JP2008545756A - 1-methyl-1H-pyrazole-4-carboxamides useful as cancer chemotherapeutic agents - Google Patents

Abstract

  The present invention relates to novel 1-methyl-1H-pyrazole-4-carboxamide compounds, pharmaceutical compositions containing such compounds, and the use of these compounds or compositions as cancer chemotherapeutic agents.

Description

  The present invention relates to novel 1-methyl-1H-pyrazole-4-carboxamide compounds, pharmaceutical compositions containing such compounds, and the use of these compounds or compositions as cancer chemotherapeutic agents.

  Many medical conditions are known to involve uncontrolled angiogenesis. These include retinopathy; chronic inflammatory disorders including arthritis; atherosclerosis; macular degeneration; and neoplastic disorders such as cancer. In recent years, much work has been done to find inhibitors of angiogenesis in the hope of developing treatments for such disorders.

  WO 2004/063330 discloses (2-carboxamide) (3-amino) thiophene compounds for the treatment of cancer.

  US Pat. No. 6,448,277 (Novartis) discloses and claims certain benzamide derivatives for inhibiting VEGF receptor tyrosine kinase, tumor growth and VEGF-dependent cell proliferation.

  Published PCT application WO 02/066470 (Amgen) broadly discloses heterocycles containing amide and amino substituents for preventing and treating diseases mediated by angiogenesis. Published PCT application WO 2004/005279 (Amgen) discloses certain substituted anthranilic acid amide derivatives for preventing and treating diseases mediated by angiogenesis. Published PCT application WO 2004/007458 (Amgen) relates to substituted 2-alkylamine nicotinamide derivatives and their use in the treatment of cancer and other disorders.

  Published PCT application WO 00/27819 (Schering) discloses certain anthranilic acid amides for treating diseases triggered by angiogenesis. Published PCT application WO 02/090352 (Schering) relates to selective anthranilamidopyridine amides as inhibitors of VEGFR-2 and VEGFR-3. Published PCT application WO 01/81311 (Schering) relates to substituted benzoic acid amides and their use for inhibition of angiogenesis.

Anthranilamides as angiogenesis inhibitors have been discussed in a series of research papers by Novartis and Schering scientists. Manley, et al., J. Med. Chem., 45 , 5687-5693 (2002); Furet, et al., Bioorganic & Medicinal Chemistry Letters, 13 , 2967-2971 (2003); Manley, et al., Cell Mol. Biol. Lett., 8 , 532-533 (2003); and Manley, et al., Biochimica et Biophysica Acta, 1697, 17-27 (2004).

  EP-B-832061 discloses benzamide derivatives and their use as vasopressin antagonists.

［式中、
Ａｒは、

からなる群から選択され；
Ｘは、ＣＨまたはＮであり； The present invention relates to a compound of formula (I)

[Where:
Ar is

Selected from the group consisting of:
X is CH or N;

からなる群から選択される
｛ここで、
Ｒ^１−２は、
・Ｈ、
・（Ｃ_１−Ｃ_４）アルコキシ、
・（Ｃ_１−Ｃ_４）アルキル、ここで、該（Ｃ_１−Ｃ_４）アルキルは、
−ヒドロキシ、
−（Ｃ_１−Ｃ_４）アルキルアミノ、
−（Ｃ_１−Ｃ_４）アシルオキシ、
−（Ｃ_１−Ｃ_４）アルコキシ、および、
−０個、１個または２個の（Ｃ_１−Ｃ_４）アルコキシ基で置換されている（Ｃ_２−Ｃ_４）アルコキシ
から独立して選択される０個、１個または２個の基で置換されていてもよく、
−ここで、該（Ｃ_１−Ｃ_４）アルキルは、独立して、ペルフルオロのレベルまでフッ素で置換されていることもある、
・５員または６員のヘテロアリール、
または、
・（Ｃ_１−Ｃ_４）アルキル、ハロ、ニトロ、（Ｃ_１−Ｃ_４）アルコキシおよびシアノから独立して選択される０個、１個または２個の基で置換されているフェニル
からなる群から選択され；
Ｒ^１−３は、Ｈまたは（Ｃ_１−Ｃ_４）アルキルであり； R ¹ is H, halogen,

Selected from the group consisting of {where,
R ^1-2 is
・ H,
· _(C 1 -C ₄₎ alkoxy,
(C ₁ -C ₄ ) alkyl, wherein the (C ₁ -C ₄ ) alkyl is
-Hydroxy,
- _(C 1 -C ₄₎ alkylamino,
- _(C 1 -C ₄₎ acyloxy,
- _(C 1 -C ₄₎ alkoxy and,
Zero or one or two _(C 1 -C ₄₎ is substituted with an alkoxy group _(C 2 -C ₄₎ 0 substituents independently selected from alkoxy, with one or two groups May be replaced,
Where the (C ₁ -C ₄ ) alkyl may independently be substituted with fluorine to the level of perfluoro,
5 or 6 membered heteroaryl,
Or
The group consisting of phenyl substituted with 0, 1 or 2 groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano Selected from;
R ^1-3 is H or (C ₁ -C ₄ ) alkyl;

R ^1-4 , R ^1-5 and R ^1-6 are
・ H,
・ Indan-5-yl,
Phenyl substituted with 0, 1 or 2 groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano;
5 or 6 membered heteroaryl, which is
-Cyano,
-Halo,
-Nitro,
-(C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) acyloxy, (C ₁ -C ₄ ) 0, 1 or 2 groups selected from alkoxy and (C ₂ -C ₄ ) alkoxy substituted with 0, 1 or 2 (C ₁ -C ₄ ) alkoxy groups May be replaced with
Substituted with 0, 1 or 2 groups selected from
· _(C 1 -C _{4) alkyl, (C} 1 -C ₄₎ alkoxy, 0 groups selected from cyano and halo, one or which is substituted with two groups _(C 3 -C ₆₎ cycloalkyl ,and,
(C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is
-NH _2,
- _(C 1 -C ₄₎ alkoxy,
Independently substituted with 0, 1, 2, or 3 (C ₁ -C ₄ ) alkoxy and OH groups, and may be independently substituted with fluorine to the perfluoro level ( C ₂ -C ₄₎ alkoxy,
-Carboxyl,
- _(C 1 -C ₄₎ alkoxycarbonyl,
- _(C 1 -C ₄₎ alkylamino,
-Aminocarbonyl,
- _(C 1 -C ₄₎ alkylsulfonyl,
- _(C 1 -C ₄₎ phenyl alkyl, halo, _nitro, substituted with zero, one or two groups independently selected from _(C 1 -C ₄₎ alkoxy and cyano,
5 independently substituted with 0, 1, 2 or 3 groups selected from-(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro Or 6-membered heteroaryl, and
- _(C 1 -C _{4) alkyl,} 0 groups selected from _(C 1 -C ₄₎ alkoxy, cyano and halo, one, two or three heterocycle are independently substituted by a group Independently substituted with 0 or 1 group of choice,
-And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups,
-And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected independently from the group consisting of;
And
When R ^1-3 and R ^1-4 , R ^1-3 and R ^1-5 , and R ^1-3 and R ^1-6 are bonded to the same nitrogen atom, the N to which they are bonded 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl, and piperidinyl (optionally substituted on N with (C ₁ -C ₄ ) alkyl) together with the atom May be formed}]
Or a pharmaceutically acceptable salt thereof.

  The invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above plus a pharmaceutically acceptable carrier.

  In addition, the present invention relates to a method for treating cancer, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as defined above.

Pharmaceutically acceptable salts of compound (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, Examples include toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid salts.

  Pharmaceutically acceptable salts of compound (I) also include conventional base salts such as, and preferably, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium. Salt) and ammonia or organic amines having 1 to 16 carbon atoms (exemplarily and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethyl) Ammonium salts derived from aminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, arginine, lysine, ethylenediamine and methylpiperidine, and the like.

For the purposes of the present invention, solvates are forms of compounds that coordinate with solvent molecules to form a complex in the solid or liquid state. Hydrates are a special form of solvates whose coordination is with water.

For the purposes of the present invention, substituents have the following meanings unless otherwise indicated:
The terms “halogen” and “halo” mean Cl, Br, F and I, with Cl, Br and F being preferred.

The terms “(C ₁ -C ₄ ) alkyl” and “(C ₁ -C ₆ ) alkyl” are straight chain each having about 1 to about 4 C atoms or about 1 to about 6 C atoms. Or a branched saturated carbon group. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

The term “(C ₃ -C ₆ ) cycloalkyl” means a saturated carbocyclic ring group having about 3 to about 6 C atoms. Such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “(C ₁ -C ₄ ) alkoxy” is a straight or branched saturated carbon group having from about 1 to about 4 C atoms, wherein the carbon group is bonded to an O atom. Means what The O atom is the point of attachment of the alkoxy substituent to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and the like.

The term “(C ₁ -C ₄ ) alkylamino” means an amino group having one or two (independently selected) (C ₁ -C ₄ ) alkyl substituents, illustratively , Methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methyl Amino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino, Nn- Represents hexyl-N-methylamino and the like;

The term “(C ₁ -C ₄ ) alkylsulfonyl” means a sulfonyl group having a (C ₁ -C ₄ ) alkyl substituent, illustratively methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, t-butylsulfonyl. Etc.

The term “(C ₁ -C ₄ ) alkoxycarbonyl” refers to (C ₁ — C ₄ ) means an alkoxy group, and illustratively represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, t-butoxycarbonyl and the like.

The term “(C ₁ -C ₄ ) acyloxy” is attached to the C atom of the carboxyl group [—C (O) O—], which is attached to the rest of the molecule by an oxygen atom. (C ₁ -C ₄ ) group, and illustratively represents formyloxy, acetyloxy (acetoxy), propanoyloxy, butanoyloxy, t-butanoyloxy and the like.

The term “5- or 6-membered heteroaryl” is each
(1) an aromatic ring consisting of 5 atoms, each having 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, the remainder being C atoms; However, more than one O or S atom cannot be present in a heteroaryl. The heteroaryl is attached to the core molecule at any available C or N atom and may be substituted by any of the substituents listed at any available C or N atom. Such groups include pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole and tetrazole in all possible isomers thereof; Or
(2) An aromatic ring consisting of six atoms, one, two or three of which are N atoms, the rest being C, the heterocycle is any available C atom in the nucleus molecule It may be attached and substituted by any of the substituents listed on any available C atom. Such groups include pyridine, pyrimidine, pyridazine and thiazine in all possible isomers thereof.

  The term “heterocycle” contains 1-2 heteroatoms selected from O, S or N, the remaining atoms being a 5- or 6-membered saturated or partially saturated heterocyclic ring consisting of C atoms. Meaning that when there are two O atoms, they must not be adjacent. This heterocycle is attached to the core molecule by any available C or N atom and may be substituted by any of the substituents listed on any available C or N atom. Such groups include pyrrolidine, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyrano, piperidinyl, imidazolinyl, pyrazolinyl, morpholinyl, thiomorpholinyl, etc. in all possible isomers thereof.

  The symbol * next to the bond indicates a bond point in the molecule.

  The compounds of the present invention may contain one or more asymmetric centers depending on the position and nature of the various desired substituents. Asymmetric carbon atoms can be present in the (R) or (S) configuration. All possible stereoisomers (including enantiomers and diastereomers) are intended to be included within the scope of the present invention. Preferred compounds are those having the absolute configuration of the compounds of the invention that exhibit the more desirable biological activity. Separated, pure or partially purified stereoisomers or racemic mixtures of the compounds of the invention are also included within the scope of the invention. Purification of the isomer and separation of the stereoisomer mixture can be accomplished by standard techniques known in the art.

からなる群から選択され；
Ｘが、ＣＨまたはＮであり； In another embodiment, the invention provides a compound of the formula:
Ar is

Selected from the group consisting of:
X is CH or N;

からなる群から選択される
｛ここで、
Ｒ^１−２は、
・（Ｃ_１−Ｃ_４）アルキル、ここで、該（Ｃ_１−Ｃ_４）アルキルは、
−ヒドロキシ、
−（Ｃ_１−Ｃ_４）アルキルアミノ、
−（Ｃ_１−Ｃ_４）アシルオキシ、
−（Ｃ_１−Ｃ_４）アルコキシ、および、
−０個、１個または２個の（Ｃ_１−Ｃ_４）アルコキシ基で置換されている（Ｃ_２−Ｃ_４）アルコキシ
から独立して選択される１個または２個の基で置換されており、
−ここで、該（Ｃ_１−Ｃ_４）アルキルは、独立して、ペルフルオロのレベルまでフッ素で置換されていることもある、
・５員または６員のヘテロアリール、
または、
・（Ｃ_１−Ｃ_４）アルキル、ハロ、ニトロ、（Ｃ_１−Ｃ_４）アルコキシおよびシアノから独立して選択される１個または２個の基で置換されているフェニル
からなる群から選択され；
Ｒ^１−３は、Ｈまたは（Ｃ_１−Ｃ_４）アルキルであり； R ¹ is

Selected from the group consisting of {where,
R ^1-2 is
(C ₁ -C ₄ ) alkyl, wherein the (C ₁ -C ₄ ) alkyl is
-Hydroxy,
- _(C 1 -C ₄₎ alkylamino,
- _(C 1 -C ₄₎ acyloxy,
- _(C 1 -C ₄₎ alkoxy and,
Zero or one or two _(C 1 -C ₄₎ is substituted with an alkoxy group _(C 2 -C ₄₎ substituted by one or two groups independently selected from alkoxy And
Where the (C ₁ -C ₄ ) alkyl may independently be substituted with fluorine to the level of perfluoro,
5 or 6 membered heteroaryl,
Or
Selected from the group consisting of phenyl substituted by one or two groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano. ;
R ^1-3 is H or (C ₁ -C ₄ ) alkyl;

R ^1-4 and R ^1-5 are
・ Indan-5-yl,
Phenyl substituted with one or two groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano,
5 or 6 membered heteroaryl, which is
-Cyano,
-Halo,
-Nitro,
-(C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) acyloxy, (C ₁ -C ₄ ) 0, 1 or 2 groups selected from alkoxy and (C ₂ -C ₄ ) alkoxy substituted with 0, 1 or 2 (C ₁ -C ₄ ) alkoxy groups May be replaced with
Substituted with one or two groups selected from
(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl substituted with one or two groups selected from cyano and halo, and
(C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is
-NH _2,
- _(C 1 -C ₄₎ alkoxy,
Independently substituted with 0, 1, 2, or 3 (C ₁ -C ₄ ) alkoxy and OH groups, and may be independently substituted with fluorine to the perfluoro level ( C ₂ -C ₄₎ alkoxy,
-Carboxyl,
- _(C 1 -C ₄₎ alkoxycarbonyl,
- _(C 1 -C ₄₎ alkylamino,
-Aminocarbonyl,
- _(C 1 -C ₄₎ alkylsulfonyl,
- _(C 1 -C ₄₎ phenyl alkyl, halo, _nitro, substituted with zero, one or two groups independently selected from _(C 1 -C ₄₎ alkoxy and cyano,
5 independently substituted with 0, 1, 2 or 3 groups selected from-(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro Or 6-membered heteroaryl, and
- _(C 1 -C _{4) alkyl,} 0 groups selected from _(C 1 -C ₄₎ alkoxy, cyano and halo, one, two or three heterocycle are independently substituted by a group Independently substituted with one selected group;
-And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups,
-And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected independently from the group consisting of

R ^1-6 is
・ H,
・ Indan-5-yl,
Phenyl substituted with 0, 1 or 2 groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano;
5 or 6 membered heteroaryl, which is
-Cyano,
-Halo,
-Nitro,
-(C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) acyloxy, (C ₁ -C ₄ ) 0, 1 or 2 groups selected from alkoxy and (C ₂ -C ₄ ) alkoxy substituted with 0, 1 or 2 (C ₁ -C ₄ ) alkoxy groups May be replaced with
Substituted with 0, 1 or 2 groups selected from
· _(C 1 -C _{4) alkyl, (C} 1 -C ₄₎ alkoxy, 0 groups selected from cyano and halo, one or which is substituted with two groups _(C 3 -C ₆₎ cycloalkyl ,and,
(C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is
-NH _2,
- _(C 1 -C ₄₎ alkoxy,
Independently substituted with 0, 1, 2, or 3 (C ₁ -C ₄ ) alkoxy and OH groups, and may be independently substituted with fluorine to the perfluoro level ( C ₂ -C ₄₎ alkoxy,
-Carboxyl,
- _(C 1 -C ₄₎ alkoxycarbonyl,
- _(C 1 -C ₄₎ alkylamino,
-Aminocarbonyl,
- _(C 1 -C ₄₎ alkylsulfonyl,
- _(C 1 -C ₄₎ phenyl alkyl, halo, _nitro, substituted with zero, one or two groups independently selected from _(C 1 -C ₄₎ alkoxy and cyano,
5 independently substituted with 0, 1, 2 or 3 groups selected from-(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro Or 6-membered heteroaryl, and
- _(C 1 -C _{4) alkyl,} 0 groups selected from _(C 1 -C ₄₎ alkoxy, cyano and halo, one, two or three heterocycle are independently substituted by a group Independently substituted with 0 or 1 group of choice,
-And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups,
-And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected independently from the group consisting of
And
When R ^1-3 and R ^1-4 , R ^1-3 and R ^1-5 , and R ^1-3 and R ^1-6 are bonded to the same nitrogen atom, the N to which they are bonded 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and piperidinyl (optionally substituted on N with (C ₁ -C ₄ ) alkyl) together with the atom May form}
It relates to compounds of formula (I), or pharmaceutically acceptable salts thereof.

からなる群から選択され；
ＸがＣＨであり； In another embodiment, the invention provides a compound of the formula:
Ar is

Selected from the group consisting of:
X is CH;

からなる群から選択される
｛ここで、
Ｒ^１−３は、Ｈまたは（Ｃ_１−Ｃ_４）アルキルであり；
Ｒ^１−５は、
インダン−５−イル、
（Ｃ_１−Ｃ_４）アルキル、ハロ、ニトロ、（Ｃ_１−Ｃ_４）アルコキシおよびシアノから独立して選択される１個または２個の基で置換されているフェニル、
５員または６員のヘテロアリール、これは、シアノ、ハロ、ニトロ、（Ｃ_１−Ｃ_４）アルキル（ここで、該（Ｃ_１−Ｃ_４）アルキルは、（Ｃ_１−Ｃ_４）アルキルアミノ、（Ｃ_１−Ｃ_４）アシルオキシ、（Ｃ_１−Ｃ_４）アルコキシ、および、（Ｃ_２−Ｃ_４）アルコキシ（これは、０個、１個または２個までの（Ｃ_１−Ｃ_４）アルコキシ基で置換されている）から選択される０個、１個または２個の基で置換されていることもある）から選択される１個または２個の基で置換されている、
（Ｃ_１−Ｃ_４）アルキル、（Ｃ_１−Ｃ_４）アルコキシ、シアノおよびハロから選択される１個または２個の基で置換されている（Ｃ_３−Ｃ_６）シクロアルキル、および、
（Ｃ_１−Ｃ_６）アルキル、ここで、該（Ｃ_１−Ｃ_６）アルキルは、ＮＨ_２、（Ｃ_１−Ｃ_４）アルコキシ、（Ｃ_２−Ｃ_４）アルコキシ（これは、０個、１個、２個または３個の（Ｃ_１−Ｃ_４）アルコキシおよびＯＨ基で独立して置換されており、ペルフルオロのレベルまでフッ素で独立して置換されていることもある）、カルボキシル、（Ｃ_１−Ｃ_４）アルコキシカルボニル、（Ｃ_１−Ｃ_４）アルキルアミノ、アミノカルボニル、（Ｃ_１−Ｃ_４）アルキルスルホニル、フェニル（これは、（Ｃ_１−Ｃ_４）アルキル、ハロ、ニトロ、（Ｃ_１−Ｃ_４）アルコキシおよびシアノから独立して選択される０個、１個または２個の基で置換されている）、５員または６員のヘテロアリール（これは、（Ｃ_１−Ｃ_４）アルキル、（Ｃ_１−Ｃ_４）アルコキシ、シアノ、ハロおよびニトロから選択される０個、１個、２個または３個の基で独立して置換されている）、および、複素環（これは、（Ｃ_１−Ｃ_４）アルキル、（Ｃ_１−Ｃ_４）アルコキシ、シアノおよびハロから選択される０個、１個、２個または３個の基で独立して置換されている）から選択される１個の基で独立して置換されており、そして、該（Ｃ_１−Ｃ_６）アルキルは、０個、１個または２個のＯＨまたはハロ基で独立して置換されており、そして、該（Ｃ_１−Ｃ_６）アルキルは、ペルフルオロのレベルまでフッ素で独立して置換されていることもある、
からなる群から選択され、 R ¹ is

Selected from the group consisting of {where,
R ^1-3 is H or (C ₁ -C ₄ ) alkyl;
R ^1-5 is
Indan-5-yl,
Phenyl substituted with one or two groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano;
5- or 6-membered heteroaryl, which is cyano, halo, nitro, (C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino , (C ₁ -C ₄ ) acyloxy, (C ₁ -C ₄ ) alkoxy, and (C ₂ -C ₄ ) alkoxy (which includes 0, 1 or 2 (C ₁ -C ₄ )) Substituted with 1 or 2 groups selected from 0), 1 or 2 groups selected from
(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl substituted with one or two groups selected from cyano and halo, and
(C ₁ -C ₆ ) alkyl, wherein (C ₁ -C ₆ ) alkyl is NH ₂ , (C ₁ -C ₄ ) alkoxy, (C ₂ -C ₄ ) alkoxy (this is 0, 1, 2 or 3 (C ₁ -C ₄ ) alkoxy and OH groups independently substituted and may be independently substituted with fluorine to the perfluoro level), carboxyl, ( C ₁ -C _{4) alkoxycarbonyl, (C} 1 -C ₄₎ alkylamino, _{aminocarbonyl, (C} 1 -C ₄₎ alkylsulfonyl, phenyl (which _{is, (C} 1 -C ₄₎ alkyl, halo, nitro, (C ₁ -C ₄ ) substituted with 0, 1 or 2 groups independently selected from alkoxy and cyano), 5-membered or 6-membered heteroaryl (which is (C _1- C ₄₎ alkyl , (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro independently substituted with 0, 1, 2 or 3 groups selected from) and heterocycles (which are , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, independently substituted with 0, 1, 2 or 3 groups selected from cyano and halo) And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected from the group consisting of

R ^1-6 is
H,
Indan-5-yl,
Phenyl substituted with 0, 1 or 2 groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano;
5- or 6-membered heteroaryl, which is cyano, halo, nitro, (C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino , _(C 1 -C _{4) acyloxy, (C} 1 -C ₄₎ alkoxy, and zero, one or up to two _(C 1 -C ₄₎ is substituted with an alkoxy group _(C 2 -C ₄ ) optionally substituted with 0, 1 or 2 groups selected from alkoxy), substituted with 0, 1 or 2 groups selected from
(C ₃ -C ₆ ) cycloalkyl, substituted with 0, 1 or 2 groups selected from (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano and halo, and,
(C ₁ -C ₆ ) alkyl, wherein (C ₁ -C ₆ ) alkyl is NH ₂ , (C ₁ -C ₄ ) alkoxy, (C ₂ -C ₄ ) alkoxy (this is 0, 1, 2 or 3 (C ₁ -C ₄ ) alkoxy and OH groups independently substituted and may be independently substituted with fluorine to the perfluoro level), carboxyl, ( C ₁ -C _{4) alkoxycarbonyl, (C} 1 -C ₄₎ alkylamino, _{aminocarbonyl, (C} 1 -C ₄₎ alkylsulfonyl, phenyl (which _{is, (C} 1 -C ₄₎ alkyl, halo, nitro, (C ₁ -C ₄ ) substituted with 0, 1 or 2 groups independently selected from alkoxy and cyano), 5-membered or 6-membered heteroaryl (which is (C _1- C ₄₎ alkyl , (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro independently substituted with 0, 1, 2 or 3 groups selected from) and heterocycles (which are , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, independently substituted with 0, 1, 2 or 3 groups selected from cyano and halo) Independently substituted with 0 or 1 group, and the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups. And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected from the group consisting of
And
When R ^1-3 and R ^1-5 , and R ^1-3 and R ^1-6 are bonded to the same nitrogen atom, they are combined with the N atom to which they are bonded to form pyrrolidinyl, morpholinyl , May form a 5- or 6-membered saturated heterocyclic ring selected from thiomorpholinyl and piperidinyl (optionally substituted on N with (C ₁ -C ₄ ) alkyl)},
It relates to compounds of formula (I), or pharmaceutically acceptable salts thereof.

