hydroxide solution (0.36 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 2 hours. Then, a 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC · HCl (69 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 above (84 mg) and HOBt (33 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 61 mg of the title compound as a solid.
¹H-NMR (CDCl₃): 3.26-3.37 (1H, m), 3.52-3.85 (5H, m), 3.94-4.03 (1H, m), 4.13-4.21 ( 2H, m), 4.57 (2H, s), 5.47-5.53 (2H, m), 7.39-7.54 (8H, m), 7.62-7.74 (2H, m), 7.77-7.84 (2H, m), 8.19-8.27 (2H, m), 8.89 (1H, s), 10.93 (1H, s).
MS (ESI) m / z: 604 (M + H)⁺.
Example 28
N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl] -4- (4-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) was suspended in DMF (1 ml), and potassium carbonate (43 mg), 4 -Fluorobenzyl bromide (35 μl) was sequentially added and stirred at 50 ° C. for 5 hours. A 1N aqueous sodium hydroxide solution (0.33 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 2 hours. Then, a 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC · HCl (69 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 27 (84 mg) and HOBt (33 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 81 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.27-3.36 (1H, m), 3.51-3.85 (5H, m), 3.95-4.03 (1H, m), 4.15-4.20 ( 2H, m), 4.57 (2H, s), 5.45-5.49 (2H, m), 7.09-7.16 (2H, m), 7.45-7.54 (5H, m), 7.63-7.66 (1H, m), 7.70-7.73 (1H, m), 7.78-7.83 (2H, m), 8.21-8.26 ( 2H, m), 8.88 (1H, s), 10.92 (1H, s).
MS (ESI) m / z: 622 (M + H)⁺.
Example 29
N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl] -4- Benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 4 (72 mg) and the compound obtained in Step 1 of Example 27 (80 mg) in DMF (2 ml), EDC · HCl (48 mg) and HOBt (3.5 mg) were added. And stirred at room temperature for 4 hours. The compound (6.6 mg) obtained in Step 1 of Example 4 and EDC · HCl (4.4 mg) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the resulting solid was filtered and washed with water. The solid was purified by reverse phase HPLC (acetonitrile-water-formic acid) and then dissolved in dichloromethane. Diisopropyl ether was added and the resulting solid was collected by filtration to obtain 86 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.58 (3H, s), 3.31 (1H, t, J = 10.8 Hz), 3.54-3.62 (1H, m), 3.67-3.77 (2H, m), 3.78-3.84 (2H, m), 3.94-4.03 (1H, m), 4.14-4.20 (2H, m), 4.61 (2H, s) , 5.46 (2H, s), 7.41-7.49 (8H, m), 7.65 (1H, s), 7.71 (1H, s), 7.76-7.80 (2H M), 8.21-8.22 (1H, m), 8.80 (1H, s), 10.97 (1H, s).
MS (ESI) m / z: 618 (M + H)⁺.
Example 30
N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl] -4- (4-Fluorobenzyl) -2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Ethyl 2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) was suspended in DMF (1 ml) and potassium carbonate ( 40 mg) and 4-fluorobenzyl bromide (33 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 5 hours. To the reaction solution was added 1N aqueous sodium hydroxide solution (0.33 ml), and the mixture was stirred at 80 ° C. for 2 hours. Then, 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC.HCl (65 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 27 (79 mg) and HOBt (31 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 95 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.60 (3H, s), 3.27-3.36 (1H, m), 3.53-3.86 (5H, m), 3.95-4.03 (1H, m) 4.14-4.21 (2H, m), 4.57 (2H, s), 5.40-5.46 (2H, m), 7.07-7.16 (2H, m), 7 .41-7.55 (5H, m), 7.62-7.73 (2H, m), 7.76-7.83 (2H, m), 8.20-8.25 (1H, m) , 8.79 (1H, s), 10.97 (1H, s).
MS (ESI) m / z: 636 (M + H)⁺.
Example 31
[Step 1] Ethyl 2-methoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

To a methanol solution (10 ml) of dimethyl cyanocarbonodithioimidate (1.00 g) was added 28% sodium methoxide methanol solution (2.64 g) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. Thereafter, pyridine hydrochloride (1.74 g) was added and stirred at 0 ° C. for 1 hour. To the reaction solution was added hydrazine monohydrate (498 μl), and the mixture was heated to reflux for 6 hours. Diethyl ethoxymethylenemalonate (2.07 ml) and acetic acid (10 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was heated to reflux for 13 hours. After adding diisopropyl ether to the reaction solution, 201 mg of the title compound was obtained by filtration and washing with diisopropyl ether.
[Step 2] Ethyl 4-benzyl-2-methoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

The compound (101 mg) obtained in the above step 1 was suspended in DMF (1 ml), potassium carbonate (76 mg) and benzyl bromide (60 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 8 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 2: 1 (v / v)] to obtain 57 mg of the title compound.
MS (ESI) m / z: 329 (M + H)⁺.
[Step 3] N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl ] -4-Benzyl-2-methoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

A 1N aqueous sodium hydroxide solution (0.21 ml) was added to an ethanol (1 ml) solution of the compound obtained in the above step 2 (57 mg) and the mixture was stirred at room temperature for 2 hours. Then, a 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with dichloromethane. Dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC · HCl (50 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 27 (61 mg) and HOBt (24 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 57 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.27-3.36 (1H, m), 3.52-3.86 (5H, m), 3.86-3.94 (1H, m), 4.15-4.19 ( 2H, m), 4.19 (3H, s), 4.56 (2H, s), 5.39-5.43 (2H, m), 7.40-7.54 (8H, m), 7 .63-7.66 (1H, m), 7.70-7.73 (1H, m), 7.76-7.81 (2H, m), 8.21-8.24 (1H, m) , 8.75 (1H, s), 11.05 (1H, s).
MS (ESI) m / z: 634 (M + H)⁺.
Example 32
[Step 1] Ethyl 2-methoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

The compound (101 mg) obtained in Step 1 of Example 31 was suspended in DMF (1 ml), and potassium carbonate (146 mg), 2- (bromomethyl) pyridine hydrobromide (60 mg) were successively added at 50 ° C. Stir for 8 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: methanol = 50: 1 (v / v)] to obtain 44 mg of the title compound.
MS (ESI) m / z: 330 (M + H)⁺.
[Step 2] N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl ] -2-Methoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in step 1 (44 mg) in ethanol (1 ml) was added 1N aqueous sodium hydroxide solution (0.15 ml) and stirred at room temperature for 2 hours, and then 1N aqueous hydrochloric acid solution was added, followed by extraction with dichloromethane. Dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC · HCl (38 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 27 (43 mg) and HOBt (19 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was subjected to lyophilization using dioxane to obtain 9.2 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.27-3.36 (1H, m), 3.53-3.85 (5H, m), 3.94-4.03 (1H, m), 4.16 (3H, s) 4.16-4.21 (2H, m), 4.58 (2H, s), 5.48-5.52 (2H, m), 7.27-7.33 (1H, m), 7 .43-7.53 (4H, m), 7.64-7.66 (1H, m), 7.70-7.78 (2H, m), 7.79-7.84 (2H, m) , 8.21-8.24 (1H, m), 8.54-8.58 (1H, m), 8.97 (1H, s), 11.09 (1H, s).
MS (ESI) m / z: 635 (M + H)⁺.
Example 33
[Step 1] Ethyl 2-ethoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

A mixture of cyanamide (1.00 g) and tetraethoxymethane (4.97 ml) was heated and stirred at 110 ° C. for 1 hour. Thereafter, ethanol (20 ml) and hydrazine monohydrate (1.15 ml) were sequentially added, and the mixture was heated to reflux for 6 hours. Diethyl ethoxymethylenemalonate (5.29 ml) and acetic acid (20 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was heated to reflux for 14 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 3.59 g of the title compound.
MS (ESI) m / z: 253 (M + H)⁺.
[Step 2] Ethyl 4-benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

The compound (500 mg) obtained in the above Step 1 was suspended in DMF (10 ml), potassium carbonate (356 mg) and benzyl bromide (283 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 1: 1 (v / v)] to obtain 556 mg of the title compound as a solid.
MS (ESI) m / z: 343 (M + H)⁺.
[Step 3] 4-Benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid

Ethanol (4 ml) and 1N aqueous sodium hydroxide solution (0.88 ml) were sequentially added to the compound obtained in Step 2 (200 mg), and the mixture was stirred at 50 ° C. for 3 hours. To the reaction solution was added 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 151 mg of the title compound.
MS (ESI) m / z: 315 (M + H)⁺.
[Step 4] N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl ] -4-Benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 3 (75 mg), Step 1 of Example 27 (84 mg) and HOBt (33 mg) in DMF (2 ml) was added EDC · HCl (69 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 105 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 1.51 (3H, t, J = 7.2 Hz), 3.27-3.35 (1H, m), 3.52-3.85 (5H, m), 3.95-4. 04 (1H, m), 4.15-4.20 (2H, m), 4.48-4.62 (4H, m), 5.38-5.43 (2H, m), 7.37- 7.54 (8H, m), 7.64-7.66 (1H, m), 7.70-7.72 (1H, m), 7.76-7.81 (2H, m), 8. 20-8.23 (1H, m), 8.74 (1H, s), 11.07 (1H, s).
MS (ESI) m / z: 648 (M + H)⁺.
Example 34
[Step 1] Ethyl 2-ethoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

The compound (500 mg) obtained in Step 1 of Example 33 was suspended in DMF (10 ml), and potassium carbonate (685 mg), 2- (bromomethyl) pyridine hydrobromide (602 mg) were successively added at 50 ° C. Stir for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: methanol = 50: 1 (v / v)] to obtain 500 mg of the title compound.
MS (ESI) m / z: 344 (M + H)⁺.
[Step 2] N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl ] -2-Ethoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

1N Aqueous sodium hydroxide solution (0.22 ml) was added to an ethanol (2 ml) solution of the compound obtained in step 1 above (75 mg) and stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure. To a solution of the compound obtained in Step 1 of Example 27 (77 mg) and HOBt (30 mg) in DMF (2 ml), EDC · HCl (63 mg) was added at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 56 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 1.48 (3H, t, J = 7.0 Hz), 3.26-3.36 (1H, m), 3.52-3.86 (5H, m), 3.95-4. 03 (1H, m), 4.14-4.21 (2H, m), 4.53 (2H, q, J = 7.0 Hz), 4.58 (2H, s), 5.47-5. 52 (2H, m), 7.20-7.33 (1H, m), 7.33-7.54 (5H, m), 7.60-7.85 (4H, m), 8.20- 8.24 (1H, m), 8.54-8.59 (1H, m), 8.97 (1H, s), 11.10 (1H, s).
MS (ESI) m / z: 649 (M + H)⁺.
Example 35
[Step 1] 1-[(2R) -1,4-dioxan-2-ylmethyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -Pyrazole

4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (200 mg) is dissolved in THF, and potassium tert-butoxide (150 mg) is added to room temperature. And stirred for 30 minutes. (2S) -1,4-Dioxane-2-ylmethyl methanesulfonate (202 mg) and tetrabutylammonium iodide (38 mg) were added to the reaction mixture, and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled, a solution of ethylenediamine (62 mg) in THF (1 ml) was added dropwise at 0 ° C., and the mixture was stirred at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 275 mg of a crude product of the title compound as an oily substance.
[Step 2] N- [4- (2-amino-5- {1-[(2R) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl ] -4-Benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Using the compound (200 mg) obtained in Step 1 of Example 24 and the compound (166 mg) obtained in Step 1 above, synthesis was performed in the same manner as in Step 2 of Example 24 to obtain 130 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.45 (3H, s), 3.23-4.14 (9H, m), 5.57 (2H, br s), 5.59 (2H, s), 7.34-7. 56 (8H, m), 7.80-7.84 (3H, m), 8.07 (1H, s), 8.21 (1H, d, J = 2.3 Hz), 9.11 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 618 (M + H)⁺.
Example 36
[Step 1] 1- (2-Fluoroethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole

Solution of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (300 mg) and 1-fluoro-2-iodoethane (350 mg) in dioxane (10 ml) Was added cesium carbonate (755 mg), and the mixture was stirred at room temperature for 22 hours. The insoluble material was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 19: 1 (v / v)] to give 345 mg of the title compound as an oil. Obtained as material.
[Step 2] N- (4- {2-amino-5- [1- (2-fluoroethyl) -1H-pyrazol-4-yl] pyridin-3-yl} phenyl) -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 24 (100 mg) and the compound obtained in Step 1 above (48 mg) in ethylene glycol dimethyl ether (4 ml), water (0.5 ml), cesium carbonate (80 mg), tetrakis (triphenyl) Phosphine) palladium (22 mg) was added, and the mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. After cooling, the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 19: 1 (v / v)], and further silica gel column chromatography (NH) [chloroform: methanol = 99: 1 → 19: 1 (v / v)], and the resulting solid was washed with ethyl acetate to obtain 55 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.45 (3H, s), 4.39 (1H, t, J = 4.6 Hz), 4.44 (1H, t, J = 4.9 Hz), 4.74 (1H, t, J = 4.6 Hz), 4.83 (1H, t, J = 4.9 Hz), 5.58-5.60 (4H, m), 7.35-7.42 (3H, m), 7. 47-7.57 (5H, m), 7.82 (2H, d, J = 8.6 Hz), 7.88 (1H, s), 8.15 (1H, s), 8.22 (1H, d, J = 2.3 Hz), 9.11 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 564 (M + H)⁺.
Example 37
[Step 1] 1- (2-methoxyethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole

Performed with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (300 mg) and 1-bromo-2-methoxyethane (280 mg) Synthesis in the same manner as in Step 1 of Example 36 gave 320 mg of the title compound as a solid.
[Step 2] N- (4- {2-amino-5- [1- (2-methoxyethyl) -1H-pyrazol-4-yl] pyridin-3-yl} phenyl) -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Using the compound (100 mg) obtained in Step 1 of Example 24 and the compound (49 mg) obtained in Step 1 above, synthesis was performed in the same manner as in Step 2 of Example 24 to obtain 40 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.45 (3H, s), 3.24 (3H, s), 3.70 (2H, t, J = 5.4 Hz), 4.24 (2H, t, J = 5.4 Hz) , 5.57-5.59 (4H, m), 7.35-7.42 (3H, m), 7.47-7.56 (5H, m), 7.82 (3H, d, J = 8.6 Hz), 8.08 (1 H, s), 8.21 (1 H, d, J = 2.3 Hz), 9.11 (1 H, s), 10.99 (1 H, s).
MS (ESI) m / z: 576 (M + H)⁺.
Example 38
[Step 1] tert-butyl 4- {4- [6-amino-5- (4-{[(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) carbonyl] amino} phenyl) pyridin-3-yl] -1H-pyrazol-1-yl} piperidine-1-carboxylate

The compound (75 mg) obtained in Step 1 of Example 24 and tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole Synthesis was performed in the same manner as in Step 2 of Example 24 using [-1-yl] piperidine-1-carboxylate (59 mg) to obtain 133 mg of a crude product of the title compound as an oily substance.
MS (ESI) m / z: 701 (M + H)⁺.
[Step 2] N- {4- [2-Amino-5- (1-piperidin-4-yl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4-benzyl-2-methyl- 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Trifluoroacetic acid (1 ml) was added to a solution of (99 mg) obtained in Step 1 above in dichloromethane (2 ml) and stirred at room temperature. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase HPLC [acetonitrile: water: formic acid], and then silica gel column chromatography (NH) [chloroform: methanol = 99: 1 → 9: 1 (v / v)]. Further, the obtained solid was washed with ethyl acetate to obtain 40 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.72-1.82 (2H, m), 1.94-1.98 (2H, m), 2.45 (3H, s), 2.54-2.60 (2H, m) , 3.01-3.05 (2H, m), 4.10-4.18 (1H, m), 5.55 (2H, br s), 5.59 (2H, s), 7.34- 7.42 (3H, m), 7.47-7.53 (4H, m), 7.58 (1H, d, J = 2.3 Hz), 7.80-7.83 (3H, m), 8.16 (1H, s), 8.22 (1H, d, J = 2.3 Hz), 9.12 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 601 (M + H)⁺.
Example 39
[Step 1] tert-butyl 2-methyl-2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl] propanoate

Using 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (300 mg) and tert-butyl 2-bromoisobutyrate (517 mg), Synthesis was performed in the same manner as in Step 1 of Example 36 to obtain 178 mg of the title compound as a solid.
MS (ESI) m / z: 337 (M + H)⁺.
[Step 2] tert-butyl 2- {4- [6-amino-5- (4-{[(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) carbonyl] amino} phenyl) pyridin-3-yl] -1H-pyrazol-1-yl} -2-methylpropanate

Using the compound obtained in Step 1 of Example 24 (200 mg) and the compound obtained in Step 1 above (139 mg), the compound was synthesized in the same manner as in Step 2 of Example 24 to obtain 157 mg of the title compound as a solid.
MS (ESI) m / z: 660 (M + H)⁺.
[Step 3] 2- {4- [6-Amino-5- (4-{[(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1, 5-a] pyrimidin-6-yl) carbonyl] amino} phenyl) pyridin-3-yl] -1H-pyrazol-1-yl} -2-methylpropanoic acid

To a solution of the compound obtained in Step 2 (210 mg) in dichloromethane (3 ml) was added dropwise trifluoroacetic acid (1 ml) under ice cooling, and the mixture was stirred overnight while gradually returning to room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)], and the resulting crude product was further purified with ethyl acetate. To give 24 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.76 (6H, s), 2.45 (3H, s), 5.59 (2H, s), 7.35-7.42 (4H, m), 7.47-7.50. (2H, m), 7.56 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 8.01-8.03 (1H, m), 8 .18 (1H, s), 8.27-8.29 (1H, m), 8.53 (1H, s), 9.12 (1H, s), 11.07 (1H, s).
MS (ESI) m / z: 604 (M + H)⁺.
Example 40
N- {4- [2-amino-5- (1- {2-[(3R) -3-hydroxypyrrolidin-1-yl] -1,1-dimethyl-2-oxoethyl} -1H-pyrazole-4- Yl) pyridin-3-yl] phenyl} -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

In Step 3 of Example 39, a solution of the compound (60 mg) in DMF (2 ml) was added (R)-(−)-3-pyrrolidinol monohydrochloride (25 mg), EDC · HCl (29 mg), HOBt (20 mg), N-methylmorpholine (22 μl) was added and stirred overnight at room temperature. The reaction solution was evaporated under reduced pressure, the residue was diluted with water, extracted with chloroform containing 10% methanol, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)], and the resulting crude product was further mixed with ethyl acetate and hexane. Washing with a solvent gave 40 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.58-1.72 (8H, m), 2.36-2.39 (1H, m), 2.45 (3H, s), 2.54-2.57 (1H, m) 3.39-3.42 (2H, m), 3.40-3.42 (1H, m), 4.03-4.11 (1H, m), 4.78-4.83 (1H, m), 5.58-5.60 (4H, m), 7.35-7.42 (3H, m), 7.47-7.49 (2H, m), 7.52 (2H, d, J = 8.6 Hz), 7.66 (1H, s), 7.82 (2H, d, J = 8.6 Hz), 7.94 (1H, s), 8.29 (1H, d, J = 2.3 Hz), 8.33-8.34 (1H, m), 9.11 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 673 (M + H)⁺.
Example 41
[Step 1] 1-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} -4- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1H-pyrazole

4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (200 mg) was dissolved in DMF and 55% oily sodium hydride (100 mg) was added. Stir at room temperature for 30 minutes. [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl 4-methylbenzenesulfonate (575 mg) was added to the reaction mixture, and the mixture was stirred at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 4: 1 → 1: 2 (v / v)] to obtain 245 mg of the title compound as an oily substance.
[Step 2] N- {4- [2-amino-5- (1-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} -1H-pyrazole-4- Yl) pyridin-3-yl] phenyl} -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Using the compound obtained in Step 1 of Example 24 (200 mg) and the compound obtained in Step 1 above (139 mg), the compound was synthesized in the same manner as in Step 2 of Example 24 to obtain 130 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.26 (3H, s), 1.31 (3H, s), 2.45 (3H, s), 3.75-3.78 (1H, m), 4.01-4.04 (1H, m), 4.16-4.25 (2H, m), 4.38-4.43 (1H, m), 5.57-5.59 (4H, m), 7.34-7 .42 (3H, m), 7.47-7.56 (5H, m), 7.81-7.85 (3H, m), 8.10 (1H, s), 8.21 (1H, d , J = 2.3 Hz), 9.11 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 632 (M + H)⁺.
Example 42
N- [4- (2-amino-5- {1-[(2S) -2,3-dihydroxypropyl] -1H-pyrazol-4-yl} pyridin-3-yl) phenyl] -4-benzyl-2 -Methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a THF (2 ml) solution of the compound (100 mg) obtained in Step 2 of Example 41, a 4N dioxane hydrochloride (1 ml) solution was added dropwise under ice cooling, followed by stirring at room temperature for 90 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was washed with ethyl acetate, collected by filtration, and further washed with 5% methanol-containing ethyl acetate to obtain 82 mg of the hydrochloride of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.45 (3H, s), 3.29-3.33 (1H, m), 3.80-3.84 (2H, m), 3.95-4.00 (1H, m) 4.21-4.25 (1H, m), 5.59 (2H, s), 7.35-7.60 (9H, m), 7.91 (2H, d, J = 8.6 Hz). , 7.99 (1H, s), 8.18 (1H, d, J = 2.3 Hz), 8.27 (2H, s), 9.12 (1H, s), 11.07 (1H, s) ).
MS (ESI) m / z: 592 (M + H)⁺.
Example 43
[Step 1] 3- (4-Aminophenyl) -5- (3,4-dimethoxyphenyl) pyridin-2-amine

To a solution of the compound obtained in Step 1 of Example 1 (2.48 g) in dioxane (40 ml) and water (10 ml) was added tetrakis (triphenylphosphine) palladium (1.09 g), 3,4-dimethoxyphenylboronic acid. (1.92 g) and potassium carbonate (3.89 g) were added at room temperature. The reaction mixture was stirred at 95 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [chloroform: methanol = 9: 1 (v / v)] to obtain 2.48 g of the title compound as a solid.
¹H-NMR (cdcl₃) Δ: 3.80 (2H, br s), 3.91 (3H, s), 3.93 (3H, s), 4.60 (2H, br s), 6.77-6.81 (2H) M), 6.93 (1H, d, J = 8.3 Hz), 7.03 (1H, d, J = 2.3 Hz), 7.08 (1H, dd, J = 8.3, 2.. 3 Hz), 7.28-7.32 (2 H, m), 7.53 (1 H, d, J = 2.3 Hz), 8.23 (1 H, d, J = 2.3 Hz).
MS (ESI) m / z: 322 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl) -7-oxo-4,7- Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 3 (101 mg) and the compound obtained in Step 1 above (113 mg) and HOBt (48 mg) in DMF (2 ml), EDC · HCl (101 mg) was added at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give the title compound. 77 mg was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.92 (3H, s), 3.94 (3H, s), 4.64 (2H, s), 5.44-5.49 (2H, m), 6.90-7.16 (5H, m), 7.33-7.58 (5H, m), 7.77-7.83 (2H, m), 8.21-8.30 (2H, m), 8.88 (1H , S), 10.91 (1H, s).
MS (ESI) m / z: 592 (M + H)⁺.
Example 44
N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2 , 4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound (97 mg) obtained in Step 1 of Example 4 and the compound (108 mg) obtained in Step 1 of Example 43 and HOBt (47 mg) in DMF (2 ml), EDC · HCl (97 mg) was added at room temperature. It was. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 136 mg of the title compound as a solid.
¹H-NMR (CDCl₃): 2.60 (3H, s), 3.92 (3H, s), 3.94 (3H, s), 4.62 (2H, s), 5.44-5.49 (2H, m) ), 6.91-7.12 (3H, m), 7.38-7.59 (8H, m), 7.77-7.85 (2H, m), 8.26-8.30 (1H) , M), 8.80 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 588 (M + H)⁺.
Example 45
N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -2-methyl-7-oxo-4- (1-phenylethyl) -4,7- Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Ethyl 2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) was suspended in DMF (1 ml) and potassium carbonate ( 40 mg) and (1-bromoethyl) benzene (37 μl) were sequentially added, and the mixture was stirred at 70 ° C. for 5 hours. To the reaction solution was added 1N aqueous sodium hydroxide solution (0.33 ml), and the mixture was stirred at 80 ° C. for 2 hours. Then, 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC.HCl (65 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43 (72 mg) and HOBt (31 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 10: 10: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 68 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.01 (3H, d, J = 7.1 Hz), 2.60 (3H, s), 3.92 (3H, s), 3.94 (3H, s), 4.61 (2H) , S), 6.26 (1H, q, J = 7.1 Hz), 6.91-7.12 (3H, m), 7.39-7.59 (8H, m), 7.76-7. .83 (2H, m), 8.26-8.30 (1H, m), 8.76 (1H, s), 11.01 (1H, s).
MS (ESI) m / z: 602 (M + H)⁺.
Example 46
[Step 1] 4-[(3-Fluoropyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl

To a solution of (3-fluoropyridin-2-yl) methanol (100 mg) in dichloromethane (1 ml) was added thionyl chloride (86 μl), stirred at room temperature for 1 hour, and concentrated. To a solution of the residue in DMF (1 ml) was added ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (100 mg) and potassium carbonate (61 mg). Sequentially added and stirred at 70 ° C. for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate] to obtain 133 mg of the title compound.
MS (ESI) m / z: 318 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4-[(3-fluoropyridin-2-yl) methyl] -7 -Oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 (75 mg) in ethanol (1 ml) was added 1N aqueous sodium hydroxide solution (0.5 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1N aqueous hydrochloric acid solution (0.5 ml), and the mixture was concentrated under reduced pressure. To the obtained residue, EDC · HCl (68 g) was added at room temperature to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43 (76 mg) and HOBt (33 mg). After stirring at room temperature for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was subjected to lyophilization using dioxane to obtain 5.3 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.92 (3H, s), 3.95 (3H, s), 4.68 (2H, s), 5.71-5.76 (2H, m), 6.91-7.39 (3H, m), 7.45-7.60 (5H, m), 7.82-7.88 (2H, m), 8.08-8.37 (3H, m), 9.03 (1H , S), 10.98 (1H, s).
MS (ESI) m / z: 593 (M + H)⁺.
Example 47
[Step 1] 2-Methyl-4-[(6-methylpyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine- 6-ethyl carboxylate

2-Methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (500 mg) was suspended in DMF (10 ml) and 2- ( Bromomethyl) -6-methylpyridine (502 mg) and potassium carbonate (404 mg) were sequentially added, and the mixture was stirred at 70 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate] to obtain 328 mg of the title compound.
MS (ESI) m / z: 328 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -2-methyl-4-[(6-methylpyridin-2-yl) Methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

1N Aqueous sodium hydroxide solution (0.23 ml) was added to a solution of the compound obtained in Step 1 (75 mg) in ethanol (1 ml), stirred at room temperature for 2 hours, and concentrated under reduced pressure. To the obtained residue, EDC · HCl (66 mg) was added at room temperature to a DMF (2 ml) solution of the compound (74 mg) obtained in Step 1 of Example 43 and HOBt (32 mg). After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 88 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.50 (3H, s), 2.55 (3H, s), 3.92 (3H, s), 3.94 (3H, s), 4.63 (2H, s), 5. 49-5.52 (2H, m), 6.90-7.17 (4H, m), 7.20-7.33 (1H, m), 7.46-7.66 (4H, m), 7.79-7.90 (2H, m), 8.26-8.30 (1H, m), 9.03 (1H, s), 11.04 (1H, s).
MS (ESI) m / z: 603 (M + H)⁺.
Example 48
[Step 1] Ethyl 2-methyl-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

2-Methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (500 mg) was suspended in DMF (10 ml) and 2- ( Bromomethyl) pyridine hydrobromide (683 mg) and potassium carbonate (778 mg) were sequentially added, and the mixture was stirred at 70 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate] to obtain 494 mg of the title compound.
MS (ESI) m / z: 314 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -2-methyl-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