からなる群から選択され；
ＸがＣＨであり； In another embodiment, the invention provides a compound of the formula:
Ar is

Selected from the group consisting of:
X is CH;

からなる群から選択される
｛ここで、
Ｒ^１−３はＨであり；
Ｒ^１−５は、（Ｃ_１−Ｃ_６）アルキルであり、ここで、該（Ｃ_１−Ｃ_６）アルキルは、（Ｃ_１−Ｃ_４）アルコキシ、（Ｃ_２−Ｃ_４）アルコキシ（これは、０個、１個または２個の（Ｃ_１−Ｃ_４）アルコキシおよびＯＨ基で独立して置換されており、ペルフルオロのレベルまでフッ素で独立して置換されていることもある）から選択される１個の基で独立して置換されており、そして、該（Ｃ_１−Ｃ_６）アルキルは、０個、１個または２個のＯＨまたはハロ基で独立して置換されており、そして、該（Ｃ_１−Ｃ_６）アルキルは、ペルフルオロのレベルまでフッ素で独立して置換されていることもあり、
Ｒ^１−６は、Ｈおよび（Ｃ_１−Ｃ_６）アルキルからなる群から選択され、ここで、該（Ｃ_１−Ｃ_６）アルキルは、（Ｃ_１−Ｃ_４）アルコキシ、（Ｃ_２−Ｃ_４）アルコキシ（これは、０個、１個、２個または３個の（Ｃ_１−Ｃ_４）アルコキシおよびＯＨ基で独立して置換されており、ペルフルオロのレベルまでフッ素で独立して置換されていることもある）から選択される０個または１個の基で独立して置換されており、そして、該（Ｃ_１−Ｃ_６）アルキルは、０個、１個または２個のＯＨまたはハロ基で独立して置換されており、そして、該（Ｃ_１−Ｃ_６）アルキルは、ペルフルオロのレベルまでフッ素で独立して置換されていることもある｝、
式（Ｉ）の化合物、またはそれらの医薬的に許容し得る塩に関する。 R ¹ is

Selected from the group consisting of {where,
R ^1-3 is H;
R ^1-5 is (C ₁ -C ₆ ) alkyl, wherein (C ₁ -C ₆ ) alkyl is (C ₁ -C ₄ ) alkoxy, (C ₂ -C ₄ ) alkoxy (this Are independently substituted with 0, 1 or 2 (C ₁ -C ₄ ) alkoxy and OH groups, and may be independently substituted with fluorine to the perfluoro level) And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
R ^1-6 is selected from the group consisting of H and (C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is (C ₁ -C ₄ ) alkoxy, (C _2- C ₄ ) alkoxy (which is independently substituted with 0, 1, 2 or 3 (C ₁ -C ₄ ) alkoxy and OH groups and independently substituted with fluorine to the perfluoro level. And (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH, which may be independently substituted with 0 or 1 group selected from Or independently substituted with a halo group, and the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro},
It relates to compounds of formula (I), or pharmaceutically acceptable salts thereof.

からなる群から選択され；
ＸがＣＨであり；
Ｒ^１が、

からなる群から選択される
｛ここで、
Ｒ^１−３はＨであり；
Ｒ^１−６は、Ｈおよび（Ｃ_１−Ｃ_６）アルキルからなる群から選択され、ここで、該（Ｃ_１−Ｃ_６）アルキルは、（Ｃ_１−Ｃ_４）アルコキシ、（Ｃ_２−Ｃ_４）アルコキシ（これは、０個、１個、２個または３個の（Ｃ_１−Ｃ_４）アルコキシおよびＯＨ基で独立して置換されており、ペルフルオロのレベルまでフッ素で独立して置換されていることもある）から選択される０個または１個の基で独立して置換されており、そして、該（Ｃ_１−Ｃ_６）アルキルは、０個、１個または２個のＯＨまたはハロ基で独立して置換されており、そして、該（Ｃ_１−Ｃ_６）アルキルは、ペルフルオロのレベルまでフッ素で独立して置換されていることもある｝、
式（Ｉ）の化合物、またはそれらの医薬的に許容し得る塩に関する。 In another embodiment, the invention provides a compound of the formula:
Ar is

Selected from the group consisting of:
X is CH;
R ¹ is

Selected from the group consisting of {where,
R ^1-3 is H;
R ^1-6 is selected from the group consisting of H and (C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is (C ₁ -C ₄ ) alkoxy, (C _2- C ₄ ) alkoxy (which is independently substituted with 0, 1, 2 or 3 (C ₁ -C ₄ ) alkoxy and OH groups and independently substituted with fluorine to the perfluoro level. And (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH, which may be independently substituted with 0 or 1 group selected from Or independently substituted with a halo group, and the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro},
It relates to compounds of formula (I), or pharmaceutically acceptable salts thereof.

（式中、ＸおよびＲ^１は上記の意味を有し、Ｒ'は低級アルキルである）
の化合物を、式Ａｒ−ＮＨ_２（ＶＩＩＩ）
（式中、Ａｒは上記の意味を有する）
の化合物と、例えばＰｙＢＯＰなどのカップリング剤の存在下で反応させる；または、 In another embodiment, the present invention relates to a process for the preparation of a compound of formula (I), which comprises any of the following:
(A) Formula (VI) with or without first hydrolyzing the ester group -COOR '

Wherein X and R ¹ have the above meanings and R ′ is lower alkyl.
A compound of formula Ar—NH ₂ (VIII)
(Wherein Ar has the above meaning)
In the presence of a coupling agent such as PyBOP; or

（式中、Ａｒは上記の意味を有する）
の化合物を、式（ＩＶ）

（式中、ＸおよびＲ^１は上記の意味を有する）
の化合物と反応させ、続いて、得られる化合物を還元する；または、 (B) Formula (IX)

(Wherein Ar has the above meaning)
A compound of formula (IV)

(Wherein X and R ¹ have the above meanings)
Or subsequently reducing the resulting compound; or

（式中、ｌｇは、ハロ、ＯＴｓまたはＯＭｓなどの脱離基を表す）
の化合物と反応させる；または、 (C) a compound of formula (IX) (wherein Ar has the above meaning)

(Wherein lg represents a leaving group such as halo, OTs or OMs)
Or react with a compound of

（式中、ＸおよびＲ^１は上記の意味を有し、Ｒ'は低級アルキルである）
の化合物を、式（ＶＩＩＩ）
ＡｒＮＨ_２（ＶＩＩＩ）
（式中、Ａｒは上記の意味を有する）
の化合物と、（Ｒ'）_３Ａｌ（式中、Ｒ'は低級アルキルである）の存在下で反応させる；または、
（Ｅ）最初に上記の式（ＩＩａ）の化合物のエステル基−ＣＯＯＲ'を加水分解し、続いて、得られる化合物を上記の式（ＶＩＩＩ）の化合物と、例えばＰｙＢＯＰなどのカップリング剤の存在下で反応させる。 (D) Formula (IIa)

Wherein X and R ¹ have the above meanings and R ′ is lower alkyl.
A compound of formula (VIII)
ArNH ₂ (VIII)
(Wherein Ar has the above meaning)
Or in the presence of (R ′) ₃ Al where R ′ is lower alkyl; or
(E) First hydrolysis of the ester group -COOR 'of the compound of formula (IIa) above, followed by the presence of a compound of formula (VIII) above and a coupling agent such as PyBOP Let it react below.

General Preparation Methods Compounds of formula (I) may be prepared by synthetic methods known to those skilled in the art or by methods analogous thereto. These methods are summarized below in Reaction Scheme 1.
Unless otherwise defined, R ¹ and X have the same meaning as defined herein above.

Reaction scheme 1

  As illustrated in Reaction Scheme 1, two general synthetic routes can be used to prepare compounds of formula (I).

In one route, the amino group of a compound of formula (III) is reductively aminated using a reducing agent such as pyridine or pyrimidinecarboxaldehyde of formula (IV) and sodium triacetoxyborohydride, or a compound of formula (V) pyridine or halide pyrimidine methyl, tosylate or mesylate, and, optionally subjected to direct N- alkylation using a base such as pyridine or K ₂ CO ₃ or a catalyst such as sodium iodide. The formed product, formula (VI), is then converted into an aromatic amine of formula (VIII) and a coupling agent such as (R ′) ₃ Al (where R ′ = lower alkyl). To obtain a compound of formula (I) or alternatively hydrolyze the ester of formula (VI) to an acid, which is then used in amine (VIII) with a coupling agent such as PyBOP To make a coupling.

In the second route, the compound of formula (III) is protected directly by reaction with the aromatic amine of formula (VIII) above, or first the amino function is protected, for example as a BOC derivative (VII) and then , (R ′) ₃ Al directly or via hydrolysis to (VIII) followed by coupling in the presence of PyBOP followed by deprotection to give a compound of formula (IX) To the aminoamide. The compound of formula (IX) is then converted to the compound of formula (I) using the method of reductive amination described above for the preparation of (VI) or direct N-alkylation.

Additional routes shown in Scheme 1a below are possible. The amino group of the compound of formula (III) can be acylated using acylating agents such as acetic anhydride and formic acid. The acylated product formula (II) is N-alkylated using a pyridine or pyrimidine methyl halide of formula (V), tosylate or mesylate and a base such as DBU or K ₂ CO ₃ . The formed product formula (IIa) is then reacted with an aromatic amine of formula (VIII) in the presence of a coupling agent such as (R ′) ₃ Al (where R ′ = lower alkyl). After basic work-up to obtain a compound of formula (I) or alternatively hydrolyze the ester of formula (IIa) to an acid, where the N-formyl group is also removed, Is coupled to amine (VIII) using a coupling agent such as PyBOP.

Reaction Scheme 1a

  Starting materials of formula (III), (IV), (V) and (VIII) can be purchased (eg Lanxess, Germany) or by standard means well known in the art or in reaction scheme 2- 8 can be produced.

Reaction scheme 2

であり、ｌｇがＣｌである式（Ｖ）］の化合物は、反応スキーム２に示す通り、酸塩化物を、式（Ｘ）のクロロメチルヘテロアリールアミンと、一般的にトリエチルアミンなどの塩基の存在下で反応させることにより、製造し得る。 Formula (Va) [R ¹ is

And lg is Cl, the compound of formula (V)] can be prepared by reacting the acid chloride with the chloromethylheteroarylamine of formula (X) and the presence of a base such as triethylamine, as shown in Reaction Scheme 2. It can manufacture by making it react under.

Reaction scheme 3

である式（Ｖ）］の化合物は、式（ＸＩ）のヒドロキシメチルヘテロアリールアミンから、反応スキーム３に示す通りに製造できる。アルコールの保護および式（ＸＩＩＩ）のＢＯＣ−誘導体への変換に続き、Ｎ−アルキル化により式（ＸＩＶ）の中間体を得る。アルコールおよびアミンの脱保護に続き、ヒドロキシ基を脱離基に変換し（例えば、ｌｇがＣｌであるとき、ＳＯＣｌ_２を使用する）、式（Ｖｂ）の中間体を得る。 Formula (Vb) [R ¹ is

The compound of formula (V)] can be prepared from the hydroxymethylheteroarylamine of formula (XI) as shown in Reaction Scheme 3. Following protection of the alcohol and conversion of the formula (XIII) to a BOC-derivative, N-alkylation provides the intermediate of formula (XIV). Following deprotection of the alcohol and amine, the hydroxy group is converted to a leaving group (eg, using SOCl ₂ when lg is Cl) to give an intermediate of formula (Vb).

Reaction scheme 4

である、式（Ｖ）］の化合物は、反応スキーム４で例示説明する経路により製造できる。式（ＸＶＩ）のクロロヘテロアリールカルボン酸誘導体を、リチウムボロヒドリドなどの標準的な物質で式（ＸＶＩＩ）のクロロヘテロアリールアルコールに還元する。クロロ化合物の式（Ｒ^１−３）（Ｒ^１−５）ＮＨのアミンとの反応は、式（ＸＶＩＩＩ）のアルコールの中間体をもたらす。このアルコールの脱離基、例えばメシレートへの変換は、式（Ｖｃ）の化合物の合成を完了させる。 Formula (Vc) [R ¹ is

The compound of formula (V)] can be prepared by the route illustrated and illustrated in Reaction Scheme 4. The chloroheteroarylcarboxylic acid derivative of formula (XVI) is reduced to a chloroheteroaryl alcohol of formula (XVII) with a standard substance such as lithium borohydride. Reaction of the chloro compound with an amine of formula (R ^1-3 ) (R ^1-5 ) NH results in an alcohol intermediate of formula (XVIII). Conversion of this alcohol to a leaving group, such as mesylate, completes the synthesis of the compound of formula (Vc).

Reaction scheme 5

である、式（Ｖ）］の化合物は、反応スキーム５に示す通りに、式（ＸＩＸ）のジカルボン酸から、半酸エステル（ＸＸ）を介して、式（ＸＸＩ）の酸アミドに変換することにより製造できる。（ＸＸＩ）のエステル化は、（ＸＸＩＩ）をもたらし、それを、水素化ホウ素ナトリウムでアルコール（ＸＸＩＩＩ）に還元でき、次いで、例えばＭｓＣｌおよびトリエチルアミンなどの塩基を使用して、式（Ｖｄ）の化合物に変換する。 Formula (Vd) [R ¹ is

The compound of formula (V)] is converted from the dicarboxylic acid of formula (XIX) to the acid amide of formula (XXI) via the hemiester (XX) as shown in Reaction Scheme 5. Can be manufactured. Esterification of (XXI) results in (XXII), which can be reduced to alcohol (XXIII) with sodium borohydride, then using a base such as MsCl and triethylamine, for example, compound of formula (Vd) Convert to

Reaction scheme 6

An alternative to the preparation of the pyridine amide ester of formula (XXII) is via the Minisci reaction shown in Reaction Scheme 6, in which the pyridine carboxylic acid ester is cooled to 10 ° C. in formamide. While stirring in the presence of equivalent concentrated H ₂ SO ₄ , FeSO ₄ and H ₂ O ₂ .

Reaction Scheme 8

である式（Ｖ）］の化合物は、反応スキーム８に示す経路で製造できる。右のＲ^１−３がＨである場合、式（Ｘ）の中間体を、式Ｒ^１−６ＮＣＯのイソシアネートと、ジクロロメタンなどの非プロトン性溶媒中で反応させる。右のＲ^１−３がアルキルであるか、または、Ｒ^１−３およびＲ^１−６が環状構造中で組み合わされている場合、式（Ｘ）の中間体を式Ｒ^１−６Ｒ^１−３ＮＣＯＣｌのカルバモイルクロリドと、ジクロロメタンなどの非プロトン性溶媒中、トリエチルアミンまたは炭酸カリウムなどの塩基の存在下で反応させる。左のＲ^１−３がアルキルである式（Ｘ）の出発物質の使用は、Ｒ^１が

であり、左のＲ^１−３基がアルキルである、構造（Ｖｆ）のウレアの製造をもたらす。 Formula (Vf) [R ¹ is

A compound of formula (V)] can be prepared by the route shown in Reaction Scheme 8. When R ^{1-3 on the} right is H, the intermediate of formula (X) is reacted with an isocyanate of formula R ^1-6 NCO in an aprotic solvent such as dichloromethane. When R ^{1-3 on the} right is alkyl, or R ^1-3 and R ^1-6 are combined in a cyclic structure, the intermediate of formula (X) is represented by the formula R ^1-6 R ^{1- 3.} Reaction of carbamoyl chloride of NCOCl with an aprotic solvent such as dichloromethane in the presence of a base such as triethylamine or potassium carbonate. The use of a starting material of formula (X) wherein R ^{1-3 on the} left is alkyl is used when R ¹ is

Resulting in the preparation of a urea of structure (Vf), wherein the left R ^1-3 group is alkyl.

If an isocyanate of formula R ^1-6 NCO is not commercially available (and R ^1-3 is H on the right side), it can be represented by formula R ^1-6 NH ₂ , where R ^1-6 is aryl or heteroaryl. Can be conveniently prepared by treating phosgene, diphosgene or triphosgene with a suitable solvent such as ethyl acetate. When R ^1-6 is alkyl or substituted alkyl, the preferred method is to treat the corresponding alkyl halide or dialkyl sulfate with an inorganic cyanate. These methods, as well as others, are well known to those skilled in the art, examples SR Sandler and W. Karo "Organic Functional Group Preparations," vol 12, 2 nd ed., P 364-375, 1983, Academic Press and It is described in the literature cited there.

If a carbamoyl chloride of formula R ^1-6 R ^1-3 NCOCl cannot be purchased, the amine of formula R ^1-6 R ^1-3 NH can be converted to 0-4 with phosgene, diphosgene or triphosgene in a suitable solvent such as dichloromethane. It can be conveniently manufactured by processing at ℃. Optionally, N-benzyl protection of formula R ^1-6 R ^1-3 NCH ₂ (C ₅ H ₆ ) as described by MG Banwell, et al, J. Org. Chem. 2003, 68, 613-616. Amines can be reacted with triphosgene.

  Various compounds of formula (I) can also be prepared by conversion of compounds of formula (I) prepared by the schemes described above. These conversion methods are illustrated and illustrated below in Reaction Schemes 10-13.

Reaction scheme 10

  For example, the dimethylpyrrole compound of formula (Ij) is [2- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-4-yl] methylmethanesulfonate and 5-amino-N- (2, Prepared by coupling with 2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole-4-carboxamide as shown in Scheme 1. [2- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-4-yl] methylmethanesulfonate is obtained by combining (2-aminopyridin-4-yl) methanol with hexane-2,5-dione. It is prepared by coupling using a catalytic acid and then mesylating the alcohol produced. The dimethylpyrrole compound of formula (Ij) can be deprotected to give the compound of formula (Ia).

  The amine is then converted to an amide compound of formula (Ib), a sulfonamide of formula (Ic) or a urea of formula (Id), respectively, by reaction with an acid chloride, sulfonyl chloride or isocyanate as shown in Reaction Scheme 10. Can be converted.

Reaction scheme 11

  Furthermore, the chloro compound of formula (Ie) can be converted to the substituted amino compound of formula (If) by reacting with a base such as amine and pyridine at an elevated temperature in a sealed tube.

Reaction scheme 12

  Esters of formula (Ih) and substituted amides of formula (Ii) can be prepared from unsubstituted amides of formula (Ig) by a continuous reaction illustrated in Reaction Scheme 12. Reaction of amide (Ig) with dimethylformamide-dimethylacetal (DMF-DMA) in methanol yields an ester of formula (Ih); reaction of the ester with a substituted amine yields an amide of formula (Ii) Bring.

  In general, a desired salt of a compound of the invention can be prepared in situ during the final isolation and purification of the compound by means well known in the art. Alternatively, the desired salt can be prepared separately by reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. These methods are conventional and will be readily understood by those skilled in the art.

  In addition, sensitive or reactive groups of the compounds of the invention may require protection and deprotection during any of the above methods. Protecting groups can generally be added and removed by conventional methods well known in the art (see, eg, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999)).

  Through the use of the general scheme above and the selection of appropriate starting materials, the compounds of the invention can be prepared. In order to further illustrate the invention, the following specific examples are provided, but are not intended to limit the scope of the invention in any way.

A. Example
Abbreviations and Acronyms Throughout this disclosure, when the following abbreviations are used, they have the following meanings:

General Analytical Methods The structures of representative compounds of the present invention were confirmed using the following methods.
Electron impact mass spectrometry (EI-MS) was obtained on a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 μM coating; 30 mx 0.25 mm). The ion source was maintained at 250 ° C. and the spectrum was scanned from 50-800 amu at 2 seconds / scan.

High pressure liquid chromatography-electrospray mass spectrometry (LC-MS) was obtained using any of the following:
(A) equipped with quaternary pump, tunable wavelength detector set at 254 nm, YMC pro C-18 column (2 x 23 mm, 120A) and Finnigan LCQ ion trap mass spectrometer with electrospray ionization Hewlett-Packard 1100 HPLC. The spectrum was scanned from 120-1200 amu using variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. A gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL / min is used, with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. The total run time is 6.5 minutes.

Or
(B) Micromass LCZ single quadrupole with two Gilson 306 pumps, Gilson 215 Autosampler, Gilson diode array detector, YMC Pro C-18 column (2 x 23 mm, 120 A) and z-spray electrospray ionization Gilson HPLC system with mass spectrometer. The spectrum was scanned at 120-800 amu for 1.5 seconds. As an analog channel, ELSD (Evaporative Light Scattering Detector) data is also acquired. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. A gradient elution from 10% B to 90% over a 1.5 minute flow rate of 1.5 mL / min is used, with an initial hold of 0.5 minutes and a final hold at 90% B of 0.5 minutes. The total run time is 4.8 minutes. Pre-conversion valves are used for column conversion and regeneration.

Routine one-dimensional NMR spectroscopy is performed on a 400 MHz Varian Mercury-plus spectrometer. Samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs and transferred to 5 mm ID Wilmad NMR tubes. A spectrum was acquired at 293K. Chemical shifts are recorded in ppm scale, DMSO-d ₆ 2.49 ppm, CD ₃ CN 1.93 ppm, CD ₃ OD 3.30 ppm, CD ₂ Cl ₂ 5.32 ppm and CDCl ₃ 7.26 ppm etc. The appropriate solvent signal was referenced for the ¹ H spectrum.

Intermediate production
Intermediate A
Preparation of 5-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole-4-carboxamide

ジクロロメタン（１００ｍＬ）中のエチル５−アミノ−１−メチル−１Ｈ−ピラゾール−４−カルボキシレート（４.７ｇ、２７.７８）を、窒素下に、５００ｍＬのフラスコ中で撹拌し、ジ−ｔｅｒｔ−ブチルジカーボネート（７.８８ｇ、３６.１１ｍｍｏｌ）、続いてＮ,Ｎ−ジメチルピリジン−４−アミン（３３９ｍｇ、２.７８ｍｍｏｌ）を添加した。溶液を１６時間撹拌した。さらに５ｇのジ−ｔｅｒｔ−ブチルジカーボネートを添加し、溶液をさらに２時間撹拌した。非常に少量の出発物質しかこの時点で残らず、溶媒を蒸発させ、残渣を得、シリカゲルを使用して精製した。生成物をヘキサン中の０−８０％酢酸エチルのグラジエントで溶出し、表題の純粋な物質８.１ｇ（７９％）を得た。
¹H NMR (300 MHz, CD2Cl2-d₂) δ 7.85 (s, 1H), 4.25 (q, 2H), 2.68 (s, 3H), 1.40 (s, 18H), 1.30 (t, 3H); ES-MS m/z 370.0 [M+H]⁺, LCMS RT (分) 3.17. Step 1: Preparation of ethyl 5- [bis (tert-butoxycarbonyl) amino] -1-methyl-1H-pyrazole-4-carboxylate

Ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (4.7 g, 27.78) in dichloromethane (100 mL) was stirred in a 500 mL flask under nitrogen and di-tert- Butyl dicarbonate (7.88 g, 36.11 mmol) was added followed by N, N-dimethylpyridin-4-amine (339 mg, 2.78 mmol). The solution was stirred for 16 hours. An additional 5 g of di-tert-butyl dicarbonate was added and the solution was stirred for an additional 2 hours. There was very little starting material left at this point and the solvent was evaporated to give a residue that was purified using silica gel. The product was eluted with a gradient of 0-80% ethyl acetate in hexanes to give 8.1 g (79%) of the title pure material.
¹ H NMR (300 MHz, CD2Cl2-d ₂ ) δ 7.85 (s, 1H), 4.25 (q, 2H), 2.68 (s, 3H), 1.40 (s, 18H), 1.30 (t, 3H); ES- MS m / z 370.0 [M + H] ⁺ , LCMS RT (min) 3.17.

エタノール（１００ｍＬ）中のエチル５−［ビス（ｔｅｒｔ−ブトキシカルボニル）アミノ］−１−メチル−１Ｈ−ピラゾール−４−カルボキシレート（８.０ｇ、２１.６６ｍｍｏｌ）の溶液を、窒素下で撹拌し、水性１Ｎ水酸化ナトリウム（１０８ｍＬ）を添加した。得られた混合物を５０℃で６４時間撹拌し、外界温度に冷却し、次いで、真空で蒸発させた。２Ｎ水性ＨＣｌをゆっくりと添加することにより、ｐＨを５−６に調節した。生成物を、酢酸エチルで、次いで、ジクロロメタン中のイソプロパノールの２０％混合物で抽出した。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、次いで、トルエンを残渣に添加し、それを再度蒸発させ、すぐに次の段階に使用できる純粋な乾燥生成物３.５ｇ（６７％）を得た。
¹H NMR (300 MHz, CD3OD-d₄) δ 7.82 (s, 1H), 3.75 (s, 3H), 1.5 (s, 9H); ES-MS m/z 241.9 [M+H]⁺, LCMS RT (分) 1.81. Step 2: Preparation of 5-[(tert-butoxycarbonyl) amino] -1-methyl-1H-pyrazole-4-carboxylic acid

A solution of ethyl 5- [bis (tert-butoxycarbonyl) amino] -1-methyl-1H-pyrazole-4-carboxylate (8.0 g, 21.66 mmol) in ethanol (100 mL) was stirred under nitrogen. Aqueous 1N sodium hydroxide (108 mL) was added. The resulting mixture was stirred at 50 ° C. for 64 hours, cooled to ambient temperature and then evaporated in vacuo. The pH was adjusted to 5-6 by slowly adding 2N aqueous HCl. The product was extracted with ethyl acetate and then with a 20% mixture of isopropanol in dichloromethane. The combined extracts are dried (Na ₂ SO ₄ ) and evaporated in vacuo, then toluene is added to the residue, it is evaporated again and 3.5 g of pure dry product ready for use in the next step (67%) was obtained.
¹ H NMR (300 MHz, CD3OD-d ₄ ) δ 7.82 (s, 1H), 3.75 (s, 3H), 1.5 (s, 9H); ES-MS m / z 241.9 [M + H] ⁺ , LCMS RT (Minutes) 1.81.

無水ジメチルホルムアミド（２０ｍＬ）およびジクロロメタン（１ｍＬ）中の５−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−１−メチル−１Ｈ−ピラゾール−４−カルボン酸（１ｇ、４.１５ｍｍｏｌ）、２,２−ジフルオロ−１,３−ベンゾジオキソール−５−アミン（８６１ｍｇ、４.９７ｍｍｏｌ）、トリエチルアミン（１.１９ｍＬ、８.５５ｍｍｏｌ）および（１Ｈ−１,２,３−ベンゾトリアゾール−１−イルオキシ）（トリピロリジン−１−イル）ホスホニウムヘキサフルオロホスフェート（ＰｙＢＯＰ、２.１５ｇ、４.１５ｍｍｏｌ）を、６０℃で１２時間、窒素下で撹拌し、次いで冷却した。得られた溶液を酢酸エチルで希釈し、水で、次いで飽和塩水で洗浄した。有機層を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させた。得られた残渣を、シリカゲルを使用して、ヘキサン中の０−１００％酢酸エチルでクロマトグラフィーし、ｔｅｒｔ−ブチル（４−｛［（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）アミノ］カルボニル｝−１−メチル−１Ｈ−ピラゾール−５−イル）カルバメート（５００ｍｇ、純度＞６０％）を得、それをジクロロメタン（５ｍＬ）およびトリフルオロ酢酸（３ｍＬ）に溶解し、窒素下で２時間撹拌し、真空で蒸発させた。残渣を酢酸エチル中で溶解し、飽和水性ＮａＨＣＯ_３で洗浄した。有機相を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、シリカゲルを使用してヘキサン中の０−８０％酢酸エチルで精製し、表題化合物２５０ｍｇを得た。
¹H NMR (300 MHz, CD₃OD-d₄) δ 7.85 (bs, 1H), 7.70 (s, 1H), 7.25 (dd, 1H), 7.10(dd, 1H), 3.60 (s, 3H); ES-MS m/z 297.2 [M+H]⁺, LCMS RT (分) 3.03. Step 3: Preparation of 5-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole-4-carboxamide

5-[(tert-Butoxycarbonyl) amino] -1-methyl-1H-pyrazole-4-carboxylic acid (1 g, 4.15 mmol), 2,2-difluoro in anhydrous dimethylformamide (20 mL) and dichloromethane (1 mL) -1,3-benzodioxol-5-amine (861 mg, 4.97 mmol), triethylamine (1.19 mL, 8.55 mmol) and (1H-1,2,3-benzotriazol-1-yloxy) (tri Pyrrolidin-1-yl) phosphonium hexafluorophosphate (PyBOP, 2.15 g, 4.15 mmol) was stirred at 60 ° C. for 12 hours under nitrogen and then cooled. The resulting solution was diluted with ethyl acetate and washed with water and then saturated brine. The organic layer was dried (Na ₂ SO ₄ ) and evaporated in vacuo. The resulting residue was chromatographed on silica gel with 0-100% ethyl acetate in hexane to give tert-butyl (4-{[(2,2-difluoro-1,3-benzodioxole- 5-yl) amino] carbonyl} -1-methyl-1H-pyrazol-5-yl) carbamate (500 mg, purity> 60%) was obtained, which was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 mL), Stir for 2 hours under nitrogen and evaporate in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO ₃ . The organic phase was dried (Na ₂ SO ₄ ), evaporated in vacuo and purified with 0-80% ethyl acetate in hexane using silica gel to give 250 mg of the title compound.
¹ H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 7.85 (bs, 1H), 7.70 (s, 1H), 7.25 (dd, 1H), 7.10 (dd, 1H), 3.60 (s, 3H); ES-MS m / z 297.2 [M + H] ⁺ , LCMS RT (min) 3.03.

この中間体は、上記の中間体Ａの製造方法の使用により、しかし、段階３で２,２−ジフルオロ−１,３−ベンゾジオキソール−５−アミンではなく２,２,３,３−テトラフルオロ−２,３−ジヒドロ−１,４−ベンゾジオキシン−６−アミンを使用して製造できる。純粋な生成物をＮＭＲおよびＬＣＭＳ分光法により特徴解析する。 Intermediate B
Preparation of 5-amino-1-methyl-N- (2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) -1H-pyrazole-4-carboxamide

This intermediate is obtained by using the method for preparing intermediate A described above, but in step 3, 2,2,3,3-rather than 2,2-difluoro-1,3-benzodioxol-5-amine. It can be prepared using tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-amine. The pure product is characterized by NMR and LCMS spectroscopy.

この中間体は、上記の中間体Ａの製造方法の使用により、しかし、段階３で２,２−ジフルオロ−１,３−ベンゾジオキソール−５−アミンではなく２,２,４,４−テトラフルオロ−４Ｈ−１,３−ベンゾジオキシン−６−アミンを使用して製造できる。 Intermediate B-2
Preparation of 5-amino-1-methyl-N- (2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl) -1H-pyrazole-4-carboxamide

This intermediate is obtained by using the process for preparing intermediate A described above, but 2,2,4,4-4 instead of 2,2-difluoro-1,3-benzodioxol-5-amine in step 3. It can be prepared using tetrafluoro-4H-1,3-benzodioxin-6-amine.

この中間体は、上記の中間体Ａの製造方法の使用により、しかし、段階３で２,２−ジフルオロ−１,３−ベンゾジオキソール−５−アミンではなく４−（トリフルオロメトキシ）アニリンを使用して製造できる。 Intermediate B-3
Preparation of 5-amino-1-methyl-N- [4- (trifluoromethoxy) phenyl] -4,5-dihydro-1H-pyrazole-4-carboxamide

This intermediate is obtained by use of the process for preparing intermediate A above, but in step 3, 4- (trifluoromethoxy) aniline rather than 2,2-difluoro-1,3-benzodioxol-5-amine. Can be manufactured using.

この中間体は、上記の中間体Ａの製造方法の使用により、しかし、段階３で２,２−ジフルオロ−１,３−ベンゾジオキソール−５−アミンではなく３−（トリフルオロメトキシ）アニリンを使用して製造できる。 Intermediate B-4
Preparation of 5-amino-1-methyl-N- [3- (trifluoromethoxy) phenyl] -4,5-dihydro-1H-pyrazole-4-carboxamide

This intermediate is obtained by using the method for preparing intermediate A described above, but 3- (trifluoromethoxy) aniline rather than 2,2-difluoro-1,3-benzodioxol-5-amine in step 3. Can be manufactured using.

この中間体は、上記の中間体Ａの製造方法の使用により、しかし、段階４で２,２−ジフルオロ−１,３−ベンゾジオキソール−５−アミンではなく４−［（トリフルオロメチル）チオ］を使用して製造できる。 Intermediate B-5
Preparation of 5-amino-1-methyl-N- {4-[(trifluoromethyl) thio] phenyl} -1H-pyrazole-4-carboxamide

This intermediate is obtained by using the method for preparing intermediate A described above, but in step 4, instead of 2,2-difluoro-1,3-benzodioxol-5-amine, 4-[(trifluoromethyl) Thio] can be used.

Intermediate C
Preparation of [2- (aminocarbonyl) pyridin-4-yl] methylmethanesulfonate

ホルムアミド（２００ｍＬ）中のエチルイソニコチネート（２５.２ｍＬ、１６５ｍｍｏｌ）の溶液を、氷／メタノール浴冷却しながら撹拌し、濃硫酸（８.８０ｍＬ、１６５ｍｍｏｌ）を添加した。硫酸鉄七水和物（６９ｇ、２４８ｍｍｏｌ）および過酸化水素（２５.６ｍＬ、３０％、水中）をゆっくりと２５分間かけて交互に添加し、混合物の温度が８−１０.５℃に維持されるようにした。この添加の間に、ドライアイスの小片を浴に添加し、反応温度を所望の範囲に維持した。添加完了後、氷浴を除去し、暗色の混合物を２時間冷却せずに撹拌した。次いで、混合物を、水（７００ｍＬ）中のクエン酸三ナトリウム二水和物（８０.６ｇ）の溶液に注ぎ、次いで、反応フラスコ中に残った残渣を少量のメタノールおよび水で洗浄した。得られた混合物を大型フラスコ中で迅速に撹拌し、固体のＮａＨＣＯ_３をゆっくりと少しずつ、混合物が塩基性になるまで添加した。いくらかの飽和水性ＮａＨＣＯ_３を添加して混合物をより塩基性にし、次いで、Celite^{（登録商標）}を通して真空濾過し、固体を２００ｍＬ分のジクロロメタンで３回洗浄した。濾液の相を分離し、水層をジクロロメタンで２回抽出した。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させた。得られた固体残渣をエーテル／ヘキサン（２００ｍＬ、１：３０）で、加温および超音波処理しながら２回洗浄し、続いて冷却および濾過し、純粋な表題化合物１３.９ｇ（４４％）を得た。幾分多くの混入した所望の生成物を含有する洗浄溶液を廃棄した。
¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (d, 1H), 8.39 (d, 1H, メタカップリング), 8.24 (bs, 1H), 8.00 (d, 1H), 7.81 (bs, 1H), 4.39 (q, 2H) および 1.37 ppm (t, 3H); ES-MS m/z 195.0 [M+H]⁺, HPLC RT (分) 1.83. Step 1: Preparation of ethyl 2- (aminocarbonyl) isonicotinate

A solution of ethylisonicotinate (25.2 mL, 165 mmol) in formamide (200 mL) was stirred with ice / methanol bath cooling and concentrated sulfuric acid (8.80 mL, 165 mmol) was added. Iron sulfate heptahydrate (69 g, 248 mmol) and hydrogen peroxide (25.6 mL, 30%, in water) were slowly added alternately over 25 minutes to maintain the temperature of the mixture at 8-10. 5 ° C. It was to so. During this addition, a piece of dry ice was added to the bath to maintain the reaction temperature in the desired range. After the addition was complete, the ice bath was removed and the dark mixture was stirred without cooling for 2 hours. The mixture was then poured into a solution of trisodium citrate dihydrate (80.6 g) in water (700 mL) and then the residue remaining in the reaction flask was washed with a small amount of methanol and water. The resulting mixture was rapidly stirred in a large flask and solid NaHCO ₃ was added slowly in small portions until the mixture was basic. Some saturated aqueous NaHCO ₃ mixture was added to more basic, then vacuum filtered through ^{Celite (R)} and the solids were washed 3 times with dichloromethane 200mL minute. The filtrate phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo. The resulting solid residue was washed twice with ether / hexane (200 mL, 1:30) with warming and sonication followed by cooling and filtration to give 13.9 g (44%) of the pure title compound. Obtained. The wash solution containing some more contaminated desired product was discarded.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.83 (d, 1H), 8.39 (d, 1H, metacoupling), 8.24 (bs, 1H), 8.00 (d, 1H), 7.81 (bs, 1H ), 4.39 (q, 2H) and 1.37 ppm (t, 3H); ES-MS m / z 195.0 [M + H] ⁺ , HPLC RT (min) 1.83.

無水エタノール（１５０ｍＬ）中のエチル２−（アミノカルボニル）イソニコチネート（５.００ｇ、２５.８ｍｍｏｌ）を窒素下で撹拌し、水素化ホウ素ナトリウム（２.９２ｇ、７７.２ｍｍｏｌ）を添加した。外界温度で２２時間撹拌した後、飽和水性塩化アンモニウム１７ｍＬの添加により反応を注意深くクエンチし、続いて発泡が停止するまで撹拌し、次いで、真空で蒸発させ、白色の固体残渣を残した。飽和水性塩化ナトリウム（８０ｍＬ）を添加し、続いて、２００ｍＬ分の酢酸エチルで５回抽出した。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、純粋な表題化合物３.８５ｇ（９８％）を白色固体として得た。
¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (d, 1H), 8.00 (s, 1H), 8.07 (bs, 1H), 7.46 (d, 1H), 7.60 (bs, 1H), 5.54 (t, 1H) および 4.60 ppm (d, 2H); ES-MS m/z 154.0 [M+H, 弱いシグナル]⁺, HPLC RT (分) 1.05. Step 2: Preparation of 4- (hydroxymethyl) pyridine-2-carboxamide

Ethyl 2- (aminocarbonyl) isonicotinate (5.00 g, 25.8 mmol) in absolute ethanol (150 mL) was stirred under nitrogen and sodium borohydride (2.92 g, 77.2 mmol) was added. After stirring at ambient temperature for 22 hours, the reaction was carefully quenched by the addition of 17 mL of saturated aqueous ammonium chloride, followed by stirring until effervescence ceased, then evaporated in vacuo leaving a white solid residue. Saturated aqueous sodium chloride (80 mL) was added followed by extraction 5 times with 200 mL portions of ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 3.85 g (98%) of the pure title compound as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (d, 1H), 8.00 (s, 1H), 8.07 (bs, 1H), 7.46 (d, 1H), 7.60 (bs, 1H), 5.54 ( t, 1H) and 4.60 ppm (d, 2H); ES-MS m / z 154.0 [M + H, weak signal] ⁺ , HPLC RT (min) 1.05.

４−（ヒドロキシメチル）ピリジン−２−カルボキサミド（１.００ｇ、６.５７ｍｍｏｌ）を、酢酸エチル（８０ｍＬ）に溶解し、次いで窒素下に氷浴中で撹拌しながら０℃に冷却し、その後トリエチルアミン（１.３７ｍＬ、９.８６ｍｍｏｌ）を添加し、続いてメタンスルホニルクロリド（０.６６ｍＬ、８.５４ｍｍｏｌ、７分間かけて滴下して添加する）を添加した。氷浴を除去し、得られた懸濁液を２時間撹拌し、次いで、反応混合物を水６０ｍＬに注ぎ、迅速に１０分間撹拌した。相を分離し、水相をさらに２回酢酸エチルで抽出した。各抽出物を塩水で洗浄し、合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、純粋な生成物１.５０ｇ（９９％）を細かい白色の固体として得、それは、保存すると桃色になった。そのような色の変化後のＮＭＲによる再アッセイは、有意な分解を示さなかった。
¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (d, 1H), 8.06 (s, 1H), 8.14 (bs, 1H), 7.6 (d, 1H), 7.70 (bs, 1H), 5.41 (s, 2H) および 3.33 ppm (s, 溶媒中の水と重複する). Step 3: Preparation of [2- (aminocarbonyl) pyridin-4-yl] methyl methanesulfonate

4- (Hydroxymethyl) pyridine-2-carboxamide (1.00 g, 6.57 mmol) was dissolved in ethyl acetate (80 mL) and then cooled to 0 ° C. with stirring in an ice bath under nitrogen, followed by triethylamine. (1.37 mL, 9.86 mmol) was added followed by methanesulfonyl chloride (0.66 mL, 8.54 mmol, added dropwise over 7 minutes). The ice bath was removed and the resulting suspension was stirred for 2 hours, then the reaction mixture was poured into 60 mL of water and stirred rapidly for 10 minutes. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. Each extract was washed with brine and the combined extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 1.50 g (99%) of pure product as a fine white solid that was stored Then it turned pink. Re-assay by NMR after such a color change showed no significant degradation.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (d, 1H), 8.06 (s, 1H), 8.14 (bs, 1H), 7.6 (d, 1H), 7.70 (bs, 1H), 5.41 ( s, 2H) and 3.33 ppm (s, overlapping with water in the solvent).

この化合物は、中間体Ｃについて上記した方法を使用して、しかし、段階１においてホルムアミドではなくメチルホルムアミドで出発して、そして、段階３でメタンスルホニルクロリドではなくメタンスルホン酸無水物を用いて製造した。
¹H NMR (300 MHz, DMSO-d₆) δ 8.80 (bs, 1H), 8.64 (d, 1H), 8.03 (s, 1H), 7.58 (d, 1H), 5.41 (s, 2H), 3.29 (s, 3H) および 2.80 ppm (d, 3H); ES-MS m/z 145.1 [M+H]⁺, HPLC RT (分) 1.43. Intermediate D
Preparation of {2-[(methylamino) carbonyl] pyridin-4-yl} methylmethanesulfonate

This compound is prepared using the method described above for Intermediate C, but starting with methylformamide instead of formamide in Step 1 and using methanesulfonic anhydride instead of methanesulfonyl chloride in Step 3. did.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.80 (bs, 1H), 8.64 (d, 1H), 8.03 (s, 1H), 7.58 (d, 1H), 5.41 (s, 2H), 3.29 ( s, 3H) and 2.80 ppm (d, 3H); ES-MS m / z 145.1 [M + H] ⁺ , HPLC RT (min) 1.43.

Intermediate E
Preparation of 2-{[4- (chloromethyl) pyridin-2-yl] amino} -2-oxoethyl acetate

（２−アミノピリジン−４−イル）メタノール（１１.２ｇ、９０ｍｍｏｌ）を、氷浴で冷却しながらフラスコ中で撹拌し、塩化チオニル（６５.８ｍＬ、９０２ｍｍｏｌ）をゆっくりと添加した。約１０ｍＬを添加した後、温度が突然約５０℃に上昇し、添加を停止した。撹拌を継続できるように混合物を破砕し、塩化チオニルの残りを添加した。次いで、冷却浴を除去し、反応を２時間外界温度で撹拌し、その後真空で蒸発させ、次いで、トルエンを２回添加し、各回真空で蒸発させ、表題化合物の塩酸塩を得た。ジクロロメタン（１５０ｍＬ）中のこの物質の懸濁液を飽和水性重炭酸ナトリウム（１５０ｍＬ）と共に１.５時間撹拌した。相を分離し、有機抽出物を２回水で、１回塩水で洗浄し、次いで乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、純粋な表題化合物１０.７１ｇ（８３％）を得た。
¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, 1H), 6.48 (d, 1H), 6.45 (s, 1H), 6.04 (s, 2H) および 4.60 ppm (s, 2H); ES-MS m/z 143.2 [M+H]⁺, HPLC RT (分) 1.34. Step 1: Preparation of 4- (chloromethyl) pyridin-2-amine

(2-Aminopyridin-4-yl) methanol (11.2 g, 90 mmol) was stirred in the flask while cooling with an ice bath and thionyl chloride (65.8 mL, 902 mmol) was added slowly. After adding about 10 mL, the temperature suddenly rose to about 50 ° C. and the addition was stopped. The mixture was crushed so that stirring could continue and the remainder of thionyl chloride was added. The cooling bath was then removed and the reaction was stirred for 2 hours at ambient temperature, then evaporated in vacuo, then toluene was added twice and evaporated in vacuo each time to give the hydrochloride salt of the title compound. A suspension of this material in dichloromethane (150 mL) was stirred with saturated aqueous sodium bicarbonate (150 mL) for 1.5 hours. The phases were separated and the organic extract was washed twice with water, once with brine, then dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 10.71 g (83%) of the pure title compound. .
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.87 (d, 1H), 6.48 (d, 1H), 6.45 (s, 1H), 6.04 (s, 2H) and 4.60 ppm (s, 2H); ES -MS m / z 143.2 [M + H] ⁺ , HPLC RT (min) 1.34.

ジクロロエタン（１０ｍＬ）中の４−（クロロメチル）ピリジン−２−アミン（２.５０ｇ、１０ｍｍｏｌ）およびトリエチルアミン（１１.７ｍＬ）の懸濁液を窒素下に氷浴で冷却しながら撹拌し、アセトキシアセチルクロリド（１.８６ｍＬ、１７ｍｍｏｌ）をゆっくりと１０分間かけて添加した。冷却しながら２時間撹拌した後、ＴＬＣは、出発物質を示さなかったが、３つの主要な生成物のスポットを示した。混合物をジクロロメタンで希釈し、水で、次いで塩水で洗浄した。それを乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させた。残渣をシリカゲルのクロマトグラフィーにより、ジクロロメタン中の０−３％メタノールのグラジエントを使用して精製し、正しく純粋な表題化合物０.６２ｇ（１８％）を得た。
¹H NMR (300 MHz, DMSO-d₆) δ 10.75 (s, 1H), 8.30 (d, 1H), 8.10 (bs, 1H), 7.17 (d, 1H), 4.79 (s, 2H), 4.71 (s, 2H) および 2.13 ppm (s, 3H); ES-MS m/z 243.1 [M+H]⁺, HPLC RT (分) 1.87. Step 2: Preparation of 2-{[4- (chloromethyl) pyridin-2-yl] amino} -2-oxoethyl acetate

A suspension of 4- (chloromethyl) pyridin-2-amine (2.50 g, 10 mmol) and triethylamine (11.7 mL) in dichloroethane (10 mL) was stirred with cooling in an ice bath under nitrogen to produce acetoxyacetyl. Chloride (1.86 mL, 17 mmol) was added slowly over 10 minutes. After stirring for 2 hours with cooling, TLC showed no starting material but three major product spots. The mixture was diluted with dichloromethane and washed with water then brine. It was dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-3% methanol in dichloromethane to give 0.62 g (18%) of the correctly pure title compound.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.75 (s, 1H), 8.30 (d, 1H), 8.10 (bs, 1H), 7.17 (d, 1H), 4.79 (s, 2H), 4.71 ( s, 2H) and 2.13 ppm (s, 3H); ES-MS m / z 243.1 [M + H] ⁺ , HPLC RT (min) 1.87.

中間体Ｅの製造について記載した方法の使用により、そして、段階２においてアセトキシアセチルクロリドの代わりにアセチルクロリドを用いることにより、４−（クロロメチル）ピリジン−２−アミン２.３０ｇおよび釣り合う量の他の物質から中間体Ｆを製造した。表題化合物の収量は、シリカゲルクロマトグラフィーの後、２.０ｇ（６７％）であった。たとえ、ＮＭＲ分光法によるこの物質の調査が、それが所望の化合物とジアシル化生成物のＮ−アセチル−Ｎ−［４−（クロロメチル）ピリジン−２−イル］アセトアミドの混合物（約４５：５５）であることを示したとしても、それをそのまま次の反応で使用し、副生成物を後続の反応の後にクロマトグラフィーにより分離した。
¹H NMR (300 MHz, CD₂Cl₂) δ 8.33 (bs, 1H), 7.41 (d, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 4.65 (s, 2H) および 2.20 ppm (s, 3H); ES-MS m/z 185.0 [M+H]⁺, HPLC RT (分) 1.16. 混入しているジアシル化合物のシグナルは、¹H NMR (300 MHz, CD₂Cl₂) δ 8.56 (d, 1H), 8.18 (s, 1H), 78.24 (d, 1H), 4.75 (s, 2H) および 2.25 ppm (s, 6H); ES-MS m/z 有意な M+H⁺イオンなし、HPLC RT (分) 0.97 を示す。２種の化合物の％含有量が近接しているため、ＮＭＲピークのいくつかの割当てを所望の物質と混入物の間で入れ換えることが可能である。 Intermediate F
Production of N- [4- (chloromethyl) pyridin-2-yl] acetamide

By using the method described for the preparation of intermediate E and by using acetyl chloride instead of acetoxyacetyl chloride in step 2, 2.30 g of 4- (chloromethyl) pyridin-2-amine and other commensurate amounts Intermediate F was prepared from this material. The yield of the title compound was 2.0 g (67%) after silica gel chromatography. Even if an investigation of this material by NMR spectroscopy shows that it is a mixture of the desired compound and the diacylated product N-acetyl-N- [4- (chloromethyl) pyridin-2-yl] acetamide (about 45:55 ) Was used as such in the next reaction and the by-product was chromatographed after the subsequent reaction.
¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 8.33 (bs, 1H), 7.41 (d, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 4.65 (s, 2H) and 2.20 ppm (s, 3H); ES-MS m / z 185.0 [M + H] ⁺ , HPLC RT (min) 1.16. The signal of the contaminating diacyl compound is ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 8.56 (d, 1H), 8.18 (s, 1H), 78.24 (d, 1H), 4.75 (s, 2H) and 2.25 ppm (s, 6H); ES-MS m / z without significant M + H ⁺ ions , HPLC RT (min) 0.97 is shown. Due to the close percentage content of the two compounds, it is possible to swap several assignments of NMR peaks between the desired material and contaminants.

中間体Ｅの製造について記載した方法の使用により、そして、段階２においてアセトキシアセチルクロリドの代わりに２−メトキシアセチルクロリドを用いることにより、４−（クロロメチル）ピリジン−２−アミン７３１ｍｇおよび釣り合う量の他の物質から中間体Ｇを製造した。純粋な表題化合物の収量は、ヘキサン中の０−４０％酢酸エチルのグラジエントを使用するシリカゲルクロマトグラフィーの後、３９７ｍｇ（４５％）であった。
¹H NMR (300 MHz, CDCl₃) δ 9.00 (bs, 1H), 8.31 (d, 1H), 8.30 (s, 1H), 7.13 (d, 1H), 4.55 (s, 2H), 4.06 (s, 2H) および 3.51 ppm (s, 3H); ES-MS m/z 215.0 [M+H]⁺, HPLC RT (分) 0.71. Intermediate G
Production of N- [4- (chloromethyl) pyridin-2-yl] -2-methoxyacetamide

By using the method described for the preparation of intermediate E and by using 2-methoxyacetyl chloride instead of acetoxyacetyl chloride in step 2, 731 mg 4- (chloromethyl) pyridin-2-amine and a balanced amount Intermediate G was prepared from other materials. The yield of pure title compound was 397 mg (45%) after silica gel chromatography using a gradient of 0-40% ethyl acetate in hexane.
¹ H NMR (300 MHz, CDCl ₃ ) δ 9.00 (bs, 1H), 8.31 (d, 1H), 8.30 (s, 1H), 7.13 (d, 1H), 4.55 (s, 2H), 4.06 (s, 2H) and 3.51 ppm (s, 3H); ES-MS m / z 215.0 [M + H] ⁺ , HPLC RT (min) 0.71.