1N aqueous sodium hydroxide solution (0.24 ml) was added to an ethanol (1 ml) solution of the compound obtained in Step 1 (75 mg), and the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. To the obtained residue, EDC · HCl (68 mg) was added at room temperature to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43 (76 mg) and HOBt (33 mg). After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 114 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.55 (3H, s), 3.92 (3H, s), 3.95 (3H, s), 4.63 (2H, s), 5.54-5.57 (2H, m) ), 6.91-7.12 (3H, m), 7.21-7.35 (1H, m), 7.43-7.60 (4H, m), 7.72-7.87 (3H) M), 8.27-8.30 (1H, m), 8.54-8.59 (1H, m), 9.01 (1H, s), 11.03 (1H, s).
MS (ESI) m / z: 589 (M + H)⁺.
Example 49
N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4- (cyclohexylmethyl) -2-methyl-7-oxo-4,7-dihydro [ 1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Ethyl 2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) was suspended in DMF (1 ml) and potassium carbonate ( 40 mg) and (bromomethyl) cyclohexane (37 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 8 hours. 1N Aqueous sodium hydroxide solution (1 ml) was added and the mixture was stirred at 80 ° C. for 2 hr, 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC.HCl (65 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43 (72 mg) and HOBt (31 mg) at room temperature. After stirring at 50 ° C. for 4 and a half hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and recrystallized from ethyl acetate and diisopropyl ether to give the title compound. 71 mg was obtained as a solid.
¹H-NMR (CDCl₃): 1.02-1.33 (6H, m), 1.63-1.85 (5H, m), 2.58 (3H, s), 3.92 (3H, s), 3.95 (3H, s), 4.11-4.17 (2H, m), 4.63 (2H, s), 6.90-7.13 (3H, m), 7.48-7.60 (3H M), 7.80-7.87 (2H, m), 8.26-8.31 (1H, m), 8.72 (1H, s), 11.04 (1H, s).
MS (ESI) m / z: 594 (M + H)⁺.
Example 50
[Step 1] N- [4- (2-Amino-5-bromopyridin-3-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4 ] Triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound (1.3 g) obtained in Step 1 of Example 3 and the compound (1 g) obtained in Step 1 of Example 1 in DMF (13 ml), EDC.HCl (871 mg) and HOBt (58 mg) were added. Stir at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained residue was purified through silica gel column chromatography [chloroform: methanol] to obtain 389 mg of the title compound as a solid.
MS (ESI) m / z: 534 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (2,3-dihydro-1,4-benzodioxin-6-yl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl ) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 (70 mg) and 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (28 mg) in dioxane (0.8 ml), water (0.2 ml), sodium carbonate (42 mg) and tetrakis (triphenylphosphine) palladium (15 mg) were added, and the mixture was stirred at 150 ° C. for 15 minutes under microwave irradiation. After cooling, water was added and the mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The obtained residue was passed through silica gel column chromatography [chloroform: methanol = 96: 4 → 89: 11 (v / v)] and then purified by reverse phase HPLC [acetonitrile: water: formic acid] to give the title compound 5 Obtained 4 mg as a solid.
¹H-NMR (CDCl₃): 4.27 (4H, s), 4.67 (2H, s), 5.46 (2H, s), 6.91 (1H, d, J = 7.3 Hz), 6.99-7 .06 (2H, m), 7.11 (2H, t, J = 8.2 Hz), 7.45-7.56 (5H, m), 7.80 (2H, d, J = 8.2 Hz) , 8.21-8.26 (2H, m), 8.88 (1H, s), 10.90 (1H, s).
MS (ESI) m / z 590: (M + H)⁺.
Example 51
[Step 1] 3-Bromo-5- {4-[(2R) -1,4-dioxan-2-ylmethoxy] -3-methoxyphenyl} pyridin-2-amine

2-Methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (10.2 g), (2R) -1,4-dioxan-2-ylmethyl Methane sulfonate (8.0 g) and potassium carbonate (11.2 g) were suspended in DMF (200 ml) and stirred at 90 ° C. for 16 hours. After standing to cool, insolubles were removed and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane: ethyl acetate = 2: 1 (v / v)] to obtain 14.3 g of the title compound.
MS (ESI) m / z: 351 (M + H)⁺
[Step 2] 3-Bromo-5- {4-[(2R) -1,4-dioxan-2-ylmethoxy] -3-methoxyphenyl} pyridin-2-amine

Compound (2.64 g) obtained in Step 1 above, 3-bromo-5-iodopyridin-2-amine (2.25 g), tetrakis (triphenylphosphine) palladium (430 mg), potassium carbonate (3.12 g). Suspended in dioxane (30 ml) and water (6 ml) and stirred at 80 ° C. overnight. After standing to cool, it was diluted with chloroform and washed with water. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: hexane = 1: 1 → chloroform: methanol = 19: 1 (v / v)]. To give 2.05 g of the title compound as a solid.
MS (ESI) m / z: 395, 397 (M + H)⁺.
[Step 3] 3- (4-Aminophenyl) -5- {4-[(2R) -1,4-dioxan-2-ylmethoxy] -3-methoxyphenyl} pyridin-2-amine

Compound (2.05 g) obtained in Step 2 above, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.14 g), tetrakis (triphenyl) Phosphine) palladium (0.3 g) and potassium carbonate (2.15 g) were suspended in dioxane (30 ml) and water (6 ml), and the mixture was stirred at 100 ° C. for 2 hours. After allowing to cool, the reaction solution was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: hexane = 1: 1 → chloroform: ethanol = 19: 1 (v / v)] to obtain 1.27 g of the title compound as a solid. It was.
MS (ESI) m / z: 408 (M + H)⁺.
[Step 4] N- [4- (2-Amino-5- {4-[(2R) -1,4-dioxane-2-ylmethoxy] -3-methoxyphenyl} pyridin-3-yl) phenyl] -4 -(4-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 3 (50 mg) and the compound obtained in Step 1 of Example 3 (37 mg) in DMF (1 ml), EDC · HCl (25 mg) and HOBt (2 mg) were added, and the mixture was allowed to stand at room temperature overnight Stir. 4- (4-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid (7 mg) and EDC · HCl ( 5 mg) was added, and the mixture was stirred for 4 hours. After adding water, the mixture was extracted with ethyl acetate, dehydrated with sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was passed through silica gel column chromatography [ethyl acetate: methanol = 100: 0 → 95: 5 (v / v)] and then purified by reverse phase HPLC [acetonitrile: water: formic acid]. 25 mg of compound was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.44-4.14 (14H, m), 4.69 (2H, br s), 5.06 (2H, s), 6.94 (1H, d, J = 8.2 Hz), 6.9-7.06 (2H, m), 7.32-7.42 (5H, m), 7.43-7.50 (2H, m), 7.52-7.56 (1H, m) ), 7.73-7.78 (2H, m), 8.23 (1H, s), 8.56 (1H, s), 11.03 (1H, s).
MS (ESI) m / z: 678 (M + H)⁺.
Example 52
[Step 1] 3-Bromo-5- [3-methoxy-4- (2-pyrrolidin-1-ylethoxy) phenyl] pyridin-2-amine

To a solution of 3-bromo-5-iodopyridin-2-amine (5.00 g) in dioxane (40 ml) and water (4 ml) was added 1- {2- [2-methoxy-4- (4,4,5,5). 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethyl} pyrrolidine (5.81 g), tetrakis (triphenylphosphine) palladium (0.97 g) and potassium carbonate (6.94 g) at room temperature. Added at. The reaction mixture was stirred at 80 ° C. overnight. The reaction mixture was returned to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 50: 1 → 20: 1 → 10: 1 (v / v)] to give 4.03 g of the title compound as an oil. Obtained as material.
¹H-NMR (CDCl₃) Δ: 1.24 (4H, s), 2.62-2.68 (4H, m), 2.98 (2H, t, J = 6.4 Hz), 3.92 (3H, s), 4 .19 (2H, t, J = 6.4 Hz), 4.91 (2H, s), 6.93-7.02 (3H, m), 7.85 (1H, d, J = 1.8 Hz) , 8.22 (1H, d, J = 2.3 Hz).
MS (ESI) m / z: 392, 394 (M + H)⁺.
[Step 2] 3- (4-Aminophenyl) -5- [3-methoxy-4- (2-pyrrolidin-1-ylethoxy) phenyl] pyridin-2-amine

4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was added to a solution of the compound obtained in Step 1 (375 mg) in dioxane (10 ml) and water (1 ml). Aniline (285 mg), tetrakis (triphenylphosphine) palladium (110 mg) and potassium carbonate (396 mg) were added at room temperature. The reaction mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was returned to room temperature and extracted with chloroform. The organic layer was dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography [chloroform: methanol = 19: 1 (v / v)] to obtain 407 mg of the title compound as an oily substance.
MS (ESI) m / z: 405 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- [3-methoxy-4- (2-pyrrolidin-1-ylethoxy) phenyl] pyridin-3-yl] phenyl} -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 4 (56 mg), the compound obtained in Step 2 above (80 mg) and HOBt (30 mg) in DMF (5 ml), EDC · HCl (57 mg) was added at room temperature. After stirring at 40 ° C. for 3.5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by HPLC [acetonitrile: water: formic acid]. The obtained solid was crystallized from ethyl acetate-hexane to obtain 44 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 1.79-1.85 (4H, m), 2.60 (3H, s), 2.62-2.68 (4H, m), 2.97 (2H, t, J = 6. 4Hz), 3.91 (3H, s), 4.19 (2H, t, J = 6.4 Hz), 4.62 (2H, s), 5.46 (2H, s), 6.96 (1H) , D, J = 8.3 Hz), 7.03 (1H, d, J = 2.3 Hz), 7.06 (1H, dd, J = 8.0, 2.1 Hz), 7.41-7. 46 (5H, m), 7.49-7.53 (2H, m), 7.56 (1H, d, J = 2.8 Hz), 7.78-7.82 (2H, m), 8. 27 (1H, d, J = 2.3 Hz), 8.79 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 671 (M + H)⁺.
Example 53
N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4-benzyl-2-methoxy-7-oxo-4,7-dihydro [1,2 , 4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound (72 mg) obtained in Step 2 of Example 31 in ethanol (1 ml) was added 1N aqueous sodium hydroxide solution (0.26 ml), and the mixture was stirred at room temperature for 5 hours. Extracted and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC.HCl (63 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43 (71 mg) and HOBt (30 mg) at room temperature. After stirring at 50 ° C. for 3.5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give 43 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.92 (3H, s), 3.94 (3H, s), 4.19 (3H, s), 4.65 (2H, s), 5.38-5.43 (2H, m) ), 6.89-7.14 (3H, m), 7.36-7.61 (8H, m), 7.75-7.83 (2H, m), 8.25-8.31 (1H) , M), 8.75 (1H, s), 11.05 (1H, s).
MS (ESI) m / z: 604 (M + H)⁺.
Example 54
N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4-benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2 , 4] triazolo [1,5-a] pyrimidine-6-carboxamide

A 1N aqueous sodium hydroxide solution (0.26 ml) was added to an ethanol (1 ml) solution of the compound (75 mg) obtained in Step 2 of Example 33, and the mixture was stirred at room temperature for 2 hours. Extracted and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC.HCl (63 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43 (71 mg) and HOBt (30 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 10: 10: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 129 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 1.51 (3H, t, J = 7.2 Hz), 3.92 (3H, s), 3.94 (3H, s), 4.57 (2H, q, J = 7.2 Hz) 4.61 (2H, s), 5.39-5.42 (2H, m), 6.91-7.12 (3H, m), 7.39-7.58 (8H, m), 7 .76-7.82 (2H, m), 8.26-8.30 (1H, m), 8.75 (1H, s), 11.07 (1H, s).
MS (ESI) m / z: 618 (M + H)⁺.
Example 55
[Step 1] Ethyl 2- (2-methoxyethoxy) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

Sodium hydride (55%, 298 mg) was added to a solution of 2-methoxyethanol (2 ml) and THF (8 ml) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Dimethyl cyanocarbonodithioimidate (500 mg) was added to the reaction solution at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. Then, pyridine hydrochloride (869 mg) was added and stirred at 0 ° C. for 1 hour. To the reaction solution was added hydrazine monohydrate (249 μl), and the mixture was heated to reflux for 6 hours. Diethyl ethoxymethylenemalonate (1.04 ml) and acetic acid (2 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was heated to reflux for 13 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 70 mg of the title compound.
[Step 2] Ethyl 4-benzyl-2- (2-methoxyethoxy) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

The compound (70 mg) obtained in the above Step 1 was suspended in DMF (1 ml), potassium carbonate (47 mg) and benzyl bromide (37 μl) were successively added, and the mixture was stirred at 50 ° C. for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 2: 1 (v / v)] to obtain 63 mg of the title compound.
MS (ESI) m / z: 373 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4-benzyl-2- (2-methoxyethoxy) -7-oxo- 4,7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 2 (63 mg) in ethanol (1 ml) was added 1N aqueous sodium hydroxide solution (0.2 ml) and stirred at room temperature for 2 hours, and then 1N aqueous hydrochloric acid solution was added, followed by extraction with dichloromethane. Dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC · HCl (49 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43 (54 mg) and HOBt (23 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 10: 10: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 60 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.46 (3H, s), 3.79-3.85 (2H, m), 3.92 (3H, s), 3.94 (3H, s), 4.62 (2H, s) ), 4.62-4.69 (2H, m), 5.38-5.43 (2H, m), 6.91-7.12 (3H, m), 7.38-7.59 (8H) M), 7.76-7.82 (2H, m), 8.26-8.30 (1H, m), 8.75 (1H, s), 11.05 (1H, s).
MS (ESI) m / z: 648 (M + H)⁺.
Example 56
[Step 1] Ethyl 2- (2-fluoroethoxy) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

Sodium hydride (55%, 298 mg) was added to a solution of 2-fluoroethanol (2 ml) and THF (8 ml) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Dimethyl cyanocarbonodithioimidate (500 mg) was added to the reaction solution at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. Then, pyridine hydrochloride (869 mg) was added and stirred at 0 ° C. for 1 hour. To the reaction solution was added hydrazine monohydrate (249 μl), and the mixture was heated to reflux for 6 hours. Diethyl ethoxymethylenemalonate (1.04 ml) and acetic acid (2 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was heated to reflux for 13 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 78 mg of the title compound.
[Step 2] Ethyl 4-benzyl-2- (2-fluoroethoxy) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

The compound (78 mg) obtained in the above Step 1 was suspended in DMF (1 ml), potassium carbonate (52 mg) and benzyl bromide (41 μl) were successively added, and the mixture was stirred at 50 ° C. for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 2: 1 (v / v)] to obtain 70 mg of the title compound.
MS (ESI) m / z: 361 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4-benzyl-2- (2-fluoroethoxy) -7-oxo- 4,7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

A 1N aqueous sodium hydroxide solution (0.23 ml) was added to an ethanol (1 ml) solution of the compound obtained in the above step 2 (70 mg) and the mixture was stirred at room temperature for 2 hours. Then, a 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with dichloromethane. Dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC.HCl (56 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43 (62 mg) and HOBt (27 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 10: 10: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 79 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.92 (3H, s), 3.94 (3H, s), 4.61 (2H, s), 4.70-4.92 (4H, m), 5.38-5.45. (2H, m), 6.91-7.12 (3H, m), 7.40-7.58 (8H, m), 7.76-7.82 (2H, m), 8.26-8 .30 (1H, m), 8.77 (1H, s), 11.02 (1H, s).
MS (ESI) m / z: 636 (M + H)⁺.
Example 57
[Step 1] Ethyl 2- (difluoromethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

To an ethanol solution (10 ml) of ethyl difluoroacetate (2.00 g) and aminoguanidine sulfate hydrate (3.97 g) was added an ethanol solution of sodium ethoxide (20%, 11.0 g) at room temperature, and 8 ° C. at 8 ° C. Stir for hours. The reaction solution was brought to room temperature, filtered, and the filtrate was concentrated. To the residue were added diethyl ethoxymethylenemalonate (6.51 ml) and acetic acid (50 ml), and the mixture was heated to reflux for 1 day. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 2.88 g of the title compound.
MS (ESI) m / z: 259 (M + H)⁺.
[Step 2] Ethyl 4-benzyl-2- (difluoromethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

The compound (750 mg) obtained in the above Step 1 was suspended in DMF (10 ml), potassium carbonate (522 mg) and benzyl bromide (414 μl) were sequentially added, and the mixture was stirred at 50 ° C. for 5 hours. Saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 2: 1 (v / v)] to obtain 566 mg of the title compound.
MS (ESI) m / z: 349 (M + H)⁺.
[Step 3] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl} -4-benzyl-2- (difluoromethyl) -7-oxo-4, 7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

A 1N aqueous sodium hydroxide solution (0.33 ml) was added to an ethanol (1 ml) solution of the compound obtained in step 2 above (75 mg), and the mixture was stirred at room temperature for 3 hours. Then, a 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with dichloromethane. Dried over sodium sulfate. The solvent was distilled off under reduced pressure, and to the obtained residue, EDC · HCl (62 mg) was added at room temperature to a DMF (2 ml) solution of the compound obtained in Step 1 of Example 43) and HOBt (30 mg). After stirring at 50 ° C. for 3.5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 10: 10: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 18 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.92 (3H, s), 3.94 (3H, s), 4.63 (2H, s), 5.51-5.56 (2H, m), 6.83-7.13 (4H, m), 7.41-7.60 (8H, m), 7.76-7.84 (2H, m), 8.26-8.31 (1H, m), 8.91 (1H , S), 10.78 (1H, s).
MS (ESI) m / z: 624 (M + H)⁺.
Example 58
[Step 1] 3-Bromo-5-[(trimethylsilyl) ethynyl] pyridin-2-amine

To a solution of 3-bromo-5-iodopydin-2-amine (2.56 g) in THF (35 ml), copper (I) iodide (0.31 g), trimethylsilylacetylene (0.93 g), bis (trimethylphosphine) palladium. (II) Dichloride (0.08 g) was added, and triethylamine (15 ml) was added continuously at room temperature, followed by stirring overnight. The reaction solution was diluted with ethyl acetate and washed with water. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: hexane = 1: 4 (v / v)] to obtain 2.44 g of the title compound as a solid.
MS (ESI) m / z: 269 (M + H)⁺.
[Step 2] 3-Bromo-5-ethynylpyridin-2-amine

Tetrabutylammonium fluoride (9.10 ml) was added to a THF (30 ml) solution of the compound obtained in Step 1 (2.44 g) in an ice-water bath and stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and washed with water. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.79 g of the title compound as a solid.
MS (ESI) m / z: 198 (M + H)⁺.
[Step 3] 3-Bromo-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-1,2,3-triazol-4-yl} pyridin-2-amine

To a solution of (2R) -1,4-dioxan-2-ylmethyl methanesulfonate (216 mg) in DMSO (5 ml), sodium azide (93 mg) was added and stirred at 80 ° C. for 8 hours. After allowing to cool, the compound obtained in Step 2 (217 mg) and copper (I) iodide (63 mg) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours. The reaction solution was diluted with chloroform, and insoluble matters were removed. After washing with water, it was washed with saturated brine, and the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 19: 1 (v / v)] to obtain 341 mg of the crude title compound as an oily substance.
MS (ESI) m / z: 341 (M + H)⁺.
[Step 4] 3- (4-aminophenyl) -5- {1-[(2S) -1,4-dioxane-2-ylmethyl] -1H-1,2,3-triazol-4-yl} pyridine- 2-Amine

A solution of the compound obtained in Step 3 (341 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (120 mg) in dioxane (10 ml) was added water ( 1 ml), potassium carbonate (230 mg), tetrakis (triphenylphosphine) palladium (60 mg) were added, and the mixture was stirred at 100 ° C. for 2.3 hours. The mixture was allowed to cool and diluted with chloroform. The organic layer was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 19: 1 (v / v)] to obtain 168 mg of the title compound as a solid.
MS (ESI) m / z: 353 (M + H)⁺.
[Step 5] N- [4- (2-Amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-1,2,3-triazol-4-yl} pyridine -3-yl) phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

In a DMF (2 ml) solution of the compound obtained in Step 1 of Example 4 (94 mg) and the compound obtained in Step 4 above (130 mg), EDC · HCl (84 mg), HOBt (60 mg), N-methylmorpholine (81 μl). ) And stirred at room temperature for 2 hours. The reaction solution was diluted with water, extracted with chloroform containing 10% methanol, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 19: 1 (v / v)], and the resulting solid was washed with ethyl acetate. 120 mg of compound was obtained as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.45 (3H, s), 3.26-3.31 (1H, m), 3.43-3.48 (1H, m), 3.53-3.58 (1H, m) , 3.63-3.65 (1H, m), 3.74-3.76 (1H, m), 3.81-3.83 (1H, m), 3.92-3.96 (1H, m), 4.38-4.50 (2H, m), 5.59 (2H, s), 5.83 (2H, br s), 7.36-7.42 (3H, m), 7. 48 (2H, d, J = 6.9 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.77 (1H, d, J = 2.3 Hz), 7.83 (2H, d , J = 8.6 Hz), 8.44 (1H, s), 8.46 (1H, d, J = 2.3 Hz), 9.11 (1H, s), 11.00 (1H, s).
MS (ESI) m / z: 619 (M + H)⁺.
Example 59
N- [4- (6-Amino-3′-fluoro-3,4′-bipyridin-5-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1, 2,4] Triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 50 (70 mg) and (3-fluoropyridin-4-yl) boronic acid (37 mg) in DMF (0.65 ml), copper chloride (13 mg), cesium carbonate (42 mg) Then, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (10.2 mg) was added, and the mixture was stirred at 150 ° C. for 15 minutes under microwave irradiation. After allowing to cool, water was added and the mixture was extracted with dichloromethane, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [chloroform: methanol] and then purified by reverse phase HPLC [acetonitrile: water: formic acid] to obtain 20 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 4.83 (2H, s), 5.47 (2H, s), 7.12 (2H, t, J = 8.7 Hz), 7.37-7.43 (1H, m), 7 .45-7.54 (4H, m), 7.66-7.69 (1H, m), 7.83 (2H, d, J = 8.7 Hz), 8.24 (1H, s), 8 .37-8.40 (1H, m), 8.44 (1H, d, J = 5.0 Hz), 8.52 (1H, d, J = 3.2 Hz), 8.88 (1H, s) , 10.93 (1H, s).
MS (ESI) m / z: 551 (M + H)⁺.
Example 60
[Step 1] 5- (4-Aminophenyl) -2'-methyl-3,4'-bipyridin-6-amine

The compound (2.0 g) obtained in Step 1 of Example 1 and 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (1. 66 g) was used as a starting material and the title compound (871 mg) was obtained as a solid by the same reaction as in Step 2 of Example 1.
MS (ESI) m / z: 277 (M + H)
[Step 2] N- [4- (6-Amino-2′-methyl-3,4′-bipyridin-5-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7- Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 3 (80 mg) and the compound obtained in Step 1 above (77 mg) in DMF (0.9 ml), EDC.HCl (53 mg) and HOBt (4.3 mg) were added. Stir overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure. The obtained residue was passed through silica gel column chromatography [dichloromethane: methanol = 96: 4 → 89: 11 (v / v)] and then purified by reverse phase HPLC (acetonitrile-water-formic acid). The obtained solid was dissolved in dichloromethane, diisopropyl ether was added, and the resulting solid was collected by filtration. Further, the obtained solid was purified by NH silica gel column chromatography [dichloromethane: methanol] to obtain 41 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.58 (3H, s), 4.77 (2H, s), 5.45 (2H, s), 7.06-7.13 (2H, m), 7.24-7.27 (1H, m), 7.31 (1H, s), 7.44-7.50 (4H, m), 7.62 (1H, d, J = 2.3 Hz), 7.80 (2H, d , J = 8.7 Hz), 8.21 (1H, s), 8.36 (1H, d, J = 2.3 Hz), 8.49 (1H, d, J = 5.5 Hz), 8.86 (1H, s), 10.91 (1H, s).
MS (ESI) m / z: 547 (M + H)⁺.
Example 61
N- {4- [2-amino-5- (3,6-dihydro-2H-pyran-4-yl) pyridin-3-yl] phenyl} -4-benzyl-2-methyl-7-oxo-4, 7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Compound (150 mg) obtained in Step 1 of Example 24 and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyran Water (0.5 ml), cesium carbonate (120 mg) and tetrakis (triphenylphosphine) palladium (33 mg) were added to a solution of (62 mg) in ethylene glycol dimethyl ether (4 ml), and the mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. After standing to cool, the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 19: 1 (v / v)], and further silica gel column chromatography (NH) [chloroform: methanol = 99: 1. → 19: 1 (v / v)], and the obtained solid was washed with ethyl acetate to obtain 77 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.44 (3H, s), 3.33-3.34 (2H, m), 3.80 (2H, t, J = 5.4 Hz), 4.19 (2H, d, J = 2.3 Hz), 5.59 (2H, s), 5.68 (2H, br s), 6.12-6.14 (1 H, m), 7.36-7.42 (4H, m), 7.47-7.50 (4H, m), 7.80 (2H, d, J = 8.6 Hz), 8.05 (1H, d, J = 2.9 Hz), 9.11 (1H, s ), 10.98 (1H, s).
MS (ESI) m / z: 534 (M + H)⁺.
Example 62
[Step 1] tert-Butyl 6-amino-5-bromo-3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate

3-Bromo-5-iodopyridin-2-amine (460 mg) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6- Water (2 ml), potassium carbonate (280 mg), tetrakis (triphenylphosphine) palladium (180 mg) were added to a dioxane (8 ml) solution of dihydropyridine-1 (2H) -carboxylate (500 mg), and the mixture was stirred at 80 ° C. for 2 hours. . The mixture was allowed to cool and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)] to obtain 486 mg of the title compound as a solid.
MS (ESI) m / z: 354 (M + H)⁺.
[Step 2] tert-Butyl 6-amino-5- (4-aminophenyl) -3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate

A solution of the compound obtained in Step 1 (485 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (600 mg) in dioxane (8 ml) was added water ( 2 ml), potassium carbonate (280 mg), tetrakis (triphenylphosphine) palladium (160 mg) were added, and the mixture was stirred at 100 ° C. for 7 hours. The mixture was allowed to cool and diluted with chloroform. The organic layer was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)] to obtain 570 mg of the title compound as an oily substance.
MS (ESI) m / z: 367 (M + H)⁺.
[Step 3] tert-butyl 6-amino-5- [4-({[4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5- a] pyrimidin-6-yl] carbonyl} amino) phenyl] -3 ′, 6′-dihydro-3,4′-bipyridine-1 ′ (2′H) -carboxylate

1H-benzotriazol-1-yloxytri (1-pyrrolidinyl) phosphonium hexafluorophosphate (1 ml) in a DMF (1 ml) solution of the compound obtained in Step 2 above (100 mg) and the compound obtained in Step 1 of Example 3 (78 mg) 160 mg) and stirred at room temperature for 17 hours. The mixture was allowed to cool and diluted with chloroform. The organic layer was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)] to obtain 175 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 1.49 (9H, s), 2.47-2.51 (2H, m), 3.62-3.65 (2H, m,) 4.05-4.07 (2H, m) , 4.56-4.59 (2H, m), 5.47 (2H, s), 5.94 (1H, brs), 7.10-7.14 (2H, m), 7.39 ( 1H, d, J = 2.3 Hz), 7.46-7.50 (4H, m), 7.79 (2H, d, J = 8.6 Hz), 8.10 (1H, d, J = 2) .3 Hz), 8.24 (1H, s), 8.88 (1H, s), 10.90 (1H, s).
MS (ESI) m / z: 637 (M + H)⁺.
[Step 4] N- [4- (6-Amino-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 3 (175 mg) in dichloromethane (5 ml) was added TFA (510 μl) under ice cooling, and the mixture was stirred for 21 hours while gradually returning to room temperature. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate to obtain 54 mg of the TFA salt of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.31 (2H, s), 2.50-2.52 (2H, m), 2.90 (2H, s), 5.60 (2H, s), 5.61 (2H, s) ), 6.07-6.09 (1H, m), 7.21-7.25 (2H, m), 7.38 (1H, d, J = 2.3 Hz), 7.49 (2H, d) , J = 8.6 Hz), 7.58-7.61 (2H, m), 7.81 (2H, d, J = 8.6 Hz), 8.02 (1H, d, J = 2.3 Hz) , 8.46 (1H, s), 9.23 (1H, s), 10.94 (1H, s).
MS (ESI) m / z: 537 (M + H)⁺.
Example 63
N- [4- (1′-acetyl-6-amino-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4- (4-fluorobenzyl ) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Acetic anhydride (10 μl) was added to a DMF (5 ml) solution of the compound (50 mg) obtained in Step 4 of Example 62, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 19: 1 (v / v)] and then freeze-dried using dioxane to obtain 40 mg of the title compound as a solid. .
¹H-NMR (DMSO-D₆): 2.03-2.06 (2H, m), 3.57 (3H, s), 3.59-3.65 (2H, m), 4.05-4.11 (2H, m) , 5.60 (2H, s), 5.73 (2H, br s), 6.07 (1H, br s), 7.21-7.25 (2H, m), 7.43-7.44. (1H, m), 7.50 (2H, d, J = 8.6 Hz), 7.58-7.61 (2H, m), 7.82 (2H, d, J = 8.6 Hz), 8 .05 (1H, dd, J = 8.6, 2.3 Hz), 8.47 (1H, s), 9.23 (1H, s), 10.95 (1H, s).
MS (ESI) m / z: 579 (M + H)⁺.
Example 64
[Step 1] tert-butyl 6-amino-5- (4-{[(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a ] Pyrimidin-6-yl) carbonyl] amino} phenyl) -3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate

To a solution of the compound obtained in Step 2 of Example 62 (470 mg) and the compound obtained in Step 1 of Example 4 (420 mg) in DMF (10 ml), EDC · HCl (370 mg) and HOBt (260 mg) were added, and the mixture was brought to room temperature. And stirred overnight. The reaction mixture was diluted with water, extracted with chloroform, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)] to obtain 440 mg of the title compound as a solid.
MS (ESI) m / z: 633 (M + H)⁺.
[Step 2] N- [4- (6-Amino-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl- 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 (440 mg) in dichloromethane (10 ml) was added 4N hydrochloric acid dioxane solution, and the mixture was stirred overnight at room temperature. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform and crystallized from hexane to obtain the hydrochloride of the title compound (360 mg) as a solid. The obtained hydrochloride (45 mg) was purified by reverse phase HPLC [acetonitrile: water: formic acid] and then silica gel column chromatography (NH) [chloroform: methanol = 99: 1 → 19: 1 (v / v)] The resulting solid was washed with ethyl acetate to obtain 22 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.31-2.34 (2H, m), 2.44 (3H, s), 2.92 (2H, t, J = 5.4 Hz), 3.33-3.35 (2H, m), 5.59 (2H, s), 5.62 (2H, br s), 6.08 (1H, br s), 7.36-7.42 (4H, m), 7.47-7 .49 (4H, m), 7.80 (2H, d, J = 8.6 Hz), 8.02 (1H, d, J = 2.3 Hz), 9.11 (1H, s), 10.98 (1H, s).
MS (ESI) m / z: 533 (M + H)⁺.
Example 65
N- [4- (6-Amino-1′-methyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

The compound (100 mg) obtained in Step 1 of Example 24 and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3 , 6-Tetrahydropyridine (51 mg) was synthesized in the same manner as in Step 2 of Example 24 to obtain 50 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.26 (3H, s), 2.44-2.46 (5H, m), 2.54 (2H, t, J = 5.7 Hz), 2.97 (2H, d, J = 2.9 Hz), 5.59 (2 H, s), 5.63 (2 H, br s), 6.03 (1 H, br s), 7.34-7.42 (4 H, m), 7.47 −7.49 (4H, m), 7.79 (2H, d, J = 8.6 Hz), 8.03 (1H, d, J = 2.3 Hz), 9.11 (1H, s), 10 .98 (1H, s).
MS (ESI) m / z: 547 (M + H)⁺.
Example 66
N- [4- (1′-acetyl-6-amino-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Acetic anhydride (27 μl) was added to a DMF (3 ml) solution of the hydrochloride of the compound obtained in Step 2 of Example 64 (150 mg), and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)]. The obtained crude purified product (50 mg) was purified by reverse phase HPLC [acetonitrile: water: formic acid] and then silica gel column chromatography (NH) [chloroform: methanol = 99: 1 → 19: 1 (v / v) And the obtained solid was washed with ethyl acetate to obtain 25 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆): 2.03-2.06 (3H, m), 2.44 (3H, s), 3.30-3.32 (2H, m), 3.59-3.65 (2H, m) 4.04-4.11 (2H, m), 5.59 (2H, s), 5.69 (2H, brs), 6.06 (1H, brs), 7.35-7.43. (4H, m), 7.47-7.50 (4H, m), 7.80 (2H, d, J = 8.6 Hz), 8.05 (1H, dd, J = 8.6, 2.. 3 Hz), 9.11 (1H, s), 10.98 (1H, s).
MS (ESI) m / z: 575 (M + H)⁺.
Example 67
N- [4- (6-Amino-1′-glycoloyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the hydrochloride salt of the compound obtained in Step 2 of Example 64 (75 mg) and glycolic acid (10 mg) in DMF (1 ml), EDC.HCl (32 mg), HOBt (23 mg) and N-methylmorpholine (15 μl) were added. The mixture was added and stirred at room temperature. The reaction solution was diluted with water, extracted with chloroform containing 10% methanol, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by reverse phase HPLC [acetonitrile: water: formic acid] and then silica gel column chromatography (NH) [chloroform: methanol = 99: 1 → 19: 1 (v / v)] The solid obtained was washed with ethyl acetate to obtain 25 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 2.44 (3H, s), 3.29-3.32 (2H, m), 3.51-3.69 (2H, m), 4.01-4.17 (3H, m) 4.53-4.61 (1H, m), 5.59 (2H, s), 5.70 (2H, brs), 6.04-6.09 (1H, m), 7.36- 7.42 (4H, m), 7.47-7.50 (4H, m), 7.80 (2H, d, J = 8.6 Hz), 8.04-8.06 (1H, m), 9.11 (1H, s), 10.98 (1H, s).
MS (ESI) m / z: 591 (M + H)⁺.
Example 68
N- [4- (6-Amino-1′-lactoyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

The title compound (25 mg) was obtained as a solid by synthesis in the same manner as in Example 67 using hydrochloride (70 mg) and lactic acid (10 mg) of the compound obtained in Step 2 of Example 64.
¹H-NMR (DMSO-D₆): 1.17-1.22 (3H, m), 2.44 (3H, s), 3.27-3.30 (1H, m), 3.55-3.80 (2H, m) 4.07-4.26 (2H, m), 4.42-4.52 (1H, m), 4.90-4.96 (1H, m), 5.59 (2H, s), 5 .70 (2H, brs), 6.08 (1H, br s), 7.34-7.42 (4H, m), 7.47-7.50 (4H, m), 7.80 (2H) , D, J = 8.6 Hz), 8.04-8.07 (1H, m), 9.11 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 605 (M + H)⁺.
Example 69
[Step 1] tert-butyl 4- [6-amino-5- (4-aminophenyl) pyridin-3-yl] piperidine-1-carboxylate

To a solution of the compound obtained in Step 2 of Example 62 (300 mg) in ethanol (10 ml) was added 10% palladium carbon (300 mg), and the mixture was stirred at room temperature for 4 days in a hydrogen atmosphere. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 19: 1 (v / v)] to give 175 mg of the title compound as an oily substance. It was.
¹H-NMR (CDCl₃) Δ: 1.47 (9H, s), 1.76-1.83 (4H, m), 2.54-2.60 (1H, m), 2.75-2.82 (2H, m) , 3.74-3.79 (2H, m), 4.23 (2H, br s), 4.49 (2H, br s), 6.76 (2H, d, J = 9.1 Hz), 7 .17 (1H, d, J = 2.3 Hz), 7.23 (2H, d, J = 9.1 Hz), 7.87 (1H, d, J = 2.3 Hz).
MS (ESI) m / z: 369 (M + H)⁺.
[Step 2] tert-butyl 4- [6-amino-5- (4-{[(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1, 5-a] pyrimidin-6-yl) carbonyl] amino} phenyl) pyridin-3-yl] piperidine-1-carboxylate

The compound obtained in Step 1 above (170 mg) and the compound obtained in Step 1 of Example 4 (125 mg) were synthesized in the same manner as in Step 1 of Example 64 to obtain 210 mg of the title compound as a solid.
MS (ESI) m / z: 635 (M + H)⁺.
[Step 3] N- [4- (2-Amino-5-piperidin-4-ylpyridin-3-yl) phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2 , 4] triazolo [1,5-a] pyrimidine-6-carboxamide

TFA (1 ml) was added to a dichloromethane (2 ml) solution of the compound (210 mg) obtained in the above Step 2 under ice cooling, and the mixture was stirred for 2 hours while gradually returning to room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH) [chloroform: methanol = 99: 1 → 9: 1 (v / v)] to obtain 210 mg of a crude product of the title compound as a solid. It was.
MS (ESI) m / z: 535 (M + H)⁺.
[Step 4] N- {4- [5- (1-acetylpiperidin-4-yl) -2-aminopyridin-3-yl] phenyl} -4-benzyl-2-methyl-7-oxo-4,7 -Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Using the compound (105 mg) obtained in Step 3 above, synthesis was performed in the same manner as in Example 63 to obtain 57 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.38-1.47 (1H, m), 1.56-1.64 (1H, m), 1.72-1.78 (2H, m), 2.01 (3H, s) , 2.44 (3H, s), 2.52-2.58 (1H, m), 2.64-2.69 (1H, m), 3.06-3.12 (1H, m), 3 .88-3.91 (1H, m), 4.49-4.52 (1H, m), 5.44 (2H, brs), 5.59 (2H, s), 7.25 (1H, d, J = 2.3 Hz), 7.34-7.42 (3H, m), 7.47-7.49 (4H, m), 7.79 (2H, d, J = 8.6 Hz), 7.84 (1H, d, J = 2.3 Hz), 9.10 (1H, s), 10.97 (1H, s).
MS (ESI) m / z: 577 (M + H)⁺.
Example 70
N- [4- (6-Amino-2 ′, 2 ′, 6 ′, 6′-tetramethyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) Phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Compound (75 mg) obtained in Step 1 of Example 24 and 2,2,6,6-tetramethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1,2,3,6-Tetrahydropyridine (39 mg) was synthesized in the same manner as in Step 2 of Example 24 to obtain 25 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.07-1.22 (12H, m), 2.44 (3H, s), 3.31-3.40 (2H, m), 5.58-5.65 (4H, m) , 5.97 (1H, br s), 7.35-7.42 (4H, m), 7.47-7.50 (3H, m), 7.80 (2H, d, J = 8.6 Hz) ), 8.00-8.02 (1H, m), 9.11 (1H, s), 10.98 (1H, s).
MS (ESI) m / z: 589 (M + H)⁺.
Example 71
[Step 1] tert-butyl 3- [6-amino-5- (4-{[(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1, 5-a] pyrimidin-6-yl) carbonyl] amino} phenyl) pyridin-3-yl] -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate

Compound (150 mg) obtained in Step 1 of Example 24 and tert-butyl 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -8-azabicyclo [3. 2.1] Using oct-2-ene-8-carboxylate (104 mg), synthesis was carried out in the same manner as in Step 2 of Example 24 to obtain 95 mg of the title compound as a solid.
MS (ESI) m / z: 659 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (8-azabicyclo [3.2.1] oct-2-en-3-yl) pyridin-3-yl] phenyl} -4-benzyl- 2-Methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

TFA (500 μl) was added to a solution of the compound obtained in Step 1 (95 mg) in dichloromethane (2 ml) under ice-cooling and stirred while gradually returning to room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH) [chloroform: methanol = 99: 1 → 19: 1 (v / v)] to obtain 210 mg of a crude product of the title compound. Obtained as a solid. The crude product (30 mg) was washed with ethyl acetate to give 10 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.49-1.54 (1H, m), 1.67-1.74 (1H, m), 1.81-1.90 (2H, m), 2.13 (1H, d, J = 17.2 Hz), 2.44 (3H, s), 2.63-2.68 (1H, m), 3.60-3.62 (1H, m), 3.65-3.68 ( 1H, m), 5.59-5.61 (4H, m), 6.36 (1H, d, J = 5.2 Hz), 7.33-7.42 (4H, m), 7.46- 7.48 (4H, m), 7.79 (2H, d, J = 8.6 Hz), 7.97 (1H, d, J = 2.3 Hz), 9.11 (1H, s), 10. 98 (1H, s).
MS (ESI) m / z: 559 (M + H)⁺.
Example 72
N- {4- [5- (8-acetyl-8-azabicyclo [3.2.1] oct-2-en-3-yl) -2-aminopyridin-3-yl] phenyl} -4-benzyl- 2-Methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Acetic anhydride (10 μl) was added to a DMF (2 ml) solution of the compound (50 mg) obtained in Step 2 of Example 71, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 9: 1 (v / v)], and the resulting solid was mixed with ethyl acetate and hexane. By washing with a solvent, 25 mg of the title compound was obtained as a solid.
¹H-NMR (DMSO-D₆) Δ: 1.67-1.88 (2H, m), 1.96-2.00 (3H, m), 2.18-2.40 (3H, m), 2.44 (3H, s) , 2.84-2.94 (1H, m), 4.42-4.47 (1H, m), 4.62-4.73 (1H, m), 5.59 (2H, s), 5 .70 (2H, brs), 6.38-6.43 (1H, m), 7.34-7.42 (4H, m), 7.46-7.49 (4H, m), 7. 79 (2H, d, J = 8.6 Hz), 8.00-8.01 (1H, m), 9.11 (1H, s), 10.98 (1H, s).
MS (ESI) m / z: 601 (M + H)⁺.
Example 73
[Step 1] 6-Amino-5-bromonicotinonitrile

To a solution of 6-aminonicotinonitrile (5.0 g) in DMF (50 ml) was added N-bromosuccinimide (7.8 g) under ice cooling, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain 7.0 g of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 7.21-7.47 (2H, m), 8.20 (1H, d, J = 2.3 Hz), 8.36 (1H, d, 1 = 2.3 Hz).
MS (ESI) m / z: 198 (M + H)⁺.
[Step 2] 6-amino-5- (4-aminophenyl) nicotinonitrile

Compound (1.0 g) obtained in the above step 1 and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.3 g) in dioxane (18 ml) ) Water (2 ml), potassium carbonate (1.1 g), tetrakis (triphenylphosphine) palladium (0.58 g) were added to the solution, and the mixture was stirred at 100 ° C. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with chloroform containing 10% methanol and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 99: 1 → 19: 1 (v / v)] to obtain 1.2 g of the title compound as a solid.
MS (ESI) m / z: 211 (M + H)⁺.
[Step 3] N- [4- (2-Amino-5-cyanopyridin-3-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4 ] Triazolo [1,5-a] pyrimidine-6-carboxamide