中間体Ｅの製造について記載した方法の使用により、そして、段階２においてアセトキシアセチルクロリドの代わりに２−（２−メトキシエトキシ）アセチルクロリドを用いることにより、４−（クロロメチル）ピリジン−２−アミン５９９ｍｇおよび釣り合う量の他の物質から中間体Ｈを製造した。純粋な表題化合物の収量は、２回のシリカゲルクロマトグラフィー（最初にジクロロメタン中の２−３％メタノールのグラジエントを使用し、次いで、最良の画分の２回目のクロマトグラフィーでは、ヘキサン中の酢酸エチル０−４０％のグラジエントを使用する）の後、３１４ｍｇ（２９％）であった。
¹H NMR (300 MHz, CD₂Cl₂) δ 9.39 (bs, 1H), 8.30 (d, 1H), 8.29 (s, 1H), 7.13 (d, 1H), 4.59 (s, 2H), 4.14 (s, 2H), 3.76 (t, 2H), 3.60 (t, 2H) および 3.44 ppm (s, 3H); ES-MS m/z 259.1 [M+H]⁺, HPLC RT (分) 1.46. Intermediate H
Production of N- [4- (chloromethyl) pyridin-2-yl] -2- (2-methoxyethoxy) acetamide

4- (Chloromethyl) pyridin-2-amine by using the method described for the preparation of intermediate E and by substituting 2- (2-methoxyethoxy) acetyl chloride for acetoxyacetyl chloride in step 2. Intermediate H was prepared from 599 mg and other amounts of other materials. The yield of pure title compound was obtained by two silica gel chromatography (first using a gradient of 2-3% methanol in dichloromethane, then the second fraction of the best fraction was ethyl acetate in hexane. After using 0-40% gradient), it was 314 mg (29%).
¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 9.39 (bs, 1H), 8.30 (d, 1H), 8.29 (s, 1H), 7.13 (d, 1H), 4.59 (s, 2H), 4.14 ( s, 2H), 3.76 (t, 2H), 3.60 (t, 2H) and 3.44 ppm (s, 3H); ES-MS m / z 259.1 [M + H] ⁺ , HPLC RT (min) 1.46.

Intermediate I
Production of N- [4- (chloromethyl) pyridin-2-yl] -2-methoxypropanamide

メタノール（２５％、１６ｍＬ）中のナトリウムメトキシドを、メタノール（５ｍＬ）中の２−ブロモプロピオン酸（１９.６ｍｍｏｌ）の撹拌溶液に窒素下で添加した。反応を５０℃で窒素下に終夜加熱した。次いで、反応を真空下で濃縮した。残渣を１Ｎ水性ＨＣｌの添加によりｐＨ１とし、次いで、この溶液を酢酸エチルで３回（７０ｍＬ、２５ｍＬ、１０ｍＬ）抽出した。合わせた有機層を乾燥し（Ｎａ_２ＳＯ_４）、次いで真空下で濃縮し、表題化合物を無色油状物２.０４ｇ（９９％）として得た。それは、精製せずに使用するのに十分な純度であった。¹H NMR (CD₃OD) δ 3.67 (q, 1H), 3.33 (s, 3H), および 1.33 ppm (d, 3H). Step 1: Preparation of 2-methoxypropanoic acid

Sodium methoxide in methanol (25%, 16 mL) was added to a stirred solution of 2-bromopropionic acid (19.6 mmol) in methanol (5 mL) under nitrogen. The reaction was heated at 50 ° C. under nitrogen overnight. The reaction was then concentrated under vacuum. The residue was brought to pH 1 by addition of 1N aqueous HCl and then the solution was extracted three times with ethyl acetate (70 mL, 25 mL, 10 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and then concentrated in vacuo to give the title compound as a colorless oil, 2.04 g (99%). It was pure enough to be used without purification. ¹ H NMR (CD ₃ OD) δ 3.67 (q, 1H), 3.33 (s, 3H), and 1.33 ppm (d, 3H).

２−メトキシプロパン酸（２.０４ｇ、１９.２ｍｍｏｌ）を、ジクロロメタン（３ｍＬ）に溶解し、それを窒素下で撹拌し、ジメチルホルムアミド１滴を添加した。塩化チオニルを反応に３分間かけて滴下して添加し、次いで、反応を室温で終夜撹拌した。反応溶液を真空で濃縮し、得られる淡黄色油状物を高真空下に置き、塩化チオニル最後の痕跡を除去した。純粋な表題化合物の収量は、３０３ｍｇ（１３％）であった。¹HNMR (CDCl₃) δ 4.10 (q, 1H), 3.48 (s, 3H), および 1.56 ppm (d, 3H). Step 2: Preparation of 2-methoxypropanoyl chloride

2-Methoxypropanoic acid (2.04 g, 19.2 mmol) was dissolved in dichloromethane (3 mL), it was stirred under nitrogen and 1 drop of dimethylformamide was added. Thionyl chloride was added dropwise to the reaction over 3 minutes and then the reaction was stirred at room temperature overnight. The reaction solution was concentrated in vacuo and the resulting pale yellow oil was placed under high vacuum to remove the last traces of thionyl chloride. The yield of pure title compound was 303 mg (13%). ¹ HNMR (CDCl ₃ ) δ 4.10 (q, 1H), 3.48 (s, 3H), and 1.56 ppm (d, 3H).

中間体Ｅの製造について記載した方法（段階２）の使用により、そして、アセトキシアセチルクロリドの代わりに２−メトキシプロパノイルクロリドを用いることにより、４−（クロロメチル）ピリジン−２−アミン３５２ｍｇおよび釣り合う量の他の物質から中間体Ｉを製造した。純粋な表題化合物の収量は、ヘキサン中の０−３０％酢酸エチルのグラジエントを使用するシリカゲルクロマトグラフィーの後に、３４１ｍｇ（６０％）であった。
¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (bs, 1H), 8.30 (d, 1H), 8.17 (s, 1H), 7.16 (d, 1H), 4.77 (s, 2H), 4.00 (q, 1H), 3.26 (s, 3H), および 1.27 ppm (d, 6H). Step 3: Preparation of N- [4- (chloromethyl) pyridin-2-yl] -2-methoxypropanamide

Balance with 352 mg of 4- (chloromethyl) pyridin-2-amine by using the method described for the preparation of intermediate E (step 2) and by using 2-methoxypropanoyl chloride instead of acetoxyacetyl chloride Intermediate I was prepared from quantities of other materials. The yield of pure title compound was 341 mg (60%) after silica gel chromatography using a gradient of 0-30% ethyl acetate in hexane.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.2 (bs, 1H), 8.30 (d, 1H), 8.17 (s, 1H), 7.16 (d, 1H), 4.77 (s, 2H), 4.00 ( q, 1H), 3.26 (s, 3H), and 1.27 ppm (d, 6H).

Intermediate J
N- [4- (Chloromethyl) pyridin-2-yl] -2-methoxy-2-methylpropanamide

出典明示により本明細書の一部とする JACS 70,1153 (1948) に記載の Weizmann, Sulzbacher および Bergmann の方法を、以下の通りに使用した：水５ｍＬおよびメタノール２０ｍＬ中の水酸化カリウム（８.９６ｇ、１５９.７ｍｍｏｌ）の溶液を、窒素下に氷浴で冷却しながら撹拌し、１,１,１−トリクロロ−２−メチルプロパン−２−オール（７.１０ｇ、４０.０ｍｍｏｌ）を注意深く１０分間かけて滴下して添加した。白色沈殿が形成される際、激しい発泡が観察された。１５分後に氷浴を除去した。反応を室温で２時間撹拌し、次いで３時間還流した。反応を室温に冷却し、次いで、固体を濾過により除去し、メタノール（３５０ｍＬ）ですすいだ。濾液を真空下で濃縮してメタノールを除去し、残っている水層を水性ＨＣｌの添加によりｐＨ０にし、次いで、酢酸エチル（３００ｍＬ）で抽出した。抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で濃縮し、粗生成物４.１１ｇを得た。それを減圧蒸留により精製し、純粋な表題化合物２.２８ｇ（４８％）を無色油状物として得た。それを１０５℃（２８ｍｍＨｇ）で蒸留した。¹HNMR (CDCl₃) δ 9.65 (s, 1H), 3.20 (s, 3H) および 1.32 ppm (s, 6H). Step 1: Preparation of 2-methoxy-2-methylpropanoic acid

The method of Weizmann, Sulzbacher and Bergmann described in JACS 70,1153 (1948), which is hereby incorporated by reference, was used as follows: potassium hydroxide in 5 mL water and 20 mL methanol (8. A solution of 96 g, 159.7 mmol) was stirred while cooling with an ice bath under nitrogen, and 1,1,1-trichloro-2-methylpropan-2-ol (7.10 g, 40.0 mmol) was carefully added. Added dropwise over a period of minutes. Vigorous foaming was observed when a white precipitate was formed. The ice bath was removed after 15 minutes. The reaction was stirred at room temperature for 2 hours and then refluxed for 3 hours. The reaction was cooled to room temperature and then the solid was removed by filtration and rinsed with methanol (350 mL). The filtrate was concentrated in vacuo to remove methanol and the remaining aqueous layer was brought to pH 0 by addition of aqueous HCl and then extracted with ethyl acetate (300 mL). The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 4.11 g of crude product. It was purified by distillation under reduced pressure to give 2.28 g (48%) pure title compound as a colorless oil. It was distilled at 105 ° C. (28 mmHg). ¹ HNMR (CDCl ₃ ) δ 9.65 (s, 1H), 3.20 (s, 3H) and 1.32 ppm (s, 6H).

中間体Ｉの方法（段階２）に従い、しかし、２−メトキシプロパン酸ではなく２−メトキシ−２−メチルプロパン酸（６.９９ｇ、５９.２ｍｍｏｌ）および釣り合う量の他の物質を使用することにより、表題化合物を合成した。粗生成物を減圧蒸留し、純粋な化合物２.６７１ｇ（３３％）、ｂｐ４４−４８℃（３８ｍｍＨｇ）を得た。
1HNMR (CDCl₃) δ 3.33 (s, 3H) および 1.51 ppm (s, 6H). Step 2: Preparation of 2-methoxy-2-methylpropanoyl chloride

According to the method of Intermediate I (Step 2) but using 2-methoxy-2-methylpropanoic acid (6.99 g, 59.2 mmol) and other materials in proportions instead of 2-methoxypropanoic acid The title compound was synthesized. The crude product was distilled under reduced pressure to obtain 2.671 g (33%) of pure compound, bp 44-48 ° C. (38 mmHg).
1HNMR (CDCl ₃ ) δ 3.33 (s, 3H) and 1.51 ppm (s, 6H).

中間体Ｅの製造について記載した方法（段階２）の使用により、そして、アセトキシアセチルクロリドの代わりに２−メトキシ−２−メチルプロパノイルクロリドを用いることにより、４−（クロロメチル）ピリジン−２−アミン１.０４ｇおよび釣り合う量の他の物質から、中間体Ｊを製造した。表題化合物の収量は、ヘキサン中の３０％酢酸エチルを使用するシリカゲルクロマトグラフィーの後、１.２３ｇ（６９％）であった。
¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (bs, 1H), 8.32 (d, 1H), 8.16 (s, 1H), 7.19 (d, 1H), 4.78 (s, 2H), 3.28 (s, 3H) および 1.36 ppm (s, 6H); ES-MS m/z 243.1 [M+H]⁺, HPLC RT (分) 2.12. Step 3: Preparation of N- [4- (chloromethyl) pyridin-2-yl] -2-methoxy-2-methylpropanamide

By using the method described for the preparation of intermediate E (step 2) and substituting 2-methoxy-2-methylpropanoyl chloride for acetoxyacetyl chloride, 4- (chloromethyl) pyridine-2- Intermediate J was prepared from 1.04 g of amine and a balance of other materials. The yield of the title compound was 1.23 g (69%) after silica gel chromatography using 30% ethyl acetate in hexane.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.41 (bs, 1H), 8.32 (d, 1H), 8.16 (s, 1H), 7.19 (d, 1H), 4.78 (s, 2H), 3.28 ( s, 3H) and 1.36 ppm (s, 6H); ES-MS m / z 243.1 [M + H] ⁺ , HPLC RT (min) 2.12.

Intermediate K
Production of N- [4- (chloromethyl) pyridin-2-yl] methanesulfonamide

酢酸エチル（４ｍＬ）中の４−（クロロメチル）ピリジン−２−アミン（５００ｍｇ、３.５１ｍｍｏｌ）およびトリエチルアミン（１.４７ｍＬ、１０.５ｍｍｏｌ）の溶液を、窒素下で、フラスコ中、氷浴で冷却しながら撹拌し、メタンスルホニルクロリド（０.８１ｍＬ、１０.５ｍｍｏｌ）を滴下して添加した。次いで、反応を、冷却せずに１時間撹拌し、その後それをさらなる酢酸エチルで希釈し、水で洗浄し、乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させた。得られた残渣を、酢酸エチル／ヘキサングラジエントを使用するシリカゲルのクロマトグラフィーにより精製し、純粋な表題化合物８６０ｍｇ（８２％）を得た。
¹H NMR (300 Hz, CD₂Cl₂) δ 8.56 (d, 1H), 7.50 (d, 1H), 7.41 (s, 1H), 4.66 (s, 2H), および 3.55 ppm (s, 6H); ES-MS m/z 299.0 [M+H]⁺, HPLC RT (分) 2.08. Step 1: Preparation of N- [4- (chloromethyl) pyridin-2-yl] -N- (methylsulfonyl) methanesulfonamide

A solution of 4- (chloromethyl) pyridin-2-amine (500 mg, 3.51 mmol) and triethylamine (1.47 mL, 10.5 mmol) in ethyl acetate (4 mL) was placed in an ice bath in a flask under nitrogen. Stirring with cooling, methanesulfonyl chloride (0.81 mL, 10.5 mmol) was added dropwise. The reaction was then stirred without cooling for 1 hour after which it was diluted with more ethyl acetate, washed with water, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The resulting residue was purified by chromatography on silica gel using an ethyl acetate / hexane gradient to give 860 mg (82%) of the pure title compound.
¹ H NMR (300 Hz, CD ₂ Cl ₂ ) δ 8.56 (d, 1H), 7.50 (d, 1H), 7.41 (s, 1H), 4.66 (s, 2H), and 3.55 ppm (s, 6H); ES-MS m / z 299.0 [M + H] ⁺ , HPLC RT (min) 2.08.

メタノール（１０ｍＬ）中のＮ−［４−（クロロメチル）ピリジン−２−イル］−Ｎ−（メチルスルホニル）−メタンスルホンアミド（７００ｍｇ、２.３４ｍｍｏｌ）の懸濁液および水性水酸化ナトリウム（１Ｎ、１１.７ｍＬ、１１.７ｍｍｏｌ）を外界温度で撹拌し、出発物質を１０分間かけて溶解した。さらに１０分後、水性塩酸（２Ｎ）の添加により反応をｐＨ３ないし６に調節し、所望の生成物を白色固体として沈殿させ、それを濾過により回収し、メタノールで洗浄し、真空で乾燥した。表題化合物の収量は、２５０ｍｇ（４８％）であった。
¹H NMR (300 MHz, DMSO-d₆) δ 10.93 (bs, 1H), 8.21 (d, 1H), 7.02 (m, 2H), 4.73 (s, 2H), および 3.23 ppm (s, 3H); ES-MS m/z 221.1 [M+H]⁺, HPLC RT (分) 1.45. Step 2: Preparation of N- [4- (chloromethyl) pyridin-2-yl] methanesulfonamide

A suspension of N- [4- (chloromethyl) pyridin-2-yl] -N- (methylsulfonyl) -methanesulfonamide (700 mg, 2.34 mmol) in methanol (10 mL) and aqueous sodium hydroxide (1N 11.7 mL, 11.7 mmol) was stirred at ambient temperature and the starting material was dissolved over 10 minutes. After an additional 10 minutes, the reaction was adjusted to pH 3-6 by addition of aqueous hydrochloric acid (2N) and the desired product precipitated as a white solid that was collected by filtration, washed with methanol and dried in vacuo. The yield of title compound was 250 mg (48%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.93 (bs, 1H), 8.21 (d, 1H), 7.02 (m, 2H), 4.73 (s, 2H), and 3.23 ppm (s, 3H); ES-MS m / z 221.1 [M + H] ⁺ , HPLC RT (min) 1.45.

ＤＭＦ３ｍＬ中の４−（クロロメチル）ピリジン−２−アミン（１００ｍｇ、０.７０ｍｍｏｌ）に、エチルイソシアネート（５９ｍｇ、０.８４ｍｍｏｌ）を添加し、得られた混合物を窒素下で１６時間撹拌した。反応をＥｔＯＡｃ（１５ｍＬ）で希釈し、Ｈ_２Ｏで３回洗浄し、乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させた。粗製の残渣を、ヘキサン中の２５％ＥｔＯＡｃを使用するシリカゲルのカラムクロマトグラフィーにより精製し、Ｎ−［４−（クロロメチル）ピリジン−２−イル］−Ｎ'−エチルウレア１１０ｍｇ（７３％）を得た。
¹H NMR (DMSO-d₆) δ 9.22 (s, 1H), 8.14-8.16(m, 1H), 7.91-7.94 (m, 1H), 7.45 (d, J=0.8Hz, 1H), 6.93-6.95 (m, 1H), 4.70 (s, 2H), 3.12-3.14(m, 2H), 1.01-1.09(m, 3H) ppm; LCMS: 214.1 [M+H]⁺, RT 0.47 分. Intermediate L
Production of N- [4- (chloromethyl) pyridin-2-yl] -N′-ethylurea

To 4- (chloromethyl) pyridin-2-amine (100 mg, 0.70 mmol) in 3 mL of DMF was added ethyl isocyanate (59 mg, 0.84 mmol) and the resulting mixture was stirred under nitrogen for 16 hours. The reaction was diluted with EtOAc (15 mL), washed 3 times with H ₂ O, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel using 25% EtOAc in hexanes to give 110 mg (73%) of N- [4- (chloromethyl) pyridin-2-yl] -N′-ethylurea. It was.
¹ H NMR (DMSO-d ₆ ) δ 9.22 (s, 1H), 8.14-8.16 (m, 1H), 7.91-7.94 (m, 1H), 7.45 (d, J = 0.8Hz, 1H), 6.93-6.95 (m, 1H), 4.70 (s, 2H), 3.12-3.14 (m, 2H), 1.01-1.09 (m, 3H) ppm; LCMS: 214.1 [M + H] ⁺ , RT 0.47 min.

中間体Ｌの製造について記載した方法の使用により、そして、エチルイソシアネートの代わりにフェニルイソシアネートを用いることにより、中間体Ｍを製造した。４−（クロロメチル）ピリジン−２−アミン２５０ｍｇおよび釣り合う量の他の物質から、表題化合物の収量は、ヘキサン中の０−４０％酢酸エチルのグラジエントを使用するシリカゲルクロマトグラフィーの後、２１８ｍｇ（４７％）であった。ＮＭＲスペクトルにおいて、出発物質４−（クロロメチル）ピリジン−２−アミンの混入の証拠があったが、この物質をさらに精製せずに使用し、副生成物を次の段階の後でクロマトグラフィーにより分離した。
¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (bs, 1H), 9.50 (bs, 1H), 8.29 (d, 1H), 7.95 (s, 1H), 7.52 (d, 1H), 7.27-7.36 (m, 2H), 7.0-7.1 (m, 2H), および 4.79 ppm (s, 2H); LCMS: 262.2 [M+H]⁺, RT 2.65 分. Intermediate M
Production of N- [4- (chloromethyl) pyridin-2-yl] -N′-phenylurea

Intermediate M was prepared by use of the method described for the preparation of Intermediate L and by using phenyl isocyanate instead of ethyl isocyanate. From 250 mg of 4- (chloromethyl) pyridin-2-amine and other materials in proportion, the yield of the title compound was 218 mg (47 mg after silica gel chromatography using a gradient of 0-40% ethyl acetate in hexane. %)Met. In the NMR spectrum there was evidence of contamination of the starting material 4- (chloromethyl) pyridin-2-amine, but this material was used without further purification and the by-product was chromatographed after the next step. separated.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.25 (bs, 1H), 9.50 (bs, 1H), 8.29 (d, 1H), 7.95 (s, 1H), 7.52 (d, 1H), 7.27- 7.36 (m, 2H), 7.0-7.1 (m, 2H), and 4.79 ppm (s, 2H); LCMS: 262.2 [M + H] ⁺ , RT 2.65 min.

中間体Ｌの製造について記載した方法の使用により、そして、エチルイソシアネートの代わりにメチルイソシアネートを用いることにより、中間体Ｎを製造した。４−（クロロメチル）ピリジン−２−アミン１８０ｍｇおよび釣り合う量の他の物質から、純粋な表題化合物の収量は、ヘキサン中の０−５０％酢酸エチルのグラジエントを使用してシリカゲルでクロマトグラフィーし、続いて混入物を除去するために残渣をエーテルでトリチュレートした後で、４２ｍｇ（１７％）であった。
¹H NMR (DMSO-d₆) δ 9.31 (s, 1H), 8.16 (d, 1H), 7.92 (bm, 1H), 7.40 (s, 1H), 6.93 (d, 1H), 4.69 (s, 2H) および 2.70 ppm (d, 3H); LCMS: 200.1 [M+H]⁺, RT 1.17 分. Intermediate N
Production of N- [4- (chloromethyl) pyridin-2-yl] -N′-methylurea

Intermediate N was prepared by using the method described for the preparation of Intermediate L and by using methyl isocyanate instead of ethyl isocyanate. From 180 mg of 4- (chloromethyl) pyridin-2-amine and other materials in proportion, the yield of pure title compound was chromatographed on silica gel using a gradient of 0-50% ethyl acetate in hexane, The residue was 42 mg (17%) after subsequent trituration with ether to remove contaminants.
¹ H NMR (DMSO-d ₆ ) δ 9.31 (s, 1H), 8.16 (d, 1H), 7.92 (bm, 1H), 7.40 (s, 1H), 6.93 (d, 1H), 4.69 (s, 2H ) And 2.70 ppm (d, 3H); LCMS: 200.1 [M + H] ⁺ , RT 1.17 min.

中間体Ｋの製造について記載した方法の使用により、そして、メタンスルホニルクロリドの代わりにジメチルカルバミン酸クロリドを用いて、中間体ＮＮを製造する。 Intermediate NN
Production of N ′-[4- (chloromethyl) pyridin-2-yl] -N, N-dimethylurea

Intermediate NN is prepared by using the method described for the preparation of intermediate K and using dimethylcarbamic acid chloride in place of methanesulfonyl chloride.

この生成物は、Biorg. Med. Chem. 2002, 10, 525 に記載の５−メチル置換類似体と同様に製造した。ＰＯＣｌ_３（９.１ｍＬ、９７.９ｍｍｏｌ）中の６−（クロロメチル）ピリミジン−２,４（１Ｈ,３Ｈ）−ジオン（５.２ｇ、３２.６ｍｍｏｌ）の撹拌懸濁液を１６時間窒素下で還流した。混合物を冷却し、蒸発させ、暗色の油状物を残した。氷水をゆっくりと添加し、生成物をジクロロメタンに抽出した。有機層を塩水で洗浄し、ＭｇＳＯ_４で乾燥し、減圧下で濃縮し、２,４−ジクロロ−６−（クロロメチル）ピリミジン（５ｇ）を黄色油状物として得た。この生成物を精製せずに次の段階に使用できたが、同じ方法で製造した別のバッチをさらにクロマトグラフィーにより精製した。これは以下のＮＭＲを示した。
¹H NMR (DMSO-d₆) δ 7.90 (s, 1H) および 4.78 ppm (s, 2H). Intermediate O
Production of 2,4-dichloro-6- (chloromethyl) pyrimidine

This product was prepared similarly to the 5-methyl substituted analog described in Biorg. Med. Chem. 2002, 10, 525. A stirred suspension of 6- (chloromethyl) pyrimidine-2,4 (1H, 3H) -dione (5.2 g, 32.6 mmol) in POCl ₃ (9.1 mL, 97.9 mmol) under nitrogen for 16 hours. At reflux. The mixture was cooled and evaporated to leave a dark oil. Ice water was added slowly and the product was extracted into dichloromethane. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure to give 2,4-dichloro-6- (chloromethyl) pyrimidine (5 g) as a yellow oil. This product could be used in the next step without purification, but another batch produced in the same way was further purified by chromatography. This showed the following NMR.
¹ H NMR (DMSO-d ₆ ) δ 7.90 (s, 1H) and 4.78 ppm (s, 2H).

Intermediate P
Preparation of 2-chloro-4- (chloromethyl) pyridine

メチル２−クロロイソニコチネート（５.００ｇ、２９.１４ｍｍｏｌ）のサンプルを、ＴＨＦ１０ｍＬに溶解し、メタノール１０滴で処理し、０℃に冷却した。溶液をリチウムボロヒドリド溶液（２１.８６ｍＬ、１Ｍ、ＴＨＦ中、４３.７１ｍｍｏｌ）で処理し、次いで、室温に温まらせた。４時間後、この溶液を０℃に冷却し、１Ｎ ＨＣｌ溶液でクエンチした。ｐＨを１Ｎ ＮａＯＨ溶液でｐＨ１０に調節し、反応混合物をＥｔＯＡｃで抽出した。有機抽出物を塩水で洗浄し、真空で濃縮し、生成物２.９６ｇ（７０.８％）を得た。
¹H NMR (300 MHz, CD₃CN) δ 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) および 3.53 ppm (bs, 1 H). Step 1: Preparation of (2-chloropyridin-4-yl) methanol

A sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 mL of THF, treated with 10 drops of methanol and cooled to 0 ° C. The solution was treated with lithium borohydride solution (21.86 mL, 1 M, 43.71 mmol in THF) and then allowed to warm to room temperature. After 4 hours, the solution was cooled to 0 ° C. and quenched with 1N HCl solution. The pH was adjusted to pH 10 with 1N NaOH solution and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine and concentrated in vacuo to give 2.96 g (70.8%) of product.
¹ H NMR (300 MHz, CD ₃ CN) δ 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).

（２−クロロピリジン−４−イル）メタノール（１１０.０ｍｇ、０.７７ｍｍｏｌ）のサンプルを無水ＴＨＦ（１.５ｍＬ）に溶解し、Ｎ,Ｎ−ジイソプロピルエチルアミン（０.２９ｍＬ、１.６９ｍｍｏｌ）で処理し、−７８℃に冷却した。メタンスルホニルクロリドを添加し（０.０７ｍＬ、０.８４ｍｍｏｌ）、反応混合物をゆっくりと室温に終夜温まらせた。次いで、反応混合物をジクロロメタンで希釈し、水で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空で濃縮し、表題化合物（１１０.０ｍｇ、８８.６％）を得た。
¹H NMR (300 MHz, CD₃CN) δ 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) および 4.63 ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]⁺, HPLC RT (分) 2.30. Step 2: Preparation of 2-chloro-4- (chloromethyl) pyridine

A sample of (2-chloropyridin-4-yl) methanol (110.0 mg, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL) and N, N-diisopropylethylamine (0.29 mL, 1.69 mmol). Treated and cooled to -78 ° C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol) and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (110.0 mg, 88.6%).
¹ H NMR (300 MHz, CD ₃ CN) δ 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63 ppm (s, 2 H); ES-MS m / z 183.2 [M + Na] ⁺ , HPLC RT (min) 2.30.

Intermediate PP
Preparation of [2- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-4-yl] methylmethanesulfonate

（２−アミノピリジン−４−イル）メタノール（７.５ｇ、６０.４１ｍｍｏｌ）、ヘキサン−２,５−ジオン（７.５８ｇ、６６.４６ｍｍｏｌ）およびｐ−トルエンスルホン酸一水和物（１.１４ｇ、６.０４）を、ディーン・スターク・トラップを取り付けたフラスコ中で、トルエン（１０ｍＬ）に溶解した。溶液を加熱し、１３５℃で１６時間還流した。溶媒を蒸発させ、酢酸エチルを添加した。有機抽出物を塩水で洗浄し、乾燥し（Ｎａ_２ＳＯ_４）、真空で濃縮した。シリカゲルをヘキサン中の１０−５０％酢酸エチルの勾配溶出で使用して残渣を精製し、生成物１０.２ｇ（８３％）を得た。
¹H NMR (300 MHz, CD2Cl2-d₂) δ 8.52 (dd, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 5.85(s, 2H), 4.78 (s, 2H), 2.08 (s, 6H); ES-MS m/z 203.2[M+H]⁺, LCMS RT (分) 2.04. Step 1: Preparation of [2- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-4-yl] methanol

(2-Aminopyridin-4-yl) methanol (7.5 g, 60.41 mmol), hexane-2,5-dione (7.58 g, 66.46 mmol) and p-toluenesulfonic acid monohydrate (1. 14 g, 6.04) was dissolved in toluene (10 mL) in a flask fitted with a Dean-Stark trap. The solution was heated and refluxed at 135 ° C. for 16 hours. The solvent was evaporated and ethyl acetate was added. The organic extract was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified using silica gel with a gradient elution of 10-50% ethyl acetate in hexanes to give 10.2 g (83%) of product.
¹ H NMR (300 MHz, CD2Cl2-d ₂ ) δ 8.52 (dd, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 5.85 (s, 2H), 4.78 (s, 2H), 2.08 ( s, 6H); ES-MS m / z 203.2 [M + H] ⁺ , LCMS RT (min) 2.04.

［２−（２,５−ジメチル−１Ｈ−ピロール−１−イル）ピリジン−４−イル］メタノール（６.８０ｇ、３３.６２ｍｍｏｌ）を、無水ジクロロメタン（３０ｍＬ）に溶解し、トリエチルアミン（１４.０６ｍＬ、１００.９ｍｍｏｌ）で処理し、０℃に冷却した。メタンスルホニルクロリドを添加し（３.９０ｍＬ、５０.４３ｍｍｏｌ）、反応混合物をゆっくりと室温に終夜温まらせた。次いで、反応混合物をジクロロメタンで希釈し、水で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空で濃縮し、ヘキサン中の１０−６０％酢酸エチルを溶離剤として使用してシリカゲルで残渣を精製し、表題化合物（７.５ｇ、８０％）を得た。
¹H NMR (300 MHz, CD2Cl2-J2) δ 8.65 (dd, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 5.88(s, 2H), 5.30 (s, 2H), 3.10 (s, 3H), 2.12 (s, 6H); ES-MS m/z 281.1[M+H]⁺, LCMS RT (分) 2.67. Step 2: Preparation of [2- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-4-yl] methylmethanesulfonate

[2- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-4-yl] methanol (6.80 g, 33.62 mmol) was dissolved in anhydrous dichloromethane (30 mL) and triethylamine (14.06 mL). , 100.9 mmol) and cooled to 0 ° C. Methanesulfonyl chloride was added (3.90 mL, 50.43 mmol) and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over _Na 2 SO _4, concentrated in vacuo, using a 10-60% ethyl acetate in hexane as eluent The residue was purified on silica gel, the title compound (7.5 g, 80%) Obtained.
^{1 H NMR (300 MHz, CD2Cl2} -J2) δ 8.65 (dd, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 5.88 (s, 2H), 5.30 (s, 2H), 3.10 (s , 3H), 2.12 (s, 6H); ES-MS m / z 281.1 [M + H] ⁺ , LCMS RT (min) 2.67.

Intermediate Q
Preparation of 4- (chloromethyl) -N- (4-methyl-1,3-thiazol-2-yl) pyridin-2-amine

ジクロロメタン（５０ｍＬ）中の（２−アミノピリジン−４−イル）メタノール（５.０ｇ、４０ｍｍｏｌ）、ｔｅｒｔ−ブチルジメチルシリルクロリド（６.０７ｇ、４０ｍｍｏｌ）、Ｎ−エチル−Ｎ−イソプロピルプロパン−２−アミン（７.０ｍＬ、４０ｍｍｏｌ）およびＮ,Ｎ−ジメチルピリジン−４−アミン（０.４９ｇ、４ｍｍｏｌ）の溶液を、２日間、外界温度で、窒素下に撹拌した。得られた反応混合物を、水性水酸化ナトリウム（１Ｎ）、水および塩水で続けて洗浄した。次いで、それを乾燥し（Ｎａ_２ＳＯ_４）、真空で濃縮した。ヘキサン中の５０％酢酸エチルを使用して、シリカゲルで残渣をクロマトグラフィーし、純粋な表題化合物（５.４７ｇ）を得た。
¹H NMR (300 MHz, CD₃CN) δ 7.75 (m, 1H), 6.39 -6.48 (m, 2H), 4.70 (bs, 1H), 4.50 (s, 2H), 0.83 (s, 9H) および 0.03 ppm (s, 6H); ES-MS m/z 239.3 [M+H]⁺, HPLC RT (分) 2.35. Step 1: Preparation of 4-({[tert-butyl (dimethyl) silyl] oxy} methyl) pyridin-2-amine

(2-Aminopyridin-4-yl) methanol (5.0 g, 40 mmol), tert-butyldimethylsilyl chloride (6.07 g, 40 mmol), N-ethyl-N-isopropylpropan-2- in dichloromethane (50 mL) A solution of amine (7.0 mL, 40 mmol) and N, N-dimethylpyridin-4-amine (0.49 g, 4 mmol) was stirred for 2 days at ambient temperature under nitrogen. The resulting reaction mixture was washed successively with aqueous sodium hydroxide (1N), water and brine. It was then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to give the pure title compound (5.47 g).
¹ H NMR (300 MHz, CD ₃ CN) δ 7.75 (m, 1H), 6.39 -6.48 (m, 2H), 4.70 (bs, 1H), 4.50 (s, 2H), 0.83 (s, 9H) and 0.03 ppm (s, 6H); ES-MS m / z 239.3 [M + H] ⁺ , HPLC RT (min) 2.35.

トルエン（２０ｍＬ）中の４−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）ピリジン−２−アミン（２.００ｇ、８.３９ｍｍｏｌ）およびベンゾイルイソチオシアネート（１.５１ｇ、９.２３ｍｍｏｌ）の溶液を、８５℃に１２時間加熱した。真空での蒸発により溶媒を除去し、ヘキサン中の０−１０％酢酸エチルのグラジエントを使用して残渣をシリカゲルのクロマトグラフィーにより精製し、純粋な表題化合物を黄色油状物として得た。それは静置すると固体化した（２.６８ｇ、７９％）。
¹H NMR (300 MHz, CD₃OD) δ 8.79 (bs, 1H), 8.18 (d, 1H), 7.83 (m, 2H), 7.50 (m, 1H), 7.40 (m, 2H), 7.04 (m, 1H), 4.68 (s, 2H), 0.82 (s, 9H) および 0.03 ppm (s, 6H); ES-MS m/z 402.0 [M+H]⁺, HPLC RT (分) 4.24. Step 2: Preparation of N-({[4-({[tert-butyl (dimethyl) silyl] oxy} methyl) pyridin-2-yl] amino} carbonothioyl) benzamide

4-({[tert-Butyl (dimethyl) silyl] oxy} methyl) pyridin-2-amine (2.00 g, 8.39 mmol) and benzoyl isothiocyanate (1.51 g, 9.23 mmol) in toluene (20 mL) Was heated to 85 ° C. for 12 hours. The solvent was removed by evaporation in vacuo and the residue was purified by chromatography on silica gel using a gradient of 0-10% ethyl acetate in hexanes to give the pure title compound as a yellow oil. It solidified upon standing (2.68 g, 79%).
¹ H NMR (300 MHz, CD ₃ OD) δ 8.79 (bs, 1H), 8.18 (d, 1H), 7.83 (m, 2H), 7.50 (m, 1H), 7.40 (m, 2H), 7.04 (m , 1H), 4.68 (s, 2H), 0.82 (s, 9H) and 0.03 ppm (s, 6H); ES-MS m / z 402.0 [M + H] ⁺ , HPLC RT (min) 4.24.

無水エタノール（１５ｍＬ）中のＮ−（｛［４−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）ピリジン−２−イル］アミノ｝カルボノチオイル）ベンズアミド（１.００ｇ、２.４９ｍｍｏｌ）の溶液を、炭酸カリウム（０.３４４ｇ、２.４９ｍｍｏｌ）と共に撹拌し、加熱して窒素下に１６時間還流し、その後、反応混合物を濾過し、濾液を真空下で蒸発させ、粗製の表題化合物（６７０ｍｇ、＞１００％）を白色固体として得、それを精製せずに次の段階に進めた。
¹H NMR (300 MHz, DMSO-d₆) δ 10.55 (bs, 2H), 8.75 (bs, 1H), 8.05 (d, 1H), 7.10 (s, 1H), 6.83 (d, 1H), 4.60 (s, 2H), 0.83 (s, 9H) および 0.03 ppm (s, 6H); ES-MS m/z 298.2 [M+H]⁺, HPLC RT (分) 3.25. Step 3: Preparation of N- [4-({[tert-butyl (dimethyl)) silyl] oxy} methyl) pyridin-2-yl] thiourea

N-({[4-({[tert-Butyl (dimethyl) silyl] oxy} methyl) pyridin-2-yl] amino} carbonothioyl) benzamide (1.00 g, 2.49 mmol in absolute ethanol (15 mL) ) Solution with potassium carbonate (0.344 g, 2.49 mmol), heated to reflux under nitrogen for 16 hours, after which the reaction mixture was filtered and the filtrate was evaporated in vacuo to give the crude title The compound (670 mg,> 100%) was obtained as a white solid, which was carried on to the next step without purification.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (bs, 2H), 8.75 (bs, 1H), 8.05 (d, 1H), 7.10 (s, 1H), 6.83 (d, 1H), 4.60 ( s, 2H), 0.83 (s, 9H) and 0.03 ppm (s, 6H); ES-MS m / z 298.2 [M + H] ⁺ , HPLC RT (min) 3.25.

エタノール（１０ｍＬ）中のＮ−［４−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）ピリジン−２−イル］チオウレア（粗製物質、６５０ｍｇ）および１−クロロアセトン（０.１８ｍＬ、２.１８ｍｍｏｌ）の溶液を、窒素下で１６時間還流し、冷却した。白色／桃色の固体を濾過により回収し、エタノールで洗浄した。濾液を真空で蒸発させ、第２の白色／桃色の固体を得た。これらの２種の固体のＮＭＲの比較は、それらが両方とも表題化合物であり、さらに精製せずに次の段階に進めるのに十分なほど純粋である（約９０％）ことを示した（合わせた残渣の収量５１６ｍｇ、＞１００％）。
¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (d, 1H), 7.05 (s, 1H), 6.83 (d, 1H), 6.58 (s, 1H), 4.42 (s, 2H) および 2.18 ppm (s, 3H); ES-MS m/z 222.2 [M+H]⁺, HPLC RT (分) 1.41. Step 4: Preparation of {2-[(4-Methyl-1,3-thiazol-2-yl) amino] pyridin-4-yl} methanol

N- [4-({[tert-Butyl (dimethyl) silyl] oxy} methyl) pyridin-2-yl] thiourea (crude material, 650 mg) and 1-chloroacetone (0.18 mL, 2 in ethanol (10 mL) .18 mmol) was refluxed under nitrogen for 16 hours and cooled. A white / pink solid was collected by filtration and washed with ethanol. The filtrate was evaporated in vacuo to give a second white / pink solid. A comparison of the NMR of these two solids showed that they were both title compounds and were pure enough (about 90%) to proceed to the next step without further purification (combined). Yield 516 mg,> 100%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (d, 1H), 7.05 (s, 1H), 6.83 (d, 1H), 6.58 (s, 1H), 4.42 (s, 2H) and 2.18 ppm (s, 3H); ES-MS m / z 222.2 [M + H] ⁺ , HPLC RT (min) 1.41.

｛２−［（４−メチル−１,３−チアゾール−２−イル）アミノ］ピリジン−４−イル｝メタノール（２００ｍｇ、０.９ｍｍｏｌ）および塩化チオニル（０.６６ｍＬ、９.０４ｍｍｏｌ）の混合物を３時間撹拌し、次いで、真空で蒸発させた。残渣を酢酸エチルに溶解し、飽和重炭酸ナトリウムで洗浄した。水層を酢酸エチルで２回、次いで、イソプロパノール、酢酸エチルおよびジクロロメタンの混合物（１：８：１）で２回、逆抽出した。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で濃縮した。得られた残渣をメタノールと混合し、蒸発させ、次いで、酢酸エチルと混合し、次いで再度蒸発させ、表題化合物を明桃色固体（２００ｍｇ、９２％）として得、それを粗製の固体として次の段階に用いた。
¹H NMR (300 MHz, CD₂Cl₂) δ 8.30 (m, 1H), 6.98 (s, 1H), 6.90 (m, 1H), 6.50 (s, 1H), 4.55 (s, 2H) および 2.33 ppm (s, 3H); ES-MS m/z 240.2 [M+H]⁺, HPLC RT (分) 1.14. Step 5: Preparation of 4- (chloromethyl) -N- (4-methyl-1,3-thiazol-2-yl) pyridin-2-amine

A mixture of {2-[(4-methyl-1,3-thiazol-2-yl) amino] pyridin-4-yl} methanol (200 mg, 0.9 mmol) and thionyl chloride (0.66 mL, 9.04 mmol) was added. Stir for 3 hours and then evaporate in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The aqueous layer was back extracted twice with ethyl acetate and then twice with a mixture of isopropanol, ethyl acetate and dichloromethane (1: 8: 1). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The resulting residue was mixed with methanol and evaporated, then mixed with ethyl acetate and then evaporated again to give the title compound as a light pink solid (200 mg, 92%) which was the next step as a crude solid. Used for.
¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 8.30 (m, 1H), 6.98 (s, 1H), 6.90 (m, 1H), 6.50 (s, 1H), 4.55 (s, 2H) and 2.33 ppm (s, 3H); ES-MS m / z 240.2 [M + H] ⁺ , HPLC RT (min) 1.14.

中間体Ｌの製造について記載した方法の使用により、そして、エチルイソシアネートの代わりにベンゾイルイソシアネート用い、溶媒としてＤＭＦではなくジクロロメタンを使用することにより、中間体Ｒを製造した。反応混合物から固体として分離した生成物を、濾過により回収し、ジクロロメタンで洗浄した。
¹H NMR (DMSO-d₆) δ 11.01 (s, 1H), 10.98 (bs, 1H), 8.06 (d, 1H), 7.82 (s, 1H), 7.73 (d, 2H), 7.37 (t, 1H), 7.25 (t, 2H), 6.90 (d, 1H), および 4.52 (s, 2H). Intermediate R
Production of N-({[4- (chloromethyl) pyridin-2-yl] amino} carbonyl) benzamide

Intermediate R was prepared by using the method described for the preparation of Intermediate L and by using benzoyl isocyanate instead of ethyl isocyanate and using dichloromethane rather than DMF as the solvent. The product separated as a solid from the reaction mixture was collected by filtration and washed with dichloromethane.
¹ H NMR (DMSO-d ₆ ) δ 11.01 (s, 1H), 10.98 (bs, 1H), 8.06 (d, 1H), 7.82 (s, 1H), 7.73 (d, 2H), 7.37 (t, 1H ), 7.25 (t, 2H), 6.90 (d, 1H), and 4.52 (s, 2H).

乾燥ジメチルホルムアミド（１.５ｍＬ）中の５−アミノ−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１−メチル−１Ｈ−ピラゾール−４−カルボキサミド（中間体Ａ、２８０ｍｇ、０.９５ｍｍｏｌ）、ヨウ化ナトリウム（２８３ｍｇ、１.８９ｍｍｏｌ）および２,６−ジ（ｔｅｒｔ）ブチル−４−メチルフェノール（１０ｍｇ）の溶液を窒素下で撹拌し、｛２−［（メチルアミノ）カルボニル］ピリジン−４−イル｝メチルメタンスルホネート（中間体Ｄ、４６１ｍｇ、１.８９ｍｍｏｌ）を添加した。得られた溶液を、ホイルで包んだフラスコ中、６０℃で２０時間撹拌した。得られた溶液を蒸発させ、次いで、１ｍＬメタノールで希釈し、水（プラス０.０５％トリフルオロ酢酸）中の１０−５０％アセトニトリルのグラジエントを使用して、２回に分けて150/20 mm C18 HPLC カラムに注入した。ＬＣＭＳにより同定される、所望の物質を含有する最良の画分を合わせ、飽和ＮａＨＣＯ_３と混合し、ジクロロメタンで３回抽出した。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、純粋な表題化合物９０ｍｇ（２１％）を得た。
¹H NMR (300 MHz, CD3OD-d₄) δ 8.50 (d, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.70 (m, 1H), 7.55 (d, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 4.65 (s, 2H), 3.70 (s, 3H), 2.95 (s,3H); ES-MS m/z 445.3 [M+H]⁺, LCMS RT (分) 2.87. Production of the compounds of the invention
Example 1
4-{[(4-{[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazol-5-yl) amino] methyl} Preparation of -N-methylpyridine-2-carboxamide

5-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole-4-carboxamide (intermediate) in dry dimethylformamide (1.5 mL) A solution of Form A, 280 mg, 0.95 mmol), sodium iodide (283 mg, 1.89 mmol) and 2,6-di (tert) butyl-4-methylphenol (10 mg) under nitrogen, {2- [(Methylamino) carbonyl] pyridin-4-yl} methyl methanesulfonate (Intermediate D, 461 mg, 1.89 mmol) was added. The resulting solution was stirred at 60 ° C. for 20 hours in a foil wrapped flask. The resulting solution was evaporated and then diluted with 1 mL methanol and 150/20 mm in two portions using a gradient of 10-50% acetonitrile in water (plus 0.05% trifluoroacetic acid). Injected onto a C18 HPLC column. The best fractions containing the desired material, identified by LCMS, were combined, mixed with saturated NaHCO ₃ and extracted three times with dichloromethane. The combined extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 90 mg (21%) of the pure title compound.
¹ H NMR (300 MHz, CD3OD-d ₄ ) δ 8.50 (d, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.70 (m, 1H), 7.55 (d, 1H), 7.25 ( m, 1H), 7.10 (m, 1H), 4.65 (s, 2H), 3.70 (s, 3H), 2.95 (s, 3H); ES-MS m / z 445.3 [M + H] ⁺ , LCMS RT ( Minutes) 2.87.

Example 2
5-{[(2-chloropyridin-4-yl) methyl] amino} -N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole- Production of 4-carboxamide

ギ酸（４ｍｌ、１０６.０２ｍｍｏｌ）および無水酢酸（６ｍｌ、６３.５９ｍｍｏｌ）の溶液を、乾燥ＴＨＦ（３０ｍＬ）中のエチル５−アミノ−１−メチル−１Ｈ−ピラゾール−４−カルボキシレート（５.００ｇ、２９.５５ｍｍｏｌ）の溶液に添加し、室温で１６時間撹拌した。次いで、反応混合物をＥｔＯＡｃで希釈し、濃ＮａＨＣＯ_３溶液で、続いて水で、次いで塩水で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空で濃縮し、粗生成物４.１６ｇ（７１.４％）を得た。この物質をさらに精製せずに使用した。
¹H NMR (300 MHz, CD₃CN) δ 8.32 (bs, 1H), 7.78 (s, 1H), 4.23 (q, 2H), 3.68 (s, 3H), 1.25 (t, 3H); ES-MS m/z 198.0 [M+H]⁺, HPLC RT (分) 1.41. Step 1: Preparation of ethyl 5- (formylamino) -1-methyl-1H-pyrazole-4-carboxylate

A solution of formic acid (4 ml, 106.02 mmol) and acetic anhydride (6 ml, 63.59 mmol) was added to ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (5.00 g) in dry THF (30 mL). 29.55 mmol) and stirred at room temperature for 16 hours. The reaction mixture was then diluted with EtOAc and washed with concentrated NaHCO ₃ solution followed by water and then brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 4.16 g (71.4%) of crude product. This material was used without further purification.
¹ H NMR (300 MHz, CD ₃ CN) δ 8.32 (bs, 1H), 7.78 (s, 1H), 4.23 (q, 2H), 3.68 (s, 3H), 1.25 (t, 3H); ES-MS m / z 198.0 [M + H] ⁺ , HPLC RT (min) 1.41.

ジクロロメタン（３０ｍｌ）中の段階１由来の粗製エチル５−（ホルミルアミノ）−１−メチル−１Ｈ−ピラゾール−４−カルボキシレート（３.００ｇ、１５.２１ｍｍｏｌ）の溶液を、ジアザビシクロ（５.４.０）ウンデカ−７−エン（３.４１ｍｌ、２２.８２ｍｍｏｌ）で処理し、室温で３０分間撹拌した。２−クロロ−４−クロロメチルピリジン（４.９３ｇ、３０.４３ｍｍｏｌ）を添加し、反応混合物を室温で１６時間撹拌した。次いで、反応混合物をＤＣＭで希釈し、濃ＮａＨＣＯ_３溶液で、続いて水で、次いで塩水で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空で濃縮した。粗製残渣をエーテルで洗浄し、エーテル洗浄液を濃縮し、ヘキサンでトリチュレートした。残渣を再度濃縮し、生成物３.９３ｇ（８０.１％）を低粘性油状物として得た。
¹H NMR (300 MHz, CD₃CN) δ 8.30 (d, 1H), 8.23 (s, 1H), 7.85 (s, 1H), 7.33 (s, 1H), 7.22 (d, 1H), 4.80 (bs, 2H), 4.17 (q, 2H), 3.67 (s, 3H), 1.23 (t, 3H); ES-MS m/z 323.1 [M+H]⁺, HPLC RT (分) 2.31. Step 2: Preparation of ethyl 5-[[(2-chloropyridin-4-yl) methyl] (formyl) amino] -1-methyl-1H-pyrazole-4-carboxylate

A solution of crude ethyl 5- (formylamino) -1-methyl-1H-pyrazole-4-carboxylate (3.00 g, 15.21 mmol) from Step 1 in dichloromethane (30 ml) was diluted with diazabicyclo (5.4. 0) Treated with undec-7-ene (3.41 ml, 22.82 mmol) and stirred at room temperature for 30 minutes. 2-Chloro-4-chloromethylpyridine (4.93 g, 30.43 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with DCM and washed with concentrated NaHCO ₃ solution followed by water and then brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was washed with ether and the ether wash was concentrated and triturated with hexane. The residue was concentrated again to give 3.93 g (80.1%) of product as a low viscosity oil.
¹ H NMR (300 MHz, CD ₃ CN) δ 8.30 (d, 1H), 8.23 (s, 1H), 7.85 (s, 1H), 7.33 (s, 1H), 7.22 (d, 1H), 4.80 (bs , 2H), 4.17 (q, 2H), 3.67 (s, 3H), 1.23 (t, 3H); ES-MS m / z 323.1 [M + H] ⁺ , HPLC RT (min) 2.31.