1H-benzotriazol-1-yloxytri (1-pyrrolidinyl) phosphonium hexafluorophosphate (DMF) was added to the DMF (5 ml) solution of the compound obtained in Step 2 above (250 mg) and the compound obtained in Step 1 of Example 3 (340 mg). 680 mg) was added and stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 1: 1 → 0: 10 (v / v)]. The obtained crude product (30 mg) was washed with 5% methanol-containing ethyl acetate to obtain 15 mg of the title compound as a solid.
¹H-NMR (DMSO-D₆) Δ: 5.60 (2H, s), 6.77 (2H, br s), 7.21-7.25 (2H, m), 7.45-7.48 (2H, m), 7. 58-7.61 (2H, m), 7.67 (1H, d, J = 2.3 Hz), 7.82-7.84 (2H, m), 8.36 (1H, d, J = 2) .3 Hz), 8.47 (1H, s), 9.23 (1H, s), 10.97 (1H, s).
MS (ESI) m / z: 481 (M + H)⁺.
Example 74
[Step 1] Ethyl 2,3-dimethyl-5-oxo-5,8-dihydroimidazo [1,2-a] pyrimidine-6-carboxylate

2-Amino-4,5-dimethylimidazole (183 mg) and diethyl ethoxymethylenemalonate (331 μl) were added to acetic acid (2 ml), and the mixture was heated to reflux for 9 hours. Water was added to the reaction solution, followed by filtration and washing with water and hexane to obtain 84 mg of the title compound.
MS (ESI) m / z: 236 (M + H)⁺.
[Step 2] 8- (4-Fluorobenzyl) -2,3-dimethyl-5-oxo-5,8-dihydroimidazo [1,2-a] pyrimidine-6-carboxylic acid

The compound (84 mg) obtained in the above Step 1 was suspended in DMF (1 ml), potassium carbonate (64 mg) and 4-fluorobenzyl bromide (52 μl) were successively added, and the mixture was stirred at room temperature for 10 hours. Ethanol (2 ml) and 1N aqueous sodium hydroxide solution (1 ml) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 14 hours. A 1N hydrochloric acid aqueous solution was added, and the precipitated solid was filtered and washed with water to obtain 37 mg of the title compound.
MS (ESI) m / z: 316 (M + H)⁺.
[Step 3] 3- (4-Amino-2-fluorophenyl) -5-bromopyridin-2-amine

5-Bromo-3-iodopyridin-2-amine (300 mg), 3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (238 mg) Tetrakis (triphenylphosphine) palladium (58 mg) and potassium carbonate (416 mg) were suspended in dioxane (5 ml) and water (0.5 ml), and the mixture was heated to reflux at 80 ° C. for 2 days. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 1: 2 (v / v)] to obtain 248 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.92 (2H, s), 4.50 (2H, s), 6.44-6.56 (2H, m), 7.06-7.13 (1H, m), 7.43 -7.48 (1H, m), 8.08-8.12 (1H, m).
MS (ESI) m / z: 282, 284 (M + H)⁺.
[Step 4] 3- (4-Amino-2-fluorophenyl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine

Compound (2g) obtained in Step 3 above, 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.62 g) Tetrakis (triphenylphosphine) palladium (0.41 g) and potassium carbonate (2.94 g) were suspended in dioxane (10 ml) and water (1 ml), and the mixture was heated to reflux at 100 ° C. for 61 hours. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: methanol = 10: 1 (v / v)] to obtain 1.88 g of the title compound as a solid.
MS (ESI) m / z: 284 (M + H)⁺.
[Step 5] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -8- (4-fluorobenzyl) -2,3 -Dimethyl-5-oxo-5,8-dihydroimidazo [1,2-a] pyrimidine-6-carboxamide
To a solution of the compound obtained in the above step 2 (37 mg) and the compound obtained in the above step 4 (33 mg) and HOBt (16 mg) in DMF (2 ml) was added EDC · HCl (34 mg) at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diethyl ether to obtain 11 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.27 (3H, s), 2.70 (3H, s), 3.94 (3H, s), 4.57 (2H, s), 5.37-5.40 (2H, m) ), 7.05-7.11 (2H, m), 7.32-7.51 (5H, m), 7.54-7.56 (1H, m), 7.67-7.69 (1H) M), 7.80-7.86 (1H, m), 8.22-8.26 (1H, m), 8.59 (1H, s), 11.22 (1H, s).
MS (ESI) m / z: 581 (M + H)⁺.
Example 75
N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -3-fluorophenyl} -4- (4-fluorobenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 3 (72 mg) and the compound obtained in Step 4 of Example 74 (71 mg) and HOBt (35 mg) in DMF (2 ml), EDC · HCl (72 mg) was added at room temperature. It was. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give 22 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.94 (3H, s), 4.49 (2H, s), 5.45-5.50 (2H, m), 6.95-7.17 (2H, m), 7.33 -7.57 (6H, m), 7.66-7.71 (1H, m), 7.81-7.87 (1H, m), 8.22-8.27 (2H, m), 8 .87 (1H, s), 10.99 (1H, s).
MS (ESI) m / z: 554 (M + H)⁺.
Example 76
[Step 1] Ethyl 7-oxo-2- (trifluoromethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate

3- (Trifluoromethyl) -1H-1,2,4-triazol-5-amine (1 g) and diethyl ethoxymethylenemalonate (1.33 ml) were added to acetic acid (10 ml), and the mixture was heated to reflux for 9 hours. Water was added to the reaction solution, followed by filtration and washing with water and hexane to obtain 635 mg of the title compound.
MS (ESI) m / z: 277 (M + H)⁺.
[Step 2] 4- (4-Fluorobenzyl) -7-oxo-2- (trifluoromethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carbon Ethyl acid

The compound (200 mg) obtained in the above Step 1 was suspended in DMF (4 ml), potassium carbonate (130 mg) and 4-fluorobenzyl bromide (107 μl) were successively added, and the mixture was stirred at 50 ° C. for 8 hours. A saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 1: 1 (v / v)] to obtain 220 mg of the title compound.
MS (ESI) m / z: 385 (M + H)⁺.
[Step 3] 4- (4-Fluorobenzyl) -7-oxo-2- (trifluoromethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carvone acid

The compound (110 mg) obtained in the above Step 2 was suspended in ethanol (2 ml) and water (1 ml), potassium carbonate (79 mg) was successively added, and the mixture was stirred at room temperature for 3 days. 1N Hydrochloric acid aqueous solution was added, filtered and washed with water to give 80 mg of the title compound.
MS (ESI) m / z: 357 (M + H)⁺.
[Step 4] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -3-fluorophenyl} -4- (4-fluorobenzyl) -7-oxo-2- (trifluoromethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 3 (80 mg) and the compound obtained in Step 4 of Example 74 (64 mg) and HOBt (31 mg) in DMF (2 ml), EDC · HCl (65 mg) was added at room temperature. After stirring at 50 ° C. for 15 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to 38 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.94 (3H, s), 4.50 (2H, s), 5.44-5.53 (2H, m), 7.08-7.18 (2H, m), 7.33 -7.42 (2H, m), 7.45-7.57 (4H, m), 7.63-7.70 (1H, m), 7.78-7.86 (1H, m), 8 21-8.26 (1H, m), 8.92 (1H, s), 10.77 (1H, s).
MS (ESI) m / z: 622 (M + H)⁺.
Example 77
[Step 1] 3-Bromo-5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine

3-Bromo-5-iodopyridin-2-amine (500 mg), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (348 mg), tetrakis (triphenylphosphine) palladium (193 mg), and potassium carbonate (693 mg) were suspended in dioxane (10 ml) and water (1 ml), and heated at 80 ° C. for 24 hours. After allowing to cool, the mixture was extracted with chloroform and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 97: 3 (v / v)] to obtain 486 mg of the title compound as a solid.
MS (ESI) m / z: 253 (M + H)⁺.
[Step 2] 3- (4-Amino-3-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine

Compound (200 mg) obtained in Step 1 above, 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (220 mg) in dioxane (5 ml) Water (1 ml), potassium carbonate (330 mg) and tetrakis (triphenylphosphine) palladium (50 mg) were added to the solution, and the mixture was stirred at 80 ° C. overnight. The mixture was allowed to cool, diluted with chloroform, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 95: 5 (v / v)] to obtain 230 mg of the title compound as a solid.
MS (ESI) m / z: 296 (M + H)⁺.
[Step 3] N- {4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -2-methoxyphenyl} -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound (44 mg) obtained in Step 1 of Example 3 and the compound (50 mg) obtained in Step 2 above and HOBt (26 mg) in DMF (5 ml), EDC · HCl (49 mg) was added at room temperature. After stirring overnight at 50 ° C., water was added, extracted with chloroform, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by HPLC [acetonitrile: water: formic acid] to obtain 9 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.95 (3H, s), 4.00 (3H, s), 4.64 (2H, s), 5.46 (2H, s), 7.04 (1H, d, J = 1) .8 Hz), 7.08-7.15 (3H, m), 7.46-7.51 (3H, m), 7.56 (1H, s), 7.69 (1H, s), 8. 20 (1 H, d, J = 2.3 Hz), 8.23 (1 H, s), 8.56 (1 H, d, J = 8.3 Hz), 8.87 (1 H, s), 11.36 ( 1H, s).
MS (ESI) m / z: 566 (M + H)⁺.
Example 78
[Step 1] 3- (4-Amino-2-methylphenyl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine

Compound (110 mg) obtained in Step 1 of Example 77, 3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (110 mg) in dioxane Water (1 ml), potassium carbonate (190 mg) and tetrakis (triphenylphosphine) palladium (30 mg) were added to the (5 ml) solution, and the mixture was stirred at 100 ° C. for 5 hours. The mixture was allowed to cool, diluted with chloroform, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 95: (v / v)] to obtain 109 mg of the title compound as a solid.
MS (ESI) m / z: 280 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -3-methylphenyl} -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 3 (55 mg) and the compound obtained in Step 1 above (59 mg) and HOBt (32 mg) in DMF (5 ml), EDC · HCl (61 mg) was added at room temperature. After stirring at 50 ° C. for 3 hours, the mixture was diluted with chloroform and washed with water. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by reverse phase HPLC [acetonitrile: water: formic acid] to obtain 14 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.23 (3H, s), 3.94 (3H, s), 4.32 (2H, s), 5.47 (2H, s), 7.07-7.16 (2H, m) ), 7.23 (1H, d, J = 8.3 Hz), 7.37 (1H, d, J = 2.3 Hz), 7.46-7.51 (2H, m), 7.54 (1H) , S), 7.60-7.69 (3H, m), 8.23-8.24 (2H, m), 8.88 (1H, s), 10.84 (1H, s).
MS (ESI) m / z: 550 (M + H)⁺.
Example 79
[Step 1] 3-Bromo-5- (3,4-dimethoxyphenyl) pyridin-2-amine

3-Bromo-5-iodopyridin-2-amine (7.50 g), 3,4-dimethoxyphenylboronic acid (4.79 g), tetrakis (triphenylphosphine) palladium (1.45 g), potassium carbonate (10. 4 g) was suspended in dioxane (100 ml) and water (10 ml) and heated at 80 ° C. for 9 and a half hours. After allowing to cool, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate] to obtain 7.36 g of the title compound as a solid.
MS (ESI) m / z: 309, 311 (M + H)⁺.
[Step 2] 3- (4-Amino-3-methoxyphenyl) -5- (3,4-dimethoxyphenyl) pyridin-2-amine

Compound (200 mg) obtained in Step 1 above, 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (153 mg) in dioxane (20 ml) Water (2 ml), potassium carbonate (268 mg) and tetrakis (triphenylphosphine) palladium (37 mg) were added to the solution, and the mixture was stirred at 100 ° C. for 5 hours. The mixture was allowed to cool, diluted with chloroform, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 96: 4 (v / v)] to obtain 207 mg of the title compound as a solid.
MS (ESI) m / z: 352 (M + H)⁺.
[Step 3] 2-Methyl-4-[(6-methylpyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine- 6-carboxylic acid

1N Aqueous sodium hydroxide solution (0.24 ml) was added to a solution of the compound obtained in Step 1 of Example 47 (80 mg) in methanol (3 ml), and the mixture was stirred at room temperature for 2 hours. 78 mg of salt was obtained as a solid.
MS (ESI) m / z: 300 (M + H)⁺.
[Step 4] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] -2-methoxyphenyl} -2-methyl-4-[(6-methylpyridine- 2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pydimidine-6-carboxamide

To a solution of the compound obtained in Step 3 above (78 mg) and the compound obtained in Step 2 above (48 mg) and HOBt (153 mg) in DMF (5 ml), EDC · HCl (39 mg) was added at room temperature. After stirring at 50 ° C. for 5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with chloroform, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by reverse phase HPLC [acetonitrile: water: formic acid] to obtain 30 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.51 (3H, s), 2.54 (3H, s), 3.92 (3H, s), 3.94 (3H, s), 4.00 (3H, s), 4. 69 (2H, s), 5.50 (2H, s), 6.95 (1H, d, J = 8.7 Hz), 7.04-7.06 (2H, m), 7.08-7. 16 (3H, m), 7.22 (1H, d, J = 7.3 Hz), 7.58-7.63 (2H, m), 8.28 (1H, d, J = 2.3 Hz), 8.61 (1H, d, J = 8.3 Hz), 9.00 (1H, s), 11.50 (1H, s).
MS (ESI) m / z: 633 (M + H)⁺.
Example 80
[Step 1] 3- (4-Amino-2-methylphenyl) -5- (3,4-dimethoxyphenyl) pyridin-2-amine

Compound (170 mg) obtained in Step 1 of Example 79, 3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (128 mg) in dioxane To the (20 ml) solution, water (2 ml), potassium carbonate (228 mg) and tetrakis (triphenylphosphine) palladium (31 mg) were added and stirred at 100 ° C. for 5 hours. The mixture was allowed to cool, diluted with chloroform, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 96: 4 (v / v)] to obtain 90 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.14 (3H, s), 3.72 (2H, s), 3.91 (3H, s), 3.93 (3H, s), 4.41 (2H, s), 6. 55-6.68 (2H, m), 6.90-6.95 (1H, m), 699-7.10 (3H, m), 7.45-7.50 (1H, m), 8.27 (1H, d, J = 2.29 Hz).
MS (ESI) m / z: 336 (M + H)⁺.
[Step 2] N- {4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] -3-methylphenyl} -2-methyl-4-[(6-methylpyridine- 2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pydimidine-6-carboxamide