ＴＨＦ（２５ｍＬ）、ＭｅＯＨ（５ｍＬ）および水（５ｍＬ）中のエチル５−［［（２−クロロピリジン−４−イル）メチル］（ホルミル）アミノ］−１−メチル−１Ｈ−ピラゾール−４−カルボキシレート（３.９３ｇ、１２.１８ｍｍｏｌ）の溶液を、ＬｉＯＨ（２.９１ｇ、１２２１.７７ｍｍｏｌ）で処理し、８０℃で終夜撹拌した。次いで、反応混合物を室温に冷却し、１Ｎ ＨＣｌを使用してｐＨを３に調節した。次いで、反応混合物をＥｔＯＡｃで希釈し、水、塩水で洗浄し、次いでＮａ_２ＳＯ_４で乾燥した。酢酸エチル溶液を真空で濃縮し、粗生成物を得、それをエーテルでトリチュレートし、生成物２.０ｇ（６１.６％）を得た。
¹H NMR (300 MHz, CD₃CN) δ 8.32 (d, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.28 (d, 1H), 6.18 (bm, 1H), 4.59 (d, 2H), 3.64 (s, 3H); ES-MS m/z 267.1 [M+H]⁺, HPLC RT (分) 1.66. Step 3: Preparation of 5-{[(2-chloropyridin-4-yl) methyl] amino} -1-methyl-1H-pyrazole-4-carboxylic acid

Ethyl 5-[[(2-chloropyridin-4-yl) methyl] (formyl) amino] -1-methyl-1H-pyrazole-4-carboxy in THF (25 mL), MeOH (5 mL) and water (5 mL) A solution of the rate (3.93 g, 12.18 mmol) was treated with LiOH (2.91 g, 1221.77 mmol) and stirred at 80 ° C. overnight. The reaction mixture was then cooled to room temperature and the pH was adjusted to 3 using 1N HCl. The reaction mixture was then diluted with EtOAc, washed with water, brine, and then dried over Na ₂ SO ₄ . The ethyl acetate solution was concentrated in vacuo to give the crude product, which was triturated with ether to give 2.0 g (61.6%) of product.
¹ H NMR (300 MHz, CD ₃ CN) δ 8.32 (d, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.28 (d, 1H), 6.18 (bm, 1H), 4.59 (d , 2H), 3.64 (s, 3H); ES-MS m / z 267.1 [M + H] ⁺ , HPLC RT (min) 1.66.

乾燥ＤＭＦ（３ｍＬ）中の５−｛［（２−クロロピリジン−４−イル）メチル］アミノ｝−１−メチル−１Ｈ−ピラゾール−４−カルボン酸（５０.０ｍｇ、０.１９ｍｍｏｌ）の溶液を、Ｎ,Ｎ−ジイソプロピルエチルアミン（０.１０ｍＬ、０.５６ｍｍｏｌ）で、続いてＰｙＢＯＰ（９７.５７ｍｇ、０.１９ｍｍｏｌ）で処理し、３０分間撹拌した。５−アミノ−２,２−ジフルオロベンゾ−１,３−ジオキソール（６４.９１ｍｇ、０.３７ｍｍｏｌ）を添加し、反応混合物を１６時間６０℃で撹拌した。次いで、反応混合物をＥｔＯＡｃで希釈し、有機物質を濃ＮａＨＣＯ_３溶液で、続いて水で、次いで塩水で洗浄した。次いで、有機物質をＮａ_２ＳＯ_４で乾燥し、真空で濃縮した。粗製の残渣を熱いヘキサンでトリチュレートし、生成物５５.０ｍｇ（６８.６％）を得た。
¹H NMR(300 MHz, CD₃CN) δ 8.43 (bs, 1H), 8.29 (d, 1H), 7.75 (d, 2H), 7.40 (s, 1H), 7.23-7.32 (m, 2H), 7.17 (d, 1H), 6.76 (bs, 1H), 4.53 (d, 2H), 3.68 (s, 3H); ES-MS m/z 422.0 [M+H]⁺, HPLC RT (分) 3.12. Step 4: 5-{[(2-chloropyridin-4-yl) methyl] amino} -N- (2.2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H -Pyrazole-4-carboxamide

A solution of 5-{[(2-chloropyridin-4-yl) methyl] amino} -1-methyl-1H-pyrazole-4-carboxylic acid (50.0 mg, 0.19 mmol) in dry DMF (3 mL). , N, N-diisopropylethylamine (0.10 mL, 0.56 mmol) followed by PyBOP (97.57 mg, 0.19 mmol) and stirred for 30 minutes. 5-Amino-2,2-difluorobenzo-1,3-dioxole (64.91 mg, 0.37 mmol) was added and the reaction mixture was stirred at 60 ° C. for 16 hours. The reaction mixture was then diluted with EtOAc and the organic material was washed with concentrated NaHCO ₃ solution followed by water and then brine. The organic material was then dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was triturated with hot hexane to give 55.0 mg (68.6%) of product.
¹ H NMR (300 MHz, CD ₃ CN) δ 8.43 (bs, 1H), 8.29 (d, 1H), 7.75 (d, 2H), 7.40 (s, 1H), 7.23-7.32 (m, 2H), 7.17 (d, 1H), 6.76 (bs, 1H), 4.53 (d, 2H), 3.68 (s, 3H); ES-MS m / z 422.0 [M + H] ⁺ , HPLC RT (min) 3.12.

ピリジン（１ｍＬ）中の５−｛［（２−クロロピリジン−４−イル）メチル］アミノ｝−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１−メチル−１Ｈ−ピラゾール−４−カルボキサミド（１００.０ｍｇ、０.２４ｍｍｏｌ）の溶液を、エタノールアミン（０.５０ｍＬ、８.２８ｍｍｏｌ）で処理し、密閉チューブ中で６時間２００℃に加熱した。次いで、反応混合物を終夜室温に冷却させた。次いで、それを水で希釈し、ＥｔＯＡｃで抽出した。有機抽出物を水で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、真空で濃縮した。ＨＰＬＣ（水中１０−９０％ＭｅＣＮのグラジエント、０.１％ＴＦＡを含有する）による粗製残渣の精製により、表題化合物２３.０ｍｇ（１７.３％）をＴＦＡ塩として得た。
¹H NMR (300 MHz, CD₃CN) δ 8.40 (bs, 1H), 7.67-7.78 (m, 3H), 7.27 (d, 1H), 7.18 (d, 1H), 7.02 (s, 1H), 6.78 (d, 1H), 4.57 (s, 2H), 3.6-3.71 (m, 4H), 3.38 (m, 2H); ES-MS m/z 447.2 [M+H]⁺, HPLC RT (分) 2.23. Example 3
N- (2,2-difluoro-1,3-benzodioxol-5-yl) -5-[({2-[(2-hydroxyethyl) amino] pyridin-4-yl} methyl) amino-1 -Methyl-1H-pyrazole-4-carboxamide production

5-{[(2-chloropyridin-4-yl) methyl] amino} -N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1- in pyridine (1 mL) A solution of methyl-1H-pyrazole-4-carboxamide (100.0 mg, 0.24 mmol) was treated with ethanolamine (0.50 mL, 8.28 mmol) and heated to 200 ° C. in a sealed tube for 6 hours. The reaction mixture was then allowed to cool to room temperature overnight. It was then diluted with water and extracted with EtOAc. The organic extract was washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude residue by HPLC (10-90% MeCN gradient in water, containing 0.1% TFA) afforded 23.0 mg (17.3%) of the title compound as a TFA salt.
¹ H NMR (300 MHz, CD ₃ CN) δ 8.40 (bs, 1H), 7.67-7.78 (m, 3H), 7.27 (d, 1H), 7.18 (d, 1H), 7.02 (s, 1H), 6.78 (d, 1H), 4.57 (s, 2H), 3.6-3.71 (m, 4H), 3.38 (m, 2H); ES-MS m / z 447.2 [M + H] ⁺ , HPLC RT (min) 2.23.

Examples 3-a through 3-e in Table A were prepared using the methods of Example 2 (Step 4) and Example 3, substituting the appropriate starting materials:
Table A

Example 4
Methyl 4-{[(4-{[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazol-5-yl) amino] methyl } Production of pyridine-2-carboxylate

以下の方法により表題化合物を製造できる。乾燥ジメチルホルムアミド中の５−アミノ−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１−メチル−１Ｈ−ピラゾール−４−カルボキサミド（中間体Ａ）、ヨウ化ナトリウムおよび２,６−ジ（ｔｅｒｔ）ブチル−４−メチルフェノールの溶液を、窒素下で撹拌し、［２−（アミノカルボニル）ピリジン−４−イル］メチルメタンスルホネート（中間体Ｃ）を添加できる。得られる溶液を、ホイルで包んだフラスコ中で、６０℃で２０時間撹拌する。得られる溶液を蒸発させ、次いでメタノールで希釈し、水（プラス０.０５％トリフルオロ酢酸）中の１０−５０％アセトニトリルのグラジエントを使用して、150/20 mm C18 HPLC カラムに注入する。ＬＣＭＳで同定される、所望の物質を含有する最良の画分を合わせ、飽和ＮａＨＣＯ_３と混合し、ジクロロメタンで３回抽出する。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、純粋な表題化合物を得る。 Step 1: 4-{[(4-{[(2,2-Difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazol-5-yl) amino ] Preparation of methyl} pyridine-2-carboxamide

The title compound can be prepared by the following method. 5-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole-4-carboxamide (intermediate A) in dry dimethylformamide, iodo A solution of sodium halide and 2,6-di (tert) butyl-4-methylphenol is stirred under nitrogen and [2- (aminocarbonyl) pyridin-4-yl] methylmethanesulfonate (Intermediate C) is added it can. The resulting solution is stirred for 20 hours at 60 ° C. in a foil wrapped flask. The resulting solution is evaporated and then diluted with methanol and injected onto a 150/20 mm C18 HPLC column using a gradient of 10-50% acetonitrile in water (plus 0.05% trifluoroacetic acid). The best fractions containing the desired material, identified by LCMS, are combined, mixed with saturated NaHCO ₃ and extracted three times with dichloromethane. The combined extracts are dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the pure title compound.

１.２ｍＬメタノール中の４−｛［（４−｛［（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）アミノ］カルボニル｝−１−メチル−１Ｈ−ピラゾール−５−イル）アミノ］メチル｝ピリジン−２−カルボキサミドの懸濁液およびＮ,Ｎ'−ジメチルホルムアミドジメチルアセタールを、撹拌しながら、密閉容器中、５０℃で加熱する。２時間の加熱後、溶液を真空で蒸発させ、ジクロロメタン中の０−１％メタノールのグラジエントを用いて、残渣をシリカゲルでクロマトグラフィーし、純粋な表題化合物を得る。 Step 2 Methyl 4-{[4-{[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} methyl-1H-pyrazol-5-yl) amino] methyl} pyridine 2-Carboxylate production

4-{[(4-{[(2,2-Difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazole-5 in 1.2 mL methanol Yl) amino] methyl} pyridine-2-carboxamide suspension and N, N′-dimethylformamide dimethyl acetal are heated at 50 ° C. in a closed vessel with stirring. After heating for 2 hours, the solution is evaporated in vacuo and the residue is chromatographed on silica gel using a gradient of 0-1% methanol in dichloromethane to give the pure title compound.

メタノール（０.６０ｍＬ）中の４−｛［（４−｛［（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）アミノ］カルボニル｝−１−メチル−１Ｈ−ピラゾール−５−イル）アミノ］メチル｝ピリジン−２−カルボキサミド（実施例４段階１由来の生成物）（９５ｍｇ、０.２１ｍｍｏｌ）のスラリーを、実施例４段階２の通りに処理し、メチル４−｛［（４−｛［（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）アミノ］カルボニル｝−１−メチル−１Ｈ−ピラゾール−５−イル）アミノ］メチル｝ピリジン−２−カルボキシレートの溶液を製造し、それを直接使用し、４−ピロリジン−１−イルブタン−１−アミン（２６６ｍｇ、１.８７ｍｍｏｌ）を添加し、６５℃で１６時間撹拌する。反応溶液を、直接注入を３回に分けて使用してＨＰＬＣにより YMC-Pack Pro C18 カラム（１５０ｘ２０ｍｍ）で精製し、水プラス０.０５％ＴＦＡ中の１０−５０％アセトニトリルのグラジエントを用いて２０ｍＬ／分で溶出する。各注入からの純粋な画分を合わせ、重炭酸ナトリウムの添加により塩基性にし、酢酸エチルで抽出する。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、純粋な表題化合物を得る。 Example 5
4-{[(4-{[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazol-5-yl) amino] methyl} Preparation of -N- (4-pyrrolidin-1-ylbutyl) pyridine-2-carboxamide

4-{[(4-{[(2,2-Difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazole-in methanol (0.60 mL) A slurry of 5-yl) amino] methyl} pyridine-2-carboxamide (product from Example 4 Step 1) (95 mg, 0.21 mmol) was treated as in Example 4 Step 2 to give methyl 4- { [(4-{[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazol-5-yl) amino] methyl} pyridine-2 -Prepare a solution of carboxylate and use it directly, add 4-pyrrolidin-1-ylbutan-1-amine (266 mg, 1.87 mmol) and stir at 65 [deg.] C for 16 h. The reaction solution was purified by HPLC on a YMC-Pack Pro C18 column (150 x 20 mm) using direct injection in three portions and 20 mL with a gradient of water plus 10-50% acetonitrile in 0.05% TFA. Elute at / min. The pure fractions from each injection are combined, basified by the addition of sodium bicarbonate and extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the pure title compound.

この物質は、実施例１について記載したものと同じ方法を使用して、しかし、４−アミノ−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１,３−チアゾール−５−カルボキサミド（中間体Ａ）、および、中間体Ｄではなく釣り合う量の中間体Ｇ、並びに、釣り合う量の他の反応成分で出発して、製造する。反応混合物を、ホイルで包んだフラスコ中、終夜６０℃に加熱し、その後粗生成物を単離する。ヘキサン中の０−６０％酢酸エチルのグラジエントを使用して、この物質をシリカゲルのクロマトグラフィーにより精製し、最終生成物を得る。 Example 6
N- (2,2-difluoro-1,3-benzodioxol-5-yl) -5-[({2 [(methoxyacetyl) amino] pyridin-4-yl} methyl) amino] -1-methyl Of 1H-pyrazole-4-carboxamide

This material was used using the same method as described for Example 1, but 4-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1, Prepared starting with 3-thiazole-5-carboxamide (Intermediate A) and a balanced amount of Intermediate G rather than Intermediate D, and a balanced amount of other reaction components. The reaction mixture is heated to 60 ° C. overnight in a foil-wrapped flask, after which the crude product is isolated. This material is purified by chromatography on silica gel using a gradient of 0-60% ethyl acetate in hexanes to give the final product.

実施例１について記載したものと同じ方法を使用して、しかし、５−アミノ−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１−メチル−１Ｈ−ピラゾール−４−カルボキサミド（中間体Ａ）ではなく５−アミノ−１−メチル−Ｎ−（２,２,３,３−テトラフルオロ−２,３−ジヒドロ−１,４−ベンゾジオキシン−６−イル）−１Ｈ−ピラゾール−４−カルボキサミド（中間体Ｂ）、および、中間体Ｄではなく釣り合う量のＮ−［４−（クロロメチル）ピリジン−２−イル］メタンスルホンアミド（中間体Ｋ）、並びに、釣り合う量の他の反応成分で出発して、表題化合物を製造する。反応混合物を、ホイルで包んだフラスコ中、１６時間６０℃に加熱し、次いで冷却する。反応混合物を酢酸エチルで希釈し、水で洗浄し、乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させる。粗生成物を分取ＨＰＬＣにより精製し、純粋な表題化合物を得る。 Example 7
1-methyl-5-[({2-[(methylsulfonyl) amino] pyridin-4-yl} methyl) amino] -N- (2,2,3,3-tetrafluoro-2,3-dihydro-1 , 4-Benzodioxin-6-yl) -1H-pyrazole-4-carboxamide

Using the same method as described for Example 1, but 5-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H- 5-amino-1-methyl-N- (2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl rather than pyrazole-4-carboxamide (intermediate A) ) -1H-pyrazole-4-carboxamide (Intermediate B) and a balanced amount of N- [4- (chloromethyl) pyridin-2-yl] methanesulfonamide (Intermediate K) rather than Intermediate D, and Starting with a balanced amount of other reaction components, the title compound is prepared. The reaction mixture is heated to 60 ° C. in a foil wrapped flask for 16 hours and then cooled. The reaction mixture is diluted with ethyl acetate, washed with water, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The crude product is purified by preparative HPLC to give the pure title compound.

Example 8
5-{[(2-{[(Ethylamino) carbonyl] amino} pyridin-4-yl) methyl] amino} -1-methyl-N- (2,2,3.3-tetrafluoro-2,3- Preparation of dihydro-1,4-benzodioxin-6-yl) -1H-pyrazole-4-carboxamide

実施例２について記載したものと同じ方法を使用して、段階１、２、３および４を使用して、表題化合物を製造した。段階２で、中間体Ｐの代わりに中間体ＰＰを使用した。
¹H NMR (300 MHz, CD3OD-d₄) δ 8.45 (d, 1H), 7.85 (s, 1H), 7.62 (m, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 7.20 (m, 2H), 5.75 (s, 1H), 4.70 (s, 2H), 3.75 (s, 3H), 1.93 (s, 6H); ES-MS m/z 485.1 [M+H]⁺, LCMS RT (分) 3.45. Step 1 5-({[2- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-4-yl] methyl} amino) -1-methyl-N- (2,2,3,3- Preparation of tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) -1H-pyrazole-4-carboxamide

The title compound was prepared using steps 1, 2, 3 and 4 using the same method as described for Example 2. In Step 2, intermediate PP was used instead of intermediate P.
¹ H NMR (300 MHz, CD3OD-d ₄ ) δ 8.45 (d, 1H), 7.85 (s, 1H), 7.62 (m, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 7.20 ( m, 2H), 5.75 (s, 1H), 4.70 (s, 2H), 3.75 (s, 3H), 1.93 (s, 6H); ES-MS m / z 485.1 [M + H] ⁺ , LCMS RT ( Min) 3.45.

エタノール（３ｍＬ）中の５−（｛［２−（２,５−ジメチル−１Ｈ−ピロール−１−イル）ピリジン−４−イル］メチル｝アミノ）−１−メチル−Ｎ−（２,２,３,３−テトラフルオロ−２,３−ジヒドロ−１,４−ベンゾジオキシン−６−イル）−１Ｈ−ピラゾール−４−カルボキサミド（３４０ｍｇ、０.６４ｍｍｏｌ）の溶液に、水（１ｍＬ）、ヒドロキシルアミン塩酸塩（４４５ｍｇ、６.４１ｍｍｏｌ）、続いてトリエチルアミン（０.１８ｍＬ）を添加した。混合物を加熱して５時間還流させ、次いで冷却した。混合物をＥｔＯＡｃで希釈し、飽和ＮａＨＣＯ_３で抽出した。有機層を乾燥し、蒸発させ、ＤＣＭ中の０−１０％ＭｅＯＨをグラジエントとして使用してシリカゲルで精製し、白色固体２２２ｍｇ（７７％）を得た。
¹H NMR (300 MHz, CD3OD-d₄) δ 7.85 (s, 1H), 7.79 (m, 2H), 7.42 (m, 1H), 7.20 (d, 1H), 6.58 (m,2H), 4.44 (s,2H), 3.74 (s,3H); ES-MS m/z 453.0 [M+H]⁺, LCMS RT (分) 2.50. Step 2 5-{[(2-Aminopyridin-4-yl) methyl] amino} -1-methyl-N- (2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzo Preparation of dioxin-6-yl) -1H-pyrazole-4-carboxamide

5-({[2- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-4-yl] methyl} amino) -1-methyl-N- (2,2 ,, in ethanol (3 mL) To a solution of 3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) -1H-pyrazole-4-carboxamide (340 mg, 0.64 mmol), water (1 mL), hydroxylamine Hydrochloride (445 mg, 6.41 mmol) was added followed by triethylamine (0.18 mL). The mixture was heated to reflux for 5 hours and then cooled. The mixture was diluted with EtOAc and extracted with saturated NaHCO ₃ . The organic layer was dried, evaporated and purified on silica gel using 0-10% MeOH in DCM as a gradient to give 222 mg (77%) of a white solid.
¹ H NMR (300 MHz, CD3OD-d ₄ ) δ 7.85 (s, 1H), 7.79 (m, 2H), 7.42 (m, 1H), 7.20 (d, 1H), 6.58 (m, 2H), 4.44 ( s, 2H), 3.74 (s, 3H); ES-MS m / z 453.0 [M + H] ⁺ , LCMS RT (min) 2.50.

ジクロロエタン（１ｍＬ）中の５−｛［（２−アミノピリジン−４−イル）メチル］アミノ｝−１−メチル−Ｎ−（２,２,３,３−テトラフルオロ−２,３−ジヒドロ−１,４−ベンゾジオキシン−６−イル）−１Ｈ−ピラゾール−４−カルボキサミド（１００ｍｇ、０.２２ｍｍｏｌ）の溶液に、エチルイソシアネート（０.３ｍＬ、３.３３ｍｍｏｌ）を添加した。混合物を室温で７２時間撹拌した。反応が進むにつれ、固体が沈殿した。エーテル（２ｍＬ）を反応混合物に添加し、固体を濾過した。固体をメタノールで洗浄し（１ｍＬ、残っている出発物質を除去するため）、再度エーテル（２ｍＬ）で洗浄し、その後、蒸発させて所望の生成物（６２ｍｇ、５３％）を得た。
¹H NMR (300 MHz, DMSO-d₆) δ 9.80 (s, 1H), 9.12 (s, 1H), 8.05 (m, 2H), 7.88 (m, 1H), 7.82 (s, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.30 (bs, 1H), 6.98 (t, 1H), 6.80 (d, 1H), 4.54 (d, 2H), 6.05 (s, 3H), 3.15 (m, 2H), 1.02 (t, 3H); ES-MS m/z 524.1 [M+H]⁺, LCMS RT (分) 2.71. Step 3 5-{[(2-{[(Ethylamino) carbonyl] amino} pyridin-4-yl) methyl] amino) -1-methyl-N- (2,2,3,3-tetrafluoro-2, Preparation of 3-dihydro-1,4-benzodioxin-6-yl) -1H-pyrazole-4-carboxamide

5-{[(2-Aminopyridin-4-yl) methyl] amino} -1-methyl-N- (2,2,3,3-tetrafluoro-2,3-dihydro-1 in dichloroethane (1 mL) , 4-Benzodioxin-6-yl) -1H-pyrazole-4-carboxamide (100 mg, 0.22 mmol) was added ethyl isocyanate (0.3 mL, 3.33 mmol). The mixture was stirred at room temperature for 72 hours. As the reaction progressed, a solid precipitated. Ether (2 mL) was added to the reaction mixture and the solid was filtered. The solid was washed with methanol (1 mL, to remove remaining starting material), washed again with ether (2 mL) and then evaporated to give the desired product (62 mg, 53%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 9.12 (s, 1H), 8.05 (m, 2H), 7.88 (m, 1H), 7.82 (s, 1H), 7.45 ( m, 1H), 7.40 (m, 1H), 7.30 (bs, 1H), 6.98 (t, 1H), 6.80 (d, 1H), 4.54 (d, 2H), 6.05 (s, 3H), 3.15 (m , 2H), 1.02 (t, 3H); ES-MS m / z 524.1 [M + H] ⁺ , LCMS RT (min) 2.71.

  The compounds of Examples 13, 14 and 15 shown in Table B were prepared according to this method, substituting the appropriate starting materials.

実施例２について記載したものと同じ方法を使用して、段階１、２、３および４を使用して、表題化合物を製造した。段階２で、２−クロロ−４−クロロメチルピリジンの代わりに中間体Ｎを使用した。段階４で、適切なアニリンで置き換えて、表題化合物を得た。
¹H NMR (300 MHz, CD₃OD-d₄) δ 8.25 (s, 1H), 8.15 (m, 1H), 7.90-7.97 (m, 2H), 7.32-7.37 (m, 1H), 7.12 (s, 1H), 6.94-6.97 (m, 1H), 4.60 (s, 2H、水のピークの下), 3.75 (s, 3H), 2.88 (s, 3H), ES-MS m/z 510.0 [M+H]⁺, LCMS RT (分) 2.67. Example 9
1-methyl-5-{[(2-{[(methylamino) carbonyl] amino} pyridin-4-yl) methyl] amino} -N- (2,2,4,4-tetrafluoro-4H-1, Preparation of 3-benzodioxin-6-yl) -1H-pyrazole-4-carboxamide

The title compound was prepared using steps 1, 2, 3 and 4 using the same method as described for Example 2. In Step 2, intermediate N was used instead of 2-chloro-4-chloromethylpyridine. In step 4, the appropriate aniline was replaced to give the title compound.
¹ H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 8.25 (s, 1H), 8.15 (m, 1H), 7.90-7.97 (m, 2H), 7.32-7.37 (m, 1H), 7.12 (s , 1H), 6.94-6.97 (m, 1H), 4.60 (s, 2H, under water peak), 3.75 (s, 3H), 2.88 (s, 3H), ES-MS m / z 510.0 (M + H] ⁺ , LCMS RT (min) 2.67.

  Examples 17, 18 and 19 shown in Table B were prepared according to this method, substituting the appropriate starting materials.

実施例２について記載したものと同じ方法を使用して、段階１、２、３および４を使用して、表題化合物を製造した。段階２で、２−クロロ−４−クロロメチルピリジンの代わりに中間体Ｒを使用した。段階３で、加水分解はホルミル基と共にベンゾイル基も除去し、エステルを加水分解する。
¹H NMR (300 MHz, CD3OD-d₄) δ 8.18 (d, 1H), 7.85 (s, 1H), 7.70 (m, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 7.13 (m, 1H), 4.75 (s, 2H), 3.74 (s, 3H); ES-MS m/z 446.0 [M+H]⁺, LCMS RT (分) 2.34. Example 10
5-[({2-[(aminocarbonyl) amino] pyridin-4-yl} methyl) amino] -N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1- Preparation of methyl-1H-pyrazole-4-carboxamide

The title compound was prepared using steps 1, 2, 3 and 4 using the same method as described for Example 2. In Step 2, intermediate R was used instead of 2-chloro-4-chloromethylpyridine. In step 3, hydrolysis removes the benzoyl group as well as the formyl group and hydrolyzes the ester.
¹ H NMR (300 MHz, CD3OD-d ₄ ) δ 8.18 (d, 1H), 7.85 (s, 1H), 7.70 (m, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 7.20 ( m, 1H), 7.13 (m, 1H), 4.75 (s, 2H), 3.74 (s, 3H); ES-MS m / z 446.0 [M + H] ⁺ , LCMS RT (min) 2.34.

  Example 16 shown in Table B was prepared according to this method, substituting the appropriate starting materials.

実施例１について記載したものと同じ方法を使用して表題化合物を製造した。中間体Ｄの代わりに中間体Ｌを使用し、濃縮したＨＰＬＣ画分を、ＮａＨＣＯ_３で遊離塩基化せずに分析した。
¹H NMR (300 MHz, CD3CN) δ 8.45 (s, 1H), 8.30 (s, 1H), 8.02 (d, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 7.26 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 4.65 (s, 2H), 3.68 (s, 3H), 3.28 (q, 2H), 1.15 (t, 3H); ES-MS m/z 474.3 [M+H]⁺, LCMS RT (分) 2.53. Example 11
N- (2,2-difluoro-1,3-benzodioxol-5-yl) -5-{[(2-{[(ethylamino) carbonyl] amino} pyridin-4-yl) methyl] amino} -1-methyl-1H-pyrazole-4-carboxamide trifluoroacetate

The title compound was prepared using the same method as described for Example 1. Intermediate L was used in place of Intermediate D and the concentrated HPLC fraction was analyzed without free basification with NaHCO ₃ .
¹ H NMR (300 MHz, CD3CN) δ 8.45 (s, 1H), 8.30 (s, 1H), 8.02 (d, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.34 (s, 1H ), 7.26 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 4.65 (s, 2H), 3.68 (s, 3H), 3.28 (q, 2H), 1.15 (t, 3H) ; ES-MS m / z 474.3 [M + H] ⁺ , LCMS RT (min) 2.53.

Example 12
N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-5-{[(2-{[(methylamino) carbonyl] amino} pyridin-4-yl) Preparation of methyl] amino} -1H-pyrazole-4-carboxamide trifluoroacetate

ＴＨＦ（７.５ｍｌ）中の実施例２段階１由来の粗製エチル５−（ホルミルアミノ）−１−メチル−１Ｈ−ピラゾール−４−カルボキシレート（５００.００ｍｇ、２.５４ｍｍｏｌ）の溶液を、ジアザビシクロ（５.４.０）ウンデカ−７−エン（０.５７ｍｌ、３.８０ｍｍｏｌ）で処理し、室温で３０分間撹拌した。２−アミノ−４−クロロメチルピリジン（７２３.０９ｍｇ、５.０７ｍｍｏｌ）を添加し、反応混合物を６０℃に１時間加熱し、次いで、室温で１６時間撹拌した。次いで、反応混合物を酢酸エチルで希釈し、飽和ＮａＨＣＯ_３溶液で、続いて水で、次いで塩水で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空で濃縮し、生成物４４０ｍｇ（５７.１％、純粋でない）を、生成物と脱ホルミル化生成物の２：１混合物として得た。
ES-MS m/z 304.1 [M+H]⁺, HPLC RT (分) 1.08. Step 1: Preparation of ethyl 5-[[(2-aminopyridin-4-yl) methyl] (formyl) amino] -1-methyl-1H-pyrazole-4-carboxylate

A solution of crude ethyl 5- (formylamino) -1-methyl-1H-pyrazole-4-carboxylate (500.00 mg, 2.54 mmol) from Example 2 Step 1 in THF (7.5 ml) was diluted with diazabicyclo. Treated with (5.4.0) undec-7-ene (0.57 ml, 3.80 mmol) and stirred at room temperature for 30 minutes. 2-Amino-4-chloromethylpyridine (723.09 mg, 5.07 mmol) was added and the reaction mixture was heated to 60 ° C. for 1 hour and then stirred at room temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate and washed with saturated NaHCO ₃ solution followed by water and then brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 440 mg (57.1%, impure) of product as a 2: 1 mixture of product and deformylated product.
ES-MS m / z 304.1 [M + H] ⁺ , HPLC RT (min) 1.08.

ＴＨＦ（５ｍｌ）中の粗製エチル５−［［（２−アミノピリジン−４−イル）メチル］（ホルミル）アミノ］−１−メチル−１Ｈ−ピラゾール−４−カルボキシレート（５００.００ｍｇ、１.６５ｍｍｏｌ）の溶液を、Ｎ,Ｎ−ジイソプロピルエチルアミン（０.３２ｍｌ、１.８１ｍｍｏｌ）および４−ジメチルアミノピリジン（２０.１４ｍｇ、０.１６ｍｍｏｌ）で処置した。ジ−ｔｅｒｔ−ブチルジカーボネート（１.８１ｍｌ、１Ｍ溶液、ＴＨＦ中）を反応混合物に添加し、室温で１６時間撹拌した。次いで、反応混合物を酢酸エチルで希釈し、濃ＮＨ_４Ｃｌ溶液で、続いて水で、次いで塩水で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空で濃縮した。粗製の残渣をエーテルでトリチュレートし、溶媒を再度蒸発させ、生成物６００ｍｇ（９０.１％、純粋でない）を得た。生成物を精製せずに使用した。 Step 2: Preparation of ethyl 5-[({2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} methyl) (formyl) amino] -1-methyl-1H-pyrazole-4-carboxylate

Crude ethyl 5-[[(2-aminopyridin-4-yl) methyl] (formyl) amino] -1-methyl-1H-pyrazole-4-carboxylate (500.00 mg, 1.65 mmol in THF (5 ml). ) Was treated with N, N-diisopropylethylamine (0.32 ml, 1.81 mmol) and 4-dimethylaminopyridine (20.14 mg, 0.16 mmol). Di-tert-butyl dicarbonate (1.81 ml, 1M solution in THF) was added to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate and washed with concentrated NH ₄ Cl solution followed by water and then brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was triturated with ether and the solvent was evaporated again to give product 600 mg (90.1%, impure). The product was used without purification.

実施例２、段階３と同様に、エチル５−［（｛２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ピリジン−４−イル｝メチル）（ホルミル）アミノ］−１−メチル−１Ｈ−ピラゾール−４−カルボキシレート（６００.０ｍｇ、１.４９ｍｍｏｌ）を出発物質として使用して、表題化合物（１３０.０ｍｇ、２５.１％）を製造した。
¹H NMR (300 MHz, CD₃CN) δ 8.28 (bs, 1H), 8.18 (d, 1H), 7.89 (s, 1H), 7.55 (d, 1H), 6.98 (m, 1H), 4.59 (m, 2H), 3.64 (s, 3H), 1.50 (s, 9H). Step 3: Preparation of 5-[({2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} methyl) amino] -1-methyl-1H-pyrazole-4-carboxylic acid

As in Example 2, Step 3, ethyl 5-[({2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} methyl) (formyl) amino] -1-methyl-1H-pyrazole-4 -The carboxylate (600.0 mg, 1.49 mmol) was used as starting material to prepare the title compound (130.0 mg, 25.1%).
¹ H NMR (300 MHz, CD ₃ CN) δ 8.28 (bs, 1H), 8.18 (d, 1H), 7.89 (s, 1H), 7.55 (d, 1H), 6.98 (m, 1H), 4.59 (m , 2H), 3.64 (s, 3H), 1.50 (s, 9H).

実施例２、段階４と同様に、５−［（｛２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ピリジン−４−イル｝メチル）アミノ］−１−メチル−１Ｈ−ピラゾール−４−カルボン酸（１３０.０ｍｇ、０.３７ｍｍｏｌ）を出発物質として使用して、表題化合物（９０.０ｍｇ、４８.４％）を製造した。この物質を精製せずに使用した。
ES-MS m/z 502.8 [M+H]⁺, HPLC RT (分) 2.83. Step 4: tert-butyl (4-{[(4-{[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazole-5 Preparation of -yl) amino] methyl} pyridin-2-yl) carbamate

As in Example 2, Step 4, 5-[({2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} methyl) amino] -1-methyl-1H-pyrazole-4-carboxylic acid ( The title compound (90.0 mg, 48.4%) was prepared using 130.0 mg, 0.37 mmol) as the starting material. This material was used without purification.
ES-MS m / z 502.8 [M + H] ⁺ , HPLC RT (min) 2.83.

ジクロロメタン（１.５ｍｌ）中のｔｅｒｔ−ブチル（４−｛［（４−｛［（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）アミノ］カルボニル｝−１−メチル−１Ｈ−ピラゾール−５−イル）アミノ］メチル｝ピリジン−２−イル）カルバメート（６６.１５ｍｇ、０.１３ｍｍｏｌ）の溶液を、トリフルオロ酢酸（１.４ｍｌ、１８.１２ｍｍｏｌ）で処理し、室温で１６時間撹拌した。次いで、反応混合物を酢酸エチルで希釈し、１Ｎ ＮａＯＨ溶液で洗浄した。水層をＥｔＯＡｃで抽出し、有機抽出物を合わせ、ＭｇＳＯ_４で乾燥した。ＥｔＯＡｃ溶液を真空で濃縮し、^１Ｈ ＮＭＲで５０％純粋であると見積もられる粗生成物６０.０ｍｇ（＞９９％）を得た。生成物を精製せずに使用した。
ES-MS m/z 403.1 [M+H]⁺, HPLC RT (分) 0.99. Step 5: 5-{[(2-Aminopyridin-4-yl) methyl] amino} -N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H -Preparation of pyrazole-4-carboxamide

Tert-Butyl (4-{[(4-{[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl- in dichloromethane (1.5 ml) A solution of 1H-pyrazol-5-yl) amino] methyl} pyridin-2-yl) carbamate (66.15 mg, 0.13 mmol) was treated with trifluoroacetic acid (1.4 ml, 18.12 mmol) at room temperature. Stir for 16 hours. The reaction mixture was then diluted with ethyl acetate and washed with 1N NaOH solution. The aqueous layer was extracted with EtOAc and the organic extracts were combined and dried over MgSO ₄ . The EtOAc solution was concentrated in vacuo to give 60.0 mg (> 99%) of crude product estimated to be 50% pure by ¹ H NMR. The product was used without purification.
ES-MS m / z 403.1 [M + H] ⁺ , HPLC RT (min) 0.99.

実施例８段階３に記載のものと同じ方法を使用して、表題化合物を製造した。段階３で、エチルイソシアネートの代わりにメチルイソシアネートを使用した。最終段階の後処理は、濃縮したＨＰＬＣ画分をＮａＨＣＯ_３で遊離塩基化せずに分析した点で異なった。
¹H NMR (300 MHz, CD3CN) δ 12.10 (s, 1H), 8.40 (s, 1H), 8.06 (bd, 2H), 7.72 (d, 2H), 7.32 (s, 1H), 7.20-7.27 (m, 2H), 7.15 (d, 1H), 4.63 (s, 2H), 3.63 (s, 3H), 2.80 (d, 3H); ES-MS m/z 460.3 [M+H]⁺, LCMS RT (分) 2.37. Step 6: N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-5-{[(2-{[(methylamino) carbonyl] amino} pyridine-4 Preparation of -yl) methyl] amino} -1H-pyrazole-4-carboxamide trifluoroacetate

The title compound was prepared using the same method as described in Example 8 Step 3. In Step 3, methyl isocyanate was used instead of ethyl isocyanate. The final work-up differed in that the concentrated HPLC fraction was analyzed without free basification with NaHCO ₃ .
¹ H NMR (300 MHz, CD3CN) δ 12.10 (s, 1H), 8.40 (s, 1H), 8.06 (bd, 2H), 7.72 (d, 2H), 7.32 (s, 1H), 7.20-7.27 (m , 2H), 7.15 (d, 1H), 4.63 (s, 2H), 3.63 (s, 3H), 2.80 (d, 3H); ES-MS m / z 460.3 [M + H] ⁺ , LCMS RT (min 2.37.

Table B

Example 20-a
N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-5-{[(2 {methyl [(methylamino) carbonyl] amino} pyridin-4-yl) Preparation of methyl] amino} -1H-pyrazole 4-carboxamide

ピリジン中の（２−クロロピリジン−４−イル）メタノール（中間体Ｐの製造、段階１由来）およびメチルアミン塩酸塩の溶液を、２００℃で、密閉チューブ中で、約１６時間加熱する。真空で蒸発させることにより溶媒を除去し、粗生成物の残渣を、ジクロロメタンから約１０％メタノールを含むジクロロメタンへのグラジエントを使用して、シリカゲルのクロマトグラフィーにより精製する。 Step 1: Preparation of [2- (methylamino) pyridin-4-yl] methanol

A solution of (2-chloropyridin-4-yl) methanol (preparation of intermediate P, from stage 1) and methylamine hydrochloride in pyridine is heated at 200 ° C. in a sealed tube for about 16 hours. The solvent is removed by evaporation in vacuo and the crude product residue is purified by chromatography on silica gel using a gradient from dichloromethane to dichloromethane containing about 10% methanol.

中間体Ｅの製造の一般方法、段階１の使用により、しかし、（２−アミノピリジン−４−イル）メタノールの代わりに［２−（メチルアミノ）ピリジン−４−イル］メタノールを用いて、表題化合物を製造する。 Step 2 Preparation of 4- (chloromethyl) -N-methylpyridin-2-amine

By using the general method for the preparation of intermediate E, step 1, but using [2- (methylamino) pyridin-4-yl] methanol instead of (2-aminopyridin-4-yl) methanol A compound is produced.

この段階は、中間体Ｌの製造について記載した方法を使用して、しかし、４−（クロロメチル）ピリジン−２−アミンではなく上記段階２の生成物を、そして、エチルイソシアネートではなくメチルイソシアネートを使用して、実施する。 Stage 3. Production of N- [4- (chloromethyl) pyridin-2-yl] -N, N′-dimethylurea

This step uses the method described for the preparation of intermediate L, but the product of step 2 above instead of 4- (chloromethyl) pyridin-2-amine and methyl isocyanate instead of ethyl isocyanate. Use and implement.

実施例１について記載したものと同じ方法を使用して、しかし、５−アミノ−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１−メチル−１Ｈ−ピラゾール−４−カルボキサミド（中間体Ａ）、および、中間体Ｄではなく釣り合う量のＮ−［４−（クロロメチル）ピリジン−２−イル］−Ｎ,Ｎ'−ジメチルウレア（段階３由来）で開始して、表題化合物を製造できる。反応混合物を、ホイルで包んだフラスコ中、６０℃で、窒素下に、２ないし２４時間、反応混合物のＬＣＭＳ分析が生成物への実質的な変換を示すまで加熱する。得られた最終粗製混合物を飽和水性重炭酸ナトリウムで希釈し、酢酸エチルで３回抽出する。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、残渣を得、それを分取Ｃ１８ＨＰＬＣにより、０.０５−０.１％ＴＦＡを添加した水からアセトニトリルへのグラジエント（通常１０−５０％）を使用して精製する。生成物を含有する画分に飽和水性ＮａＨＣＯ_３を添加し、ジクロロメタンで抽出し、続いて抽出物を乾燥させ（Ｎａ_２ＳＯ_４）、真空で濃縮することにより、ＴＦＡ塩から遊離塩基を製造し、純粋な表題化合物を得る。 Step 4: N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-5-{[(2- {methyl [(methylamino) carbonyl] amino} pyridine- 4-yl) methyl] amino} -1H-pyrazole-4-carboxamide

Using the same method as described for Example 1, but 5-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H- With pyrazole-4-carboxamide (intermediate A) and a balanced amount of N- [4- (chloromethyl) pyridin-2-yl] -N, N′-dimethylurea (from stage 3) rather than intermediate D Starting, the title compound can be prepared. The reaction mixture is heated in a foil-wrapped flask at 60 ° C. under nitrogen for 2 to 24 hours until LCMS analysis of the reaction mixture shows substantial conversion to product. The final crude mixture obtained is diluted with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a residue which was purified by preparative C18 HPLC with a gradient of water to acetonitrile with addition of 0.05-0.1% TFA (usually 10-50%). The free base is prepared from the TFA salt by adding saturated aqueous NaHCO ₃ to the product containing fraction and extracting with dichloromethane followed by drying the extract (Na ₂ SO ₄ ) and concentrating in vacuo. The pure title compound is obtained.

Examples 20-b to 20-x

中間体Ｌの製造について記載した方法の使用により、しかし、エチルイソシアネートではなく適切なアルキルまたはアリールイソシアネートを用いて（ＤＭＦまたはジクロロメタンのいずれかを使用する）、表Ｃの実施例２０−ｂないし２０−ｇ、２０−ｉおよび２０−ｏないし２０−ｗをもたらす中間体を製造する。中間体Ｅの製造について記載した方法の段階２の使用により、しかし、アセトキシアセチルクロリドではなく適切なカルバモイルクロリドを使用して、表Ｃの実施例２１−ｋないし２１−ｎをもたらす中間体を製造できる。全ての場合で、適切なイソシアネートまたはカルバモイルクロリドは、購入できるか、または、その合成は当業者にとって単純なものであり、一般的な文献で報告されている。 Step 1: Preparation of various N- [4- (chloromethyl) pyridin-2-yl] ureas having other N′-substituents

Examples 20-b to 20 in Table C by use of the method described for the preparation of intermediate L, but with the appropriate alkyl or aryl isocyanate rather than ethyl isocyanate (using either DMF or dichloromethane) Prepare intermediates that yield -g, 20-i and 20-o to 20-w. Preparation of intermediates resulting in examples 21-k to 21-n of Table C by use of step 2 of the process described for the preparation of intermediate E, but using the appropriate carbamoyl chloride rather than acetoxyacetyl chloride it can. In all cases, the appropriate isocyanates or carbamoyl chlorides can be purchased or their synthesis is simple for the person skilled in the art and reported in the general literature.

実施例１について記載したものと同じ方法を使用して、しかし、５−アミノ−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１−メチル−１Ｈ−ピラゾール−４−カルボキサミド（中間体Ａ）または中間体Ａの代わりに中間体Ｂ、Ｂ−２、Ｂ−３、Ｂ−４またはＢ−５のリストからの他の物質、および、中間体Ｄではなく釣り合う量の適切な上記段階１由来の中間体、並びに、釣り合う量の他の反応成分を使用して、表題化合物を製造できる。反応混合物を６０℃で、ホイルで包んだフラスコ中、２ないし２４時間、反応混合物のＬＣＭＳ分析が実質的な生成物への変換を示すまで加熱する。得られる最終粗製混合物を飽和水性重炭酸ナトリウムで希釈し、酢酸エチルで３回抽出する。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、残渣を得、それを、０.０５−０.１％ＴＦＡを添加した水からアセトニトリルへのグラジエント（通常１０−５０％）を使用する分取Ｃ１８ＨＰＬＣにより精製する。生成物を含有する画分に飽和水性ＮａＨＣＯ_３を添加し、ジクロロメタンで抽出し、続いて抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で濃縮することにより、ＴＦＡ塩から遊離塩基を製造し、純粋な表題化合物を得る。表題化合物２０−ｈおよび２０−ｊの場合、各々最初に保護された生成物２０−ｇおよび２０−ｉを、メタノールまたはエタノール中の炭酸カリウムによる処理で最終表題化合物に変換する。表題化合物２０−ａないし２０−ｘの構造および名称を表Ｃに示す。 Step 2: Preparation of the title compound (Table C)

Using the same method as described for Example 1, but 5-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H- For pyrazole-4-carboxamide (intermediate A) or other substances from the list of intermediate B, B-2, B-3, B-4 or B-5 instead of intermediate A, and intermediate D A balanced amount of the appropriate intermediate from Step 1 above, as well as a balanced amount of other reaction components, can be used to produce the title compound. The reaction mixture is heated at 60 ° C. in a foil wrapped flask for 2 to 24 hours until LCMS analysis of the reaction mixture shows conversion to substantial product. The resulting final crude mixture is diluted with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a residue which was gradientd from water to acetonitrile with 0.05-0.1% TFA (usually 10-50%). ) Using preparative C18 HPLC. The free base is prepared from the TFA salt by adding saturated aqueous NaHCO ₃ to the product containing fraction and extracting with dichloromethane, followed by drying the extract (Na ₂ SO ₄ ) and concentrating in vacuo. The pure title compound is obtained. In the case of the title compounds 20-h and 20-j, the initially protected products 20-g and 20-i, respectively, are converted to the final title compound by treatment with potassium carbonate in methanol or ethanol. The structures and names of the title compounds 20-a to 20-x are shown in Table C.

Table C

Example 21
N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-5-({[2- (methylamino) pyrimidin-4-yl] methyl} amino) -1H -Preparation of pyrazole-4-carboxamide

無水ＤＭＦ（０.５ｍＬ）中の２,４−ジクロロ−６−（クロロメチル）ピリミジン（中間体Ｏ、９９ｍｇ、０.５ｍｍｏｌ）およびヨウ化ナトリウム（７５ｍｇ、０.５ｍｍｏｌ）の混合物を、窒素下で、溶液が形成されるまで撹拌し、次いで、５−アミノ−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１−メチル−１Ｈ−ピラゾール−４−カルボキサミド（中間体Ａ、１００ｍｇ、０.３３ｍｍｏｌ）を添加する。得られる混合物を加熱し、窒素下に４０℃で４時間、次いで５９℃で終夜撹拌する。ＴＬＣ分析後にいくらかの残存するピラゾール出発物質が存在するならば、さらに２,４−ジクロロ−６−（クロロメチル）ピリミジン（３０ｍｇ）を添加し、反応混合物を再度５９℃でさらに２時間加熱する。得られる最終粗製混合物を飽和水性重炭酸ナトリウムで希釈し、酢酸エチルで３回抽出する。合わせた抽出物を乾燥し（Ｎａ_２ＳＯ_４）、真空で蒸発させ、残渣を得、ヘキサン中の１０−４０％酢酸エチルのグラジエントを使用して、シリカゲルのクロマトグラフィーにより精製する。 Stage 1.5-{[(2,6-dichloropyrimidin-4-yl) methyl] amino} -N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl Of 1H-pyrazole-4-carboxamide

A mixture of 2,4-dichloro-6- (chloromethyl) pyrimidine (Intermediate O, 99 mg, 0.5 mmol) and sodium iodide (75 mg, 0.5 mmol) in anhydrous DMF (0.5 mL) was added under nitrogen. Until a solution is formed, then 5-amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole-4- Carboxamide (Intermediate A, 100 mg, 0.33 mmol) is added. The resulting mixture is heated and stirred under nitrogen at 40 ° C. for 4 hours and then at 59 ° C. overnight. If some residual pyrazole starting material is present after TLC analysis, more 2,4-dichloro-6- (chloromethyl) pyrimidine (30 mg) is added and the reaction mixture is again heated at 59 ° C. for a further 2 hours. The resulting final crude mixture is diluted with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined extracts were dried (Na 2 _{SO 4),} evaporated in vacuo to give a residue, using a gradient of 10-40% ethyl acetate in hexanes and purified by chromatography on silica gel.

メタノール（１.２ｍＬ）中の５−｛［（２,６−ジクロロピリミジン−４−イル）メチル］アミノ｝−Ｎ−（２,２−ジフルオロ−１,３−ベンゾジオキソール−５−イル）−１−メチル−１Ｈ−ピラゾール−４−カルボキサミド（段階１の生成物、０.２ｍｍｏｌ）およびメチルアミン（０.４ｍｍｏｌ）の溶液を、密閉チューブ中で〜５時間撹拌できる。生成物を、分取ＨＰＬＣの直接注入により精製でき、精製された異性体が得られ、６−（メチルアミノ）ピリミジン−４−イル異性体が主要な生成物であると期待される。 Step 2.5-({[6-Chloro-2- (methylamino) pyrimidin-4-yl] methyl} amino) -N- (2,2-difluoro-1,3-benzodioxol-5-yl ) -1-Methyl-1H-pyrazole-4-carboxamide and 5-({[2-chloro-6- (methylamino) pyrimidin-4-yl] methyl} amino) -N- (2,2-difluoro-1 , 3-Benzodioxol-5-yl) -1-methyl-1H-pyrazole-4-carboxamide

5-{[(2,6-dichloropyrimidin-4-yl) methyl] amino} -N- (2,2-difluoro-1,3-benzodioxol-5-yl in methanol (1.2 mL) A solution of -1-methyl-1H-pyrazole-4-carboxamide (stage 1 product, 0.2 mmol) and methylamine (0.4 mmol) can be stirred in a sealed tube for ˜5 hours. The product can be purified by direct injection of preparative HPLC, yielding a purified isomer, and the 6- (methylamino) pyrimidin-4-yl isomer is expected to be the major product.