To a solution of the compound obtained in Step 3 of Example 79 (35 mg) and the compound obtained in Step 1 above (37 mg) and HOBt (17 mg) in DMF (5 ml), EDC · HCl (31 mg) was added at room temperature. After stirring at 50 ° C. for 5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with chloroform, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by HPLC [acetonitrile: water: formic acid] to obtain 21 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.25 (3H, s), 2.50 (3H, s), 2.55 (3H, s), 3.92 (3H, s), 3.94 (3H, s), 4. 41 (2H, s), 5.50 (2H, s), 6.94 (1H, d, J = 8.3 Hz), 7.04 (1H, d, J = 1.8 Hz), 7.09 ( 1H, dd, J = 8.3, 1.8 Hz), 7.14 (1H, d, J = 7.8 Hz), 7.22-7.27 (2H, m), 7.49 (1H, d , J = 2.3 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.65 (1H, dd, J = 8.3, 2.3 Hz), 7.69 (1H, d, J = 2.3 Hz), 8.31 (1H, d, J = 2.3 Hz), 9.02 (1H, s), 10.96 (1H, s).
MS (ESI) m / z: 617 (M + H)⁺.
Example 81
[Step 1] 3- (4-Amino-2-fluorophenyl) -5-bromopyridin-2-amine

5-Bromo-3-iodopyridin-2-amine (300 mg), 3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (238 mg) Tetrakis (triphenylphosphine) palladium (58 mg) and potassium carbonate (416 mg) were suspended in dioxane (5 ml) and water (0.5 ml), and the mixture was heated to reflux at 80 ° C. for 2 days. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 1: 2 (v / v)] to obtain 248 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.92 (2H, s), 4.50 (2H, s), 6.44-6.56 (2H, m), 7.06-7.13 (1H, m), 7.43 -7.48 (1H, m), 8.08-8.12 (1H, m).
MS (ESI) m / z: 282, 284 (M + H)⁺.
[Step 2] 1-[(2S) -1,4-dioxan-2-ylmethyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -Pyrazole

To a suspension of cesium carbonate (2.50 g) in dioxane (30 ml) was added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (2. (2R) -1,4-dioxan-2-ylmethyl methanesulfonate (2.78 g) was added, and the mixture was stirred at 90 ° C. for 4 hours. The reaction liquid was filtered after standing_to_cool and the filtrate was concentrated. The residue was purified by silica gel column chromatography [chloroform: methanol = 19: 1 (v / v)] to obtain 3.79 g of the title compound.
MS (ESI) m / z: 295 (M + H)⁺
[Step 3] 3- (4-Amino-2-fluorophenyl) -5- {1-[(2S) -1,4-dioxane-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-2- Amine

To a solution of the compound obtained in Step 1 (500 mg) and the compound obtained in Step 2 (782 mg) in dioxane (15 ml), water (1.5 ml), cesium carbonate (1730 mg), tetrakis (triphenylphosphine) palladium ( 204 mg), and stirred at 100 ° C. for 1 hour under microwave irradiation. The mixture was allowed to cool, diluted with chloroform, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform: methanol = 19: 1 (v / v)] to obtain 450 mg of the title compound as a solid.
MS (ESI) m / z: 370 (M + H)⁺.
[Step 4] N- [4- (2-Amino-5- {1-[(2S) -1,4-dioxane-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl)- 3-Fluorophenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 4 (40 mg) and the compound obtained in Step 3 above (52 mg) and HOBt (19 mg) in DMF (2 ml), EDC · HCl (41 mg) was added at room temperature. After stirring for 1 hour at 50 ° C., a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 34 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.60 (3H, s), 3.26-3.35 (1H, m), 3.53-3.85 (5H, m), 3.85-3.95 (1H, m) 4.14-4.20 (2H, m), 4.49 (2H, s), 5.44-5.49 (2H, m), 7.34-7.52 (8H, m), 7 .62-7.66 (1H, m), 7.69-7.72 (1H, m), 7.81-7.87 (1H, m), 8.24-8.29 (1H, m) , 8.78 (1H, s), 11.07 (1H, s).
MS (ESI) m / z: 636 (M + H)⁺.
Example 82
N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) -3-fluorophenyl ] -2-Ethoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 34 (50 mg) in ethanol (2 ml) was added 1N aqueous sodium hydroxide solution (0.15 ml) and stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure. To the residue, EDC · HCl (42 mg) was added at room temperature to a solution of the compound obtained in Step 3 of Example 81 (54 mg) and HOBt (20 mg) in DMF (2 ml). After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 27 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 1.48 (3H, t, J = 7.0 Hz), 3.27-3.35 (1H, m), 3.53-3.87 (5H, m), 3.94-4. 02 (1H, m), 4.14-4.21 (2H, m), 4.52 (2H, s), 4.53 (2H, q, J = 7.0 Hz), 5.46-5. 54 (2H, m), 7.25-7.54 (5H, m), 7.61-7.91 (4H, m), 8.23-8.29 (1H, m), 8.53- 8.59 (1H, m), 8.97 (1H, s), 11.18 (1H, s).
MS (ESI) m / z: 667 (M + H)⁺.
Example 83
N- [4- (2-amino-5- {1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl} pyridin-3-yl) -3-fluorophenyl ] -4-Benzyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (35 mg) was suspended in DMF (1 ml), potassium carbonate (30 mg), benzyl Bromide (24 μl) was sequentially added and stirred at 50 ° C. for 5 hours. A 1N aqueous sodium hydroxide solution (0.25 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 2 hours. Then, a 1N aqueous hydrochloric acid solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and EDC · HCl (48 mg) was added to a DMF (2 ml) solution of the compound obtained in Step 3 of Example 81 (62 mg) and HOBt (23 mg) at room temperature. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 54 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 3.26-3.37 (1H, m), 3.53-3.86 (5H, m), 3.86-3.94 (1H, m), 4.14-4.23 ( 2H, m), 4.50 (2H, s), 5.46-5.57 (2H, m), 7.34-7.54 (8H, m), 7.61-7.74 (2H, m), 7.81-7.88 (1H, m), 8.21-8.31 (2H, m), 8.88 (1H, s), 11.01 (1H, s).
MS (ESI) m / z: 622 (M + H)⁺.
Example 84
[Step 1] 5-Bromo-3-iodo-4-methoxypyridin-2-amine

NBS (171 mg) was added to a solution of 3-iodo-4-methoxypyridin-2-amine (200 mg) in DMF (2 ml), added at 0 ° C., and stirred at room temperature for 2 days. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure to obtain the title compound as a crude product.
MS (ESI) m / z: 329,331 (M + H)⁺.
[Step 2] 3- (4-Aminophenyl) -5-bromo-4-methoxypyridin-2-amine

Crude product (0.80 mmol) obtained in Step 1 above, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (184 mg), Pd (PPh3) 4 (46 mg) and potassium carbonate (332 mg) were suspended in dioxane (5 ml) and water (0.5 ml), and the mixture was heated to reflux at 80 ° C. for 18 hours. After allowing to cool, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane = 1: 1 (v / v)] to obtain 151 mg of the title compound as a solid.
MS (ESI) m / z: 294, 296 (M + H)⁺.
[Step 3] 3- (4-Aminophenyl) -4-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine

Compound (151 mg) obtained in Step 2 above, 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (112 mg), tetrakis (Triphenylphosphine) palladium (30 mg) and cesium fluoride (213 mg) were suspended in methanol (2.5 ml) and refluxed at 80 ° C. for 9 and a half hours. After allowing to cool, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] to obtain 45 mg of the title compound as a solid.
MS (ESI) m / z: 296 (M + H)⁺.
[Step 4] N- {4- [2-Amino-4-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl} -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 3 (44 mg) and the compound obtained in Step 3 above (45 mg) and HOBt (21 mg) in DMF (1 ml), EDC · HCl (44 mg) was added at room temperature. After stirring at 50 ° C for 1.5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and subjected to lyophilization using dioxane to give the title compound 9 .5 mg was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.32 (3H, s), 3.95 (3H, s), 4.44 (2H, s), 5.45-5.50 (2H, m), 7.08-7.16 (2H, m), 7.41-7.55 (4H, m), 7.64-7.68 (1H, m), 7.76-7.86 (3H, m), 8.17-8 .26 (2H, m), 8.89 (1H, s), 10.92 (1H, s).
MS (ESI) m / z: 566 (M + H)⁺.
Example 85
[Step 1] 3- (4-Aminophenyl) -4-methoxypyridin-2-amine

3-iodo-4-methoxypyridin-2-amine (350 mg), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (322 mg), [1, 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (81 mg) and cesium fluoride (580 mg) were suspended in methanol (5 ml) and heated to reflux at 80 ° C. for 19 hours. After allowing to cool, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] to obtain 245 mg of the title compound as a solid.
MS (ESI) m / z: 216 (M + H)⁺.
[Step 2] N- [4- (2-Amino-4-methoxypyridin-3-yl) phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] Triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 4 (100 mg) and the compound obtained in Step 1 above (76 mg) and HOBt (49 mg) in DMF (2 ml), EDC · HCl (101 mg) was added at room temperature. After stirring at 50 ° C. for 5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 136 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 2.59 (3H, s), 3.75 (3H, s), 4.33 (2H, s), 5.44-5.46 (2H, m), 6.37-6.42 (1H, m), 7.31-7.37 (2H, m), 7.40-7.47 (5H, m), 7.75-7.80 (2H, m), 7.98-8 .03 (1H, m), 8.79 (1H, s), 10.95 (1H, s).
MS (ESI) m / z: 482 (M + H)⁺.
Example 86
N- [4- (2-Amino-4-methoxypyridin-3-yl) phenyl] -4-benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1, 5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 3 of Example 33 (75 mg) and the compound obtained in Step 1 of Example 85 (51 mg) and HOBt (33 mg) in DMF (2 ml), EDC · HCl (69 mg) was added at room temperature. It was. After stirring at 50 ° C. for 1 hour, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)]. The obtained solid was recrystallized from ethyl acetate and diisopropyl ether to obtain 77 mg of the title compound as a solid.
¹H-NMR (CDCl₃) Δ: 1.51 (3H, t, J = 7.0 Hz), 3.75 (3H, s), 4.34 (2H, s), 4.56 (2H, q, J = 7.0 Hz) 5.39-5.41 (2H, m), 6.38-6.41 (1H, m), 7.32-7.36 (2H, m), 7.40-7.48 (5H, m), 7.74-7.78 (2H, m), 7.98-8.02 (1H, m), 8.74 (1H, s), 11.02 (1H, s).
MS (ESI) m / z: 512 (M + H)⁺.
Example 87
[Step 1] 5-Bromo-6-methoxypyrimidin-4-amine

NBS (864 mg) was added to a solution of 6-methoxypyrimidin-4-amine (500 mg) in DMF (5 ml), and the mixture was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a crude product.
MS (ESI) m / z: 204, 206 (M + H)⁺.
[Step 2] 5- (4-Aminophenyl) -6-methoxypyrimidin-4-amine

The crude product obtained in Step 1 above, 4-amino-phenylboronic acid pinacol ester (963 mg), tetrakis (triphenylphosphine) palladium (231 mg), potassium carbonate (1.66 g) in dioxane (20 ml) and water (2. 0 ml) and heated to reflux for 12 hours. After allowing to cool, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate] to obtain 677 mg of the title compound as a solid.
MS (ESI) m / z: 217 (M + H)⁺.
[Step 3] N- [4- (4-Amino-6-methoxypyrimidin-5-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4 ] Triazolo [1,5-a] pyrimidine-6-carboxamide

To a solution of the compound obtained in Step 1 of Example 3 (50 mg) and the compound obtained in Step 2 above (38 mg) and HOBt (24 mg) in DMF (2 ml), EDC · HCl (50 mg) was added at room temperature. After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate: dichloromethane: methanol = 5: 5: 1 (v / v)] and freeze-dried using dioxane to give 35 mg of the title compound. Was obtained as a solid.
¹H-NMR (CDCl₃) Δ: 3.89 (3H, s), 4.74 (2H, s), 5.43-5.51 (2H, m), 7.08-7.16 (2H, m), 7.34 -7.40 (2H, m), 7.45-7.52 (2H, m), 7.75-7.83 (2H, m), 8.20-8.31 (2H, m), 8 .88 (1H, s), 10.89 (1H, s).
MS (ESI) m / z: 487 (M + H)⁺.
(Test Example 1 cell-free Axl kinase inhibitory activity)
Kinase reaction buffer (100 mM HEPES (pH 7.4), 0.003% Brij-35, 0.004% Tween-20, 1 mM DTT, 10 mM MgCl₂), An AXL (human AXL intracellular domain 464-885 amino acid fusion protein and glutathione transferase expressed in a baculovirus expression system and purified by glutathione sepharose chromatography, Carna Bio Inc., Catalog A diluted kinase solution containing 170 ng / mL of No. 08-107) was prepared and 19 μL was added to each well of a 384 well plate.
Next, the test compound was diluted with DMSO, and 1 μL of this diluted solution was added to each well.
After pre-incubation at room temperature for 30 minutes, the substrate peptide (FL-Peptide 30 (5FAM-KKKKEIEIFFF-CONH₂), Caliper Life Sciences, catalog number 760430) and a solution containing 1.5 μM and 10 μM of ATP, respectively, and 5 μL of this solution was added to each well to initiate the kinase reaction. The plate is incubated at 28 ° C. for 1.5 hours, and 40 μL of termination buffer (100 mM HEPES (pH 7.4), 0.015% Brij-35, 40 mM EDTA, 0.1% Coating Reagent 3) is added to each well. The reaction was stopped.
The substrate peptide and phosphorylated peptide in the reaction solution were separated and quantified by EZ Reader II (Caliper Life Sciences).
The kinase reaction was evaluated by the product ratio (P / (P + S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P).
The inhibition rate (Inhibition) was calculated by the following formula (automatically calculated by EZ Reader II system software).
Inhibition (%) = 100 × (1-C_i/ C₀)
Where C_iRepresents the product ratio when the test compound is added, C₀Represents the product ratio when DMSO is added instead of the test compound.
From the inhibition rate data for the test compound concentration of 12 points, IC was performed by nonlinear regression (4 parameter logistic regression) using the following formula:₅₀Asked.
Inhibition (%) = Bottom + (Top-Bottom) / (1 + ([Compound] / IC₅₀)^slopc)
Example 1, 3, 4, 6, 7, 9-11, 22-26, 28, 31, 36, 38, 41-45, 51-57, 0.1 nM ≦ IC₅₀<1 nM, Examples 2, 5, 8, 12-17, 21, 27, 29, 30, 32, 35, 37, 47-50, 58-63, 66-68, 74-77, 79, 81, 83 , 84, 86, 87 have compounds of 1 nM ≦ IC₅₀<10 nM, compounds of Examples 18 to 20, 33, 34, 39, 40, 46, 64, 65, 72, 73, 78, 80, 82, 85 have 10 nM ≦ IC₅₀<50 nM, compound of Example 70 is IC₅₀= 63 nM, the compound of Example 71 is IC₅₀= 51 nM inhibitory activity.
(Test Example 2 Intracellular Axl phosphorylation inhibitory activity)
A phosphorylated Axl (hereinafter, pAxl) inhibition test was performed using a human non-small cell lung cancer-derived cell line NCI-H1299.
NCI-H1299 cells were suspended in a medium (RPMI1640 medium containing 10% fetal calf serum) and seeded in 96-well multiwell plates at 15000 cells / 100 μL / well, respectively, at 37 ° C., 5% CO₂Cultured for 1 day in presence. On the next day, remove the medium, add 100 μL of medium, 37 ° C, 5% CO₂Cultured for 1 day under. The test compound was dissolved in DMSO and diluted with a medium to obtain a sample solution (DMSO concentration 2%). 25 μL of medium or specimen-added medium is added to the well (DMSO concentration 0.4%), 37 ° C., 5% CO₂Incubated for 1 hour in the presence.
GAS6 (R & D, product number: 885-GS) was diluted with a medium so as to be 6 μg / mL, and 25 μL was added to each well, and after stirring, 37 ° C., 5% CO₂Incubated for 10 minutes in the presence.
The supernatant was discarded, 0.1 mL of a 37% formalin solution diluted to 4% with phosphate buffered saline (PBS) (hereinafter referred to as 4% formalin solution) was added to the wells, and the mixture was allowed to stand at room temperature for 10 minutes. Next, the 4% formalin solution was discarded, 0.2 mL of a solution obtained by diluting Triton X-100 to 0.1% with PBS (hereinafter referred to as “wash buffer”) was added, discarded with a decanter, and excess water was removed on a paper towel.
Then, NaN3 and H in the wash buffer₂O₂110 uL was added to 0.1% (hereinafter referred to as “quenching buffer”), 0.1 mL was added to the well, and the mixture was allowed to stand at room temperature for 15 minutes.
The buffer was discarded, 0.2 ml of the wash buffer was added, discarded with a decanter, and excess water was removed on a paper towel. Skimmed milk (Nacalai Tesque) was added to the wash buffer at a final concentration of 5% (blocking buffer), 0.25 mL was added to the well, and allowed to stand at room temperature for 1 hour.
Blocking buffer was discarded, and Anti-phospho-Axl (Y702) (D12B2) rabbit monoclonal antibody (Cell Signaling, catalog number 5724) was reacted at a concentration of 1/1000 and allowed to stand overnight at 4 ° C. The washing operation was repeated 5 times with Wash buffer, and Peroxidase AffiniPure Donkey Anti-Rabbit IgG (H + L) (Jackson ImmunoResearch, catalog number 711-035-152) was allowed to react at a concentration of 1/2000 for 1 hour at room temperature. The washing operation was performed in the same manner, and 0.05 mL of Super Signal ELISA, pico chemi luminescent substrate (Thermo Scientific, catalog number 37069) was added, and the mixture was lightly stirred and incubated for 20 minutes. Thereafter, the luminescence was measured with ARVO sx (Perkin Elmer), and the pAxl (Y702) level was measured.
The pAxl inhibitory activity was determined by the following formula.
Inhibition% = 100- (A-B) * 100 / (T-B)
A: Measured value of test compound
B: Luminescence value of the reaction solution containing a positive control compound at a concentration that suppresses almost 100% phosphorylation
(For example, luminescence value of the reaction solution to which 1 μM BMS-777607 was added)
T: Luminescence value of the reaction solution to which no compound was added
Based on the data on the pAxl inhibitory activity at multiple concentrations, GraphPad Prism 4 showed 50% inhibitory concentration (IC₅₀)
Examples 1 to 17, 19, 21 to 33, 35 to 38, 41 to 48, 50 to 61, 63 to 68, 75 to 79, 81, and 83 to 86 have compounds of 0 nM <IC₅₀<50 nM, compounds of Examples 18, 20, 34, 49, 62, 69, 70, 72-74, 82, 87, 50 nM ≦ IC₅₀<100 nM, compounds of Examples 40, 71, 80, 100 nM ≦ IC₅₀<500 nM, compound of Example 39 is IC₅₀= 500 nM inhibitory activity.

Claims (25)

1. General formula (1)
   

   

   [In Formula (1),
   A represents a phenylene group or a 6-membered heteroarylene group, and the relative configuration of the amino group and nitrogen-containing heterocycle bonded to A is a para configuration;
   W represents a carbon atom or a nitrogen atom (provided that when W is a nitrogen atom, R ⁴ does not exist);
   X represents CH or a nitrogen atom,
   Y represents a carbon atom or a nitrogen atom (provided that when Y is a nitrogen atom, R ⁶ does not exist);
   R ¹ is a cycloalkyl group optionally having one or more substituents selected from group 1, an aryl group optionally having one or more substituents selected from group 1, group 1 represents a heteroaryl group optionally having one or more substituents selected from 1;
   R ² is a C ₁ -C ₆ alkyl group optionally having one or more substituents selected from Group 2, —OR ^C (where R ^C is a C ₁ -C ₆ alkoxy group, A C ₁ -C ₆ alkyl group optionally having one or more substituents selected from a halogen atom and a hydroxyl group, or a hydrogen atom), one or more substituents selected from Group 2; C ₁ -C ₆ alkylthio group which may have, NR ^A R ^B (wherein R ^A and R ^B each independently represents a C ₁ -C ₆ alkyl group, a hydrogen atom, or R ^A and R ^B are taken together they may form a heterocycloalkyl group of 3 to 7-membered together with the nitrogen atom to be replaced.), have one or more substituents selected from the group 1 May represent a cycloalkyl group or a hydrogen atom,
   R ³ is a substituent on A (n is an integer of 0 to 4, and R ³ when n is 2 or more may be the same or different from each other), and is selected from Group 2 C ₁ -C ₆ alkoxy optionally having one or more substituents selected from a C ₁ -C ₆ alkyl group optionally having one or more substituents, a halogen atom and a hydroxyl group A C ₁ -C ₆ alkylthio group, a halogen atom or a hydroxyl group which may have one or more substituents selected from a group, a halogen atom and a hydroxyl group;
   R ⁴ is a substituent on W in the case where W is a carbon atom, and is a C ₁ -C ₆ alkyl group optionally having one or more substituents selected from Group 2, C _1- C ₁ -C ₆ alkoxy group optionally having one or more substituents selected from a C ₆ alkoxy group, a heterocycloalkyl group, a halogen atom and a hydroxyl group, one or more substituents selected from Group 3 A cycloalkyl group that may have a group, a cycloalkenyl group that may have one or more substituents selected from group 3, and one or more substituents selected from group 3 An optionally substituted heterocycloalkyl group, a heterocycloalkenyl group optionally having one or more substituents selected from group 3, and one or more substituents selected from group 3 Good alley A heteroaryl group, a cyano group, a halogen atom or a hydrogen atom which may have one or more substituents selected from
   R ⁵ is a C ₁ -C ₆ alkyl group optionally having one or more substituents selected from Group 2, —OR ^C (where R ^C is a C ₁ -C ₆ alkoxy group, One or more substituents selected from a C ₁ to C ₆ alkyl group, a halogen atom, a C ₁ to C ₆ alkyl group and a hydroxyl group, which may have one or more substituents selected from a halogen atom and a hydroxyl group A 3- to 7-membered heterocycloalkyl group which may have a group, or a hydrogen atom), or a hydrogen atom,
   R ⁶ is a substituent on Y in the case where Y is a carbon atom, and is a C ₁ -C ₆ alkyl group which may have one or more substituents selected from Group 2 or a hydrogen atom. Show
   R ⁷ represents a hydrogen atom or a C ₁ to C ₆ alkyl group optionally having one or more substituents selected from Group 2. ]
   Or a salt thereof.
   Group 1: a C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy group, oxo group, hydroxyl group and halogen atom which may have one or more substituents selected from a halogen atom and a hydroxyl group.
   Group 2:
   A halogen atom,
   An oxo group,
   -NR ^A R ^B , -CONR ^A R ^B (wherein R ^A and R ^B each independently have one or more substituents selected from a halogen atom, a C ₁ -C ₆ alkoxy group and a hydroxyl group) or show was good C ₁ ~ C ₆ alkyl group optionally or a hydrogen atom, together with the nitrogen atom to replace them together is R ^a and R ^B, a halogen atom, C ₁ ~ C ₆ alkyl groups, C _{A 1} to C ₆ alkoxy group and a 3- to 7-membered heterocycloalkyl group which may have one or more substituents selected from a hydroxyl group may be formed).
   -OR ^C (wherein, ^{R C} is, _{C 1} ~ _{C 6} alkoxy group, one or a plurality of which may have a substituent _{C 1} ~ _{C 6} alkyl group selected from a halogen atom and a hydroxyl group, a halogen atom shows a C ₁ ~ C ₆ alkyl group and one or a plurality of substituents may be 3-7 membered heterocycloalkyl group selected from a hydroxyl group or a hydrogen atom.),
   One or more selected from a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, an oxo group and a halogen atom, which may have one or more substituents selected from a halogen atom and a hydroxyl group An aryl group which may have a substituent,
   One or more selected from a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, an oxo group, a hydroxyl group and a halogen atom, which may have one or more substituents selected from a halogen atom and a hydroxyl group Heteroaryl group optionally having 1 substituent,
   One or more selected from a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, an oxo group, a hydroxyl group and a halogen atom, which may have one or more substituents selected from a halogen atom and a hydroxyl group 3 to 7-membered cycloalkyl group optionally having one substituent,
   One or more selected from a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, an oxo group, a hydroxyl group and a halogen atom which may have one or more substituents selected from a halogen atom and a hydroxyl group A 3- to 7-membered heterocycloalkyl group optionally having one substituent.
   Group 3: C ₁ -C ₆ alkyl group optionally having one or more substituents selected from Group 2; C optionally having one or more substituents selected from Group 2 ₁ to C ₆ acyl groups,
   A C ₁ -C ₆ alkylthio group optionally having one or more substituents selected from a halogen atom and a hydroxyl group,
   —CONR ^A R ^B (wherein R ^A and R ^B are each independently a C atom optionally having one or more substituents selected from a halogen atom, a C ₁ -C ₆ alkoxy group and a hydroxyl group) ₁ ~ _{C 6} alkyl group or a hydrogen atom, together with the nitrogen atom ^{to which R a} and ^{R B} are substituted they are taken together, a halogen atom, _{C 1} ~ _{C 6} alkyl group, _{C 1} ~ _{C 6} alkoxy group And a 3- to 7-membered heterocycloalkyl group which may have one or more substituents selected from a hydroxyl group).
   —OR ^C (wherein R ^C may have one or more substituents selected from a C ₁ -C ₆ alkoxy group, a halogen atom, a 3- to 7-membered heterocycloalkyl group, and a hydroxyl group. A C ₁ to C ₆ alkyl group, a halogen atom, a C ₁ to C ₆ alkyl group and a 3- to 7-membered heterocycloalkyl group optionally having one or more substituents selected from a hydroxyl group, or a hydrogen atom ),
   A heterocycloalkyl group optionally having one or more substituents selected from Group 2.
2. The compound or a salt thereof according to claim 1, wherein A is a phenylene group.
3. The compound or a salt thereof according to claim 1 or 2, wherein W is a carbon atom.
4. The compound or salt thereof according to any one of claims 1 to 3, wherein X and Y are nitrogen atoms.
5. N is 0, The compound or its salt of any one of Claims 1-4.
6. The compound or a salt thereof as claimed in any one of claims 5 R ⁵ is a hydrogen atom.
7. Any one compound or its salt chosen from the following group.
   

   
8. An Axl inhibitor comprising the compound according to any one of claims 1 to 7 or a salt thereof.
9. A pharmaceutical comprising the compound according to any one of claims 1 to 7 or a salt thereof as an active ingredient.
10. A disease caused by increased Axl kinase function, a disease associated with increased Axl kinase function, and / or increased Axl kinase function, comprising the compound according to any one of claims 1 to 7 or a salt thereof as an active ingredient. For the treatment of diseases involving
11. A medicament for the treatment of a hyperproliferative disease comprising the compound according to any one of claims 1 to 7 or a salt thereof as an active ingredient.
12. A medicament for the treatment of cancer comprising the compound or a salt thereof according to any one of claims 1 to 7 as an active ingredient.
13. A medicament for preventing metastasis of cancer comprising the compound or salt thereof according to any one of claims 1 to 7 as an active ingredient.
14. A medicament for relieving drug resistance comprising the compound or salt thereof according to any one of claims 1 to 7 as an active ingredient.
15. Cancer is breast cancer, colon cancer, prostate cancer, lung cancer, stomach cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, uterine cancer, esophageal cancer, squamous cell carcinoma, leukemia, osteosarcoma, melanoma, The medicament according to claim 12 or 13, which is selected from glioblastoma and neuroblastoma.
16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a salt thereof, and a pharmaceutically acceptable carrier.
17. A disease caused by hyperfunction of Axl kinase, a disease associated with hyperfunction of Axl kinase, and / or Axl kinase, characterized by using the compound according to any one of claims 1 to 7 or a salt thereof. A method for treating diseases associated with hyperfunction.
18. A method for treating a hyperproliferative disease, comprising using the compound according to any one of claims 1 to 7 or a salt thereof.
19. A method for treating cancer, comprising using the compound according to any one of claims 1 to 7 or a salt thereof.
20. A method for preventing cancer metastasis, comprising using the compound according to any one of claims 1 to 7 or a salt thereof.
21. A method for releasing drug resistance, comprising using the compound according to any one of claims 1 to 7 or a salt thereof.
22. Cancer is breast cancer, colon cancer, prostate cancer, lung cancer, stomach cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, uterine cancer, esophageal cancer, squamous cell carcinoma, leukemia, osteosarcoma, melanoma, The method according to claim 19 or 20, wherein the method is selected from glioblastoma and neuroblastoma.
23. Use of the compound according to any one of claims 1 to 7 or a salt thereof for producing a pharmaceutical.
24. Use of the compound according to any one of claims 1 to 7 or a salt thereof for the treatment of cancer.
25. Use of the compound according to any one of claims 1 to 7 or a salt thereof for preventing cancer metastasis.