Stage 3. Preparation of the title compound 5-({[6-Chloro-2- (methylamino) pyrimidin-4-yl] methyl} amino) -N- (2,2-difluoro in ethyl acetate (15 mL) and methanol (15 mL) -1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole-4-carboxamide (major product of Step 2, 0.18 mmol) plus palladium (II) hydroxide (0.36 mmol) ) And ammonium formate (1.76 mmol) can be stirred for 16 hours with heating at reflux. The solution was filtered of ^{Celite (R)} product using a filter aid, evaporated in vacuo. The residue can be purified by preparative C18 HPLC using a gradient of 5 to 45% acetonitrile in water plus 0.1% TFA. The pure compound can be obtained as the TFA salt by evaporation of the product-containing fractions. Alternatively, the product containing fractions can be mixed with saturated aqueous NaHCO ₃ and extracted with dichloromethane. The extract is dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the pure free base title compound.

この化合物は、実施例８に示す通りに製造された。これは、段階２の生成物である。 Example 22
5-{[(2-Aminopyridin-4-yl) methyl] amino} -1-methyl-N- (2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin- 6-yl) -1H-pyrazole-4-carboxamide

This compound was prepared as shown in Example 8. This is the product of stage 2.

この化合物は、実施例１２に示す通りに製造された。これは、段階４の生成物である。 Example 23
tert-Butyl (4-{[(4-{[(2,2-difluoro-1,3-benzodioxol-5-yl) amino] carbonyl} -1-methyl-1H-pyrazol-5-yl) Amino] methyl} pyridin-2-yl) carbamate

This compound was prepared as shown in Example 12. This is the product of stage 4.

この化合物は、実施例１２に示す通りに製造された。これは、段階５の生成物である。 Example 24
5-{[(2-Aminopyridin-4-yl) methyl] amino-N- (2,2-difluoro-1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazole-4 -Production of carboxamide

This compound was prepared as shown in Example 12. This is the product of stage 5.

B. Evaluation of physiological activity The usefulness of the compounds of the present invention can be illustrated, for example, by their activity in the following P-AKT / PKB cytoblot assay. The involvement of the P-AKT / PKB [PI3K / AKt] pathway as a target for cancer chemotherapy has been recognized in the art. For example, F. Chang et al, Involvement of PI3K / Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy, Leukemia, 2003, 17: p. 590-603; KA West et al, Activation of the PI3K / Akt pathway and chemotherapeutic resistance, Drug Resistance Updates, 2002, 5: p. 234-248; and P. Sen et al, Involvement of the Akt / PKB signaling pathway with disease processes, Molecular and Cellular Biochemistry, 2003, 253 : See pages 241-246.

Protocol of P-AKT / PKB cytoblot assay using H209 cells H209 small cell lung cancer cells in logarithmic phase at 50,000 cells / well, 96-well poly-lysine coated clear bottom / black wall plate (Becton-Dickinson, USA Cat # 354640) was seeded in 100 μl of RPMI medium containing 0.1% (w / v) BSA and incubated overnight at 37 ° C. in a 5% CO ₂ incubator. The next day, compounds (10 mM stock solution in DMSO) are added to the plates and 0.0, 0.01, 0.03, 0.1, 0.3, 1.0, 3.0 and for IC ₅₀ determinations. A final concentration of 10 μM was generated and incubated for 1 hour at 37 ° C. Cells were then left untreated or stimulated with Stem Cell Factor (SCF: Biosource Cat # PHC2116) at a final concentration of 25 ng / mL for 5 minutes at 37 ° C. in a 5% CO ₂ incubator. The medium was then removed using a vacuum manifold and the cells were washed once with Tris-buffered saline (TBS). Cells were then fixed by adding 200 μl of 3.7% (w / v) formaldehyde in cold TBS to each well for 15 minutes at 4 ° C. After removal of formaldehyde, cells were treated by adding 50 μl of methanol (−20 ° C.) to each well for 5 minutes. After removal of methanol, 200 μl of 1% (w / v) BSA in TBS was added to each well to block non-specific antibody binding sites and the plate was incubated at room temperature for 30 minutes.

  After removal of the blocking buffer, 50 μl of p- (S473) AKT rabbit polyclonal antibody (Cell Signaling, USA Cat # 9277S) was diluted 1: 250 with 0.1% (w / v) BSA in TBS and added. The plate was incubated for 1 hour at room temperature. The plates were then washed 3 times with cold TBS (TBS-T) containing 0.05% (v / v) Tween 20, and horse rabbit peroxidase (HRP) -conjugated goat-anti-rabbit antibody (Amersham, USA). Cat # NA934V) was added at a 1: 250 dilution in TBS-T and the plate was incubated for 1 hour at room temperature. After washing 4 times with ice-cold TBS-T, 100 μl of Enhanced Chemiluminescence (ECL) reagent (Amersham, USA Cat # RPN2209) was added to each well and mixed for 1 minute on a mini orbital shaker. The plate was then read on a Perkin Elmer Victor 5 Multilabel Counter (# 1420-0421).

The compounds of Examples 1, 3-a, 3-b, 3-c, 3-d, 8, 9, 10, 11, 12, 13, 14, 15, 16, 16, 17, 18, 19 are prepared as described above. The P-AKT / PKB cytoblot assay showed that these examples exhibited an IC ₅₀ of less than 500 nM. In certain embodiments, the invention relates to compounds that exhibit an IC ₅₀ value lower than 500 nM in this assay.

  The usefulness of the compounds of the present invention can also be illustrated, for example, by their activity in the phospho-ERK assay described below.

  Growth factor induction in the RAS / MEK / ERK signaling pathway leads to the induction of phosphorylation of a number of proteins including phospho-ERK (CJ Marshall, MAP kinase kinase kinase, MAP kinase kinase and MAP kinase, Current Opinions in Genetic Development) , 1994, 4: p. 82-89). The importance of this pathway in cancer biology has been recognized in the art. Activation of the RAS signaling pathway is an important mechanism by which cancer develops (R. Herrera, et al, Unraveling the complexities of the Raf / MAP kinase pathway for pharmacological intervention, Trends Mol. Med., 2002, 8: p. S27-31). Mutational activation of RAS or downstream effectors and the induction of growth factors for this pathway lead to increased tumor cell growth and survival (AA Adjei, Blocking oncogenic RAS signaling for cancer therapy, J. Natl. Cancer Inst. , 2001, 93 (14): p. 1062-1074; J Schlessinger, Cell signaling by receptor tyrosine kinases, Cell, 2000, 103: p. 211-225).

Protocol for Phospho-ERK cytoblot assay using MDA-MB231 cells MDA-MB-231 cells in log phase are 25,000 cells / well in 96-well opaque plates (Falcon, USA Cat # 353296) Were plated in 100 μL RPMI medium containing 10% (w / v) FBS and incubated overnight at 37 ° C. in a 5% CO ₂ incubator. The next day, the growth medium is removed from the plate by aspiration and diluted with 0.1% BSA to a final concentration of 0.0, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3. It was replaced with RPMI medium containing Example compounds at 1 and 3 μM. Cells were incubated with compounds for 1 hour at 37 ° C. in a 5% CO ₂ incubator. The medium was then removed from the plate by aspiration and the cells were washed once with 180 μL / well cold Tris-buffered saline (TBS). After removal of wash buffer, cells were fixed by adding 180 μl of 3.7% (w / v) formaldehyde in cold TBS to each well for 1 hour at 4 ° C. After removal of formaldehyde, cells were treated by adding 60 μl of −20 ° C. methanol to each well for 5 minutes at 4 ° C. Methanol was removed and cells were washed with 180 μl / well of 5% (w / v) BSA in TBS. To block nonspecific antibody binding sites, each well was treated with 180 μL / well of 5% BSA (w / v) in TBS for 30 minutes at room temperature. After removal of the blocking buffer, 50 μL of anti-phospho-p44 / 42 MAP kinase (Thr202 / Tyr204) rabbit polyclonal antibody (Cell Signaling, USA Cat # 9101) was added 1: 5 with TBS containing 5% (w / v) BSA in each well. Added at 1000 dilution and plates were incubated at 4 ° C. overnight. The plates were then washed 3 times with 300 μL / well TBS at room temperature. The plates were then incubated for 1 hour at room temperature with 50 μL of a 1: 1000 dilution of horse rabbit peroxidase (HRP) -conjugated goat-anti-rabbit antibody (Amersham, USA Cat. # NA934V) in 5% BSA-TBS. After the plate was washed 3 times with 300 μL / well TBS, 60 μL of Enhanced Chemiluminescence (ECL) reagent (Amersham, USA Cat # RPN2209) was added to each well and incubated at room temperature for 5 minutes. The plate was then read on a Perkin Elmer Victor 5 Multilabel Counter (# 1420-0421).

The compounds of Examples 1, 10, 11, 12, 13, 14, 15, 17, 18, 19 were tested. They showed IC ₅₀ values lower than 3 μM in this assay. In certain embodiments, the present invention relates to compounds that exhibit IC ₅₀ values lower than 3 μM.

  The usefulness of the compounds of the present invention can also be illustrated, for example, by their activity in the flk-1 (mouse VEGFR2) assay described below. The VEGF-VEGFR2 signaling pathway has been characterized in detail as an important regulator of angiogenesis and tumor angiogenesis (G. Yancopoulos et al, Vascular-specific growth factors and blood vessel formation, Nature, 2000, 407: p .. 242-248; D. Shweiki et al, Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency inmulticell spheroids: Implications for tumor angiogenesis, Proc. Natl. Acad. Sci, 1995, 92: p. 768-772). Inhibition of tumor cell growth by blocking this pathway has been described in detail in the art. Administration of soluble VEGFR2 receptor inhibits a wide range of tumor growth (C. Brans et al, Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal liver metastases, Cancer, 2000, 89: p. 495-499; B. Millauer et al, Glioblastoma growth inhibited in vivo by a dominant-negative FLK-I mutant, Nature, 1994, 367: p. 576-579). Neutralizing antibodies to VEGF or VEGFR2 and VEGF antisense inhibit tumor growth in vivo (K. Kim et al, Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo, Nature, 1993, 362: p. 841-844; M. Prewett et al, Antivascular endothelial growth factor receptor (fetal liver kinase I) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors, Cancer Research, 1999, 59: p. 5209-5218; M. Saleh et al, Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence, Cancer Research, 1996, 56: p. 393-401).

Flk-I (mouse VEGFR-2) biochemical assay This assay was performed in TR-FRET format in 96-well opaque plates (Costar, USA Cat # 3915). The reaction conditions were as follows: 10 μM ATP, 25 nM poly (Glu, Tyr) -biotin (CIS BIO International, USA Cat # 61 GTOBLD), 2 nM Eu-labeled phospho-TyrAb (Perkin Elmer, USA Cat # AD0067) ) 10 nM streptavidin-APC (Perkin Elmer, USA Cat # CR130-100), 7 nM Flk-1 (kinase domain), 1% DMSO, 50 mM HEPES pH 7.5, 10 mM MgCl ₂ , 0.1 mM EDTA, 0.015 % BRIJ, 0.1 mg / mL BSA, 0.1% mercapto-ethanol. Prior to enzyme addition, compounds were added at final concentrations ranging from 10 μM to 4.56 nM in 1% DMSO. The reaction started when the enzyme was added. The final reaction volume in each well was 100 μL. Time-resolved fluorescence was read after excitation at 340 nM. Luminescence readings were taken at 665 and 615 nM on a Perkin Elmer Victor V Multilabel counter 1.5-2.0 hours after the start of the reaction. The signal was calculated as follows: emission at 665 nm / emission at 615 nM x 10000 for each well.

The compounds of Examples 10, 13, 16, 17, 18, 19 were tested. They showed an IC ₅₀ lower than 500 nM in this assay. In certain embodiments, the present invention relates to compounds that exhibit IC ₅₀ values lower than 500 nM.

Methods of Treatment Accordingly, another embodiment of the present invention relates to methods of using the above-described compounds (including their salts and their corresponding compositions) as cancer chemotherapeutic agents. The method comprises administering to the patient an amount of a compound of the invention or a pharmaceutically acceptable salt thereof that is effective in treating the patient's cancer. For the purposes of the present invention, a patient is a mammal, including a human, in need of treatment for a particular cancer. Cancers include, but are not limited to, solid tumors such as breast, respiratory tract, brain, genitals, gastrointestinal tract, urinary organs, eyes, liver, skin, head and neck, thyroid, parathyroid cancer and their distant metastases. . These disorders also include lymphoma, sarcoma and leukemia.

  Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, noninvasive ductal carcinoma and noninvasive lobular carcinoma.

  Examples of respiratory tract cancers include, but are not limited to, small cell and non-small cell lung cancer, and bronchial adenoma and pleuropulmonary blastoma.

  Examples of brain cancer include brainstem and hypothalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, and neuroectodermal and pineal tumors However, it is not limited to these.

  Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive tract include, but are not limited to, endometrial, cervical, ovarian, vaginal and vulvar cancers, and uterine sarcoma.

  Gastrointestinal tumors include, but are not limited to, anus, colon, colorectal, esophagus, gallbladder, stomach, pancreas, rectum, small intestine and salivary gland cancer.

  Urological tumors include, but are not limited to, bladder, penis, kidney, renal pelvis, ureter and urethral cancer.

  Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

  Examples of cancers of the liver include hepatocellular carcinoma (carcinoma of the hepatocytes with or without fibrosis), cholangiocarcinoma (intrahepatic cholangiocarcinoma) and mixed hepatocellular cholangiocarcinoma, It is not limited to these.

  Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

  Head and neck cancers include, but are not limited to, laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.

  Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease and central nervous system lymphoma.

  Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

  Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia and hair cell leukemia.

  These disorders have been well characterized in humans, but exist in other mammals with similar etiology and can be treated by administration of the pharmaceutical compositions of the present invention.

  The compounds of the present invention can be administered as a single drug substance or in combination with one or more other drug substances if the combination does not cause unacceptable adverse effects. For example, the compounds of the present invention can be combined with known anti-hyperproliferative agents, chemotherapeutic agents or other potent substances, and mixtures and combinations thereof.

  Optional anti-hyperproliferative agents that can be added to the composition include, but are not limited to, compounds listed in the Merck Index, Eleventh Edition (1996), for example, chemotherapeutic medications for cancer, such as cisplatin. Not.

  Other anti-hyperproliferative agents suitable for use in the present invention include Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al, publ. By McGraw-Hill, pages 1225-1287, (1996). Compounds that are recognized for use in the treatment of neoplastic diseases, such as, but not limited to, idarubicin.

C. Specific examples of active compounds for pharmaceutical compositions The active compounds can act systemically, locally or both. For this purpose, it is suitable, for example, orally, parenterally, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, Alternatively, it can be administered by ear administration or in the form of an implant or stent. The active compound can be administered in forms suitable for these modes of administration.

Forms suitable for oral administration function by releasing the active compound rapidly or in a modified or controlled manner and containing the active compound in crystalline, amorphous or dissolved form, according to the prior art, for example Tablets (uncoated or coated, such as enteric coatings, or coatings that dissolve after a time delay, or insoluble coatings that control the release of the active compound), tablets that disintegrate rapidly in the oral cavity, or Films (oblates), film / lyophilizers, capsules (eg hard or soft gelatin capsules), dragees, pellets, powders, emulsions, suspensions and solutions. Summary of dosage ^{forms, Remington's Pharmaceutical Sciences, 18 th} ed. 1990, Mack Publishing Group, are described in the Enolo.

Parenteral administration avoids the resorption phase (eg, by intravenous, intraarterial, intracardiac, intraspinal or intralumbar administration) or includes absorption (eg, intramuscular, subcutaneous, intradermal or abdominal cavity) By internal administration). Suitable parenteral dosage forms are, for example, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates and sterile powders. Such parenteral pharmaceutical ^{compositions, Remington's Pharmaceutical Sciences, 18 th} ed. 1990, Mack Publishing Group, Part 8 of Enolo, are described in Chapter 84 Section.

  Dosage forms suitable for other modes of administration include, for example, inhalation devices (eg, powder inhalers, nebulizers, etc.), nasal sprays, solutions and sprays; tablets or films / oblates for tongue, sublingual or buccal administration, or Capsules, suppositories, ophthalmic and ear preparations, vaginal capsules, aqueous suspensions (lotions or shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milky lotions, pastes, foams, A dusting powder, an implant or a stent.

  The active compounds can be converted into the stated administration forms in a manner known to the person skilled in the art and according to the prior art using inert, non-toxic, pharmaceutically suitable auxiliaries. The latter include, for example, excipients (eg microcrystalline cellulose, lactose, mannitol, etc.), solvents (eg liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (eg sodium dodecyl sulfate, polyoxysorbitan oleate) Etc.), binders (eg polyvinylpyrrolidone), synthetic and / or natural polymers (eg albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxide), or , Taste and / or odor correctors.

  The total amount of active ingredient to be administered is generally about 0.01 mg / kg to about 200 mg / kg body weight, preferably about 0.1 mg / kg to about 20 mg / kg body weight per day. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques is preferably 0.01 to 200 mg / kg of total body weight. The daily oral dosage regimen is preferably 0.01 to 200 mg / kg of total body weight.

  However, depending on body weight, mode of administration, individual patient response to the active compound, type of formulation and time or interval of administration, it may be necessary to deviate from the above amounts.

If used as the active compound, the compounds according to the invention are preferably isolated in a substantially pure form, which is virtually free from residues resulting from synthetic operations. The degree of purity can be measured by methods known to chemists or pharmacist ^{(Remington's Pharmaceutical Sciences, 18 th} ed. 1990, Mack Publishing Group, see Enolo). Preferably, the compound is more than 99% (w / w) pure, but purity greater than 95%, 90% or 85% can be used if desired.

The compounds according to the invention can be converted into pharmaceutical preparations as follows:
tablet:
composition:
100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (natural), 10 mg polyvinylpyrrolidone (PVP25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
Tablet weight 212mg, diameter 8mm, curvature radius 12mm.
Manufacturing:
The mixture of active ingredient, lactose and starch is granulated with a 5% aqueous solution of PVP (m / m). After drying, the granules are mixed with magnesium stearate for 5 minutes. This mixture is tableted using a conventional tableting machine (see above for tablet shape). The tableting force applied is typically 15 kN.

Suspensions that can be administered orally:
composition:
1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
A single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.
Manufacturing:
Suspend Rhodigel in ethanol and add the active ingredient to the suspension. Add water with stirring. Stirring is continued for about 6 hours until the Rhodigel swelling is complete.

  Those skilled in the art will be able to make the most of the present invention using the above information. It will be apparent to those skilled in the art that changes and modifications can be made to the present invention without departing from the spirit or scope of the invention as described herein. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims (15)

Formula (I)

[Where:
Ar is

Selected from the group consisting of:
X is CH or N;
R ¹ is H, halogen,

Selected from the group consisting of {where,
R ^1-2 is
・ H,
· _(C 1 -C ₄₎ alkoxy,
(C ₁ -C ₄ ) alkyl, wherein the (C ₁ -C ₄ ) alkyl is
-Hydroxy,
- _(C 1 -C ₄₎ alkylamino,
- _(C 1 -C ₄₎ acyloxy,
- _(C 1 -C ₄₎ alkoxy and,
Zero or one or two _(C 1 -C ₄₎ is substituted with an alkoxy group _(C 2 -C ₄₎ 0 substituents independently selected from alkoxy, with one or two groups May be replaced,
Where the (C ₁ -C ₄ ) alkyl may independently be substituted with fluorine to the level of perfluoro,
5 or 6 membered heteroaryl,
Or
The group consisting of phenyl substituted with 0, 1 or 2 groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano Selected from;
R ^1-3 is H or (C ₁ -C ₄ ) alkyl;
R ^1-4 , R ^1-5 and R ^1-6 are
・ H,
・ Indan-5-yl,
Phenyl substituted with 0, 1 or 2 groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano;
5 or 6 membered heteroaryl, which is
-Cyano,
-Halo,
-Nitro,
-(C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) acyloxy, (C ₁ -C ₄ ) 0, 1 or 2 groups selected from alkoxy and (C ₂ -C ₄ ) alkoxy substituted with 0, 1 or 2 (C ₁ -C ₄ ) alkoxy groups May be replaced with
Substituted with 0, 1 or 2 groups selected from
· _(C 1 -C _{4) alkyl, (C} 1 -C ₄₎ alkoxy, 0 groups selected from cyano and halo, one or which is substituted with two groups _(C 3 -C ₆₎ cycloalkyl ,and,
(C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is
-NH _2,
- _(C 1 -C ₄₎ alkoxy,
Independently substituted with 0, 1, 2, or 3 (C ₁ -C ₄ ) alkoxy and OH groups, and may be independently substituted with fluorine to the perfluoro level ( C ₂ -C ₄₎ alkoxy,
-Carboxyl,
- _(C 1 -C ₄₎ alkoxycarbonyl,
- _(C 1 -C ₄₎ alkylamino,
-Aminocarbonyl,
- _(C 1 -C ₄₎ alkylsulfonyl,
- _(C 1 -C ₄₎ phenyl alkyl, halo, _nitro, substituted with zero, one or two groups independently selected from _(C 1 -C ₄₎ alkoxy and cyano,
5 independently substituted with 0, 1, 2 or 3 groups selected from-(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro Or 6-membered heteroaryl, and
- _(C 1 -C _{4) alkyl,} 0 groups selected from _(C 1 -C ₄₎ alkoxy, cyano and halo, one, two or three heterocycle are independently substituted by a group Independently substituted with 0 or 1 group of choice,
-And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups,
-And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected independently from the group consisting of;
And
When R ^1-3 and R ^1-4 , R ^1-3 and R ^1-5 , and R ^1-3 and R ^1-6 are bonded to the same nitrogen atom, the N to which they are bonded 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl, and piperidinyl (optionally substituted on N with (C ₁ -C ₄ ) alkyl) together with the atom May be formed}]
Or a pharmaceutically acceptable salt thereof. Where
Ar is

Selected from the group consisting of:
X is CH or N;
R ¹ is

Selected from the group consisting of {where,
R ^1-2 is
(C ₁ -C ₄ ) alkyl, wherein the (C ₁ -C ₄ ) alkyl is
-Hydroxy,
- _(C 1 -C ₄₎ alkylamino,
- _(C 1 -C ₄₎ acyloxy,
- _(C 1 -C ₄₎ alkoxy and,
Zero or one or two _(C 1 -C ₄₎ is substituted with an alkoxy group _(C 2 -C ₄₎ substituted by one or two groups independently selected from alkoxy And
Where the (C ₁ -C ₄ ) alkyl may independently be substituted with fluorine to the level of perfluoro,
5 or 6 membered heteroaryl,
Or
Selected from the group consisting of phenyl substituted by one or two groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano. ;
R ^1-3 is H or (C ₁ -C ₄ ) alkyl;
R ^1-4 and R ^1-5 are
・ Indan-5-yl,
Phenyl substituted with one or two groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano,
5 or 6 membered heteroaryl, which is
-Cyano,
-Halo,
-Nitro,
-(C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) acyloxy, (C ₁ -C ₄ ) 0, 1 or 2 groups selected from alkoxy and (C ₂ -C ₄ ) alkoxy substituted with 0, 1 or 2 (C ₁ -C ₄ ) alkoxy groups May be replaced with
Substituted with one or two groups selected from
(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl substituted with one or two groups selected from cyano and halo, and
(C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is
-NH _2,
- _(C 1 -C ₄₎ alkoxy,
Independently substituted with 0, 1, 2, or 3 (C ₁ -C ₄ ) alkoxy and OH groups, and may be independently substituted with fluorine to the perfluoro level ( C ₂ -C ₄₎ alkoxy,
-Carboxyl,
- _(C 1 -C ₄₎ alkoxycarbonyl,
- _(C 1 -C ₄₎ alkylamino,
-Aminocarbonyl,
- _(C 1 -C ₄₎ alkylsulfonyl,
- _(C 1 -C ₄₎ phenyl alkyl, halo, _nitro, substituted with zero, one or two groups independently selected from _(C 1 -C ₄₎ alkoxy and cyano,
5 independently substituted with 0, 1, 2 or 3 groups selected from-(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro Or 6-membered heteroaryl, and
- _(C 1 -C _{4) alkyl,} 0 groups selected from _(C 1 -C ₄₎ alkoxy, cyano and halo, one, two or three heterocycle are independently substituted by a group Independently substituted with one selected group;
-And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups,
-And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected independently from the group consisting of
R ^1-6 is
・ H,
・ Indan-5-yl,
Phenyl substituted with 0, 1 or 2 groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano;
5 or 6 membered heteroaryl, which is
-Cyano,
-Halo,
-Nitro,
-(C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) acyloxy, (C ₁ -C ₄ ) 0, 1 or 2 groups selected from alkoxy and (C ₂ -C ₄ ) alkoxy substituted with 0, 1 or 2 (C ₁ -C ₄ ) alkoxy groups May be replaced with
Substituted with 0, 1 or 2 groups selected from
· _(C 1 -C _{4) alkyl, (C} 1 -C ₄₎ alkoxy, 0 groups selected from cyano and halo, one or which is substituted with two groups _(C 3 -C ₆₎ cycloalkyl ,and,
(C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is
-NH _2,
- _(C 1 -C ₄₎ alkoxy,
Independently substituted with 0, 1, 2, or 3 (C ₁ -C ₄ ) alkoxy and OH groups, and may be independently substituted with fluorine to the perfluoro level ( C ₂ -C ₄₎ alkoxy,
-Carboxyl,
- _(C 1 -C ₄₎ alkoxycarbonyl,
- _(C 1 -C ₄₎ alkylamino,
-Aminocarbonyl,
- _(C 1 -C ₄₎ alkylsulfonyl,
- _(C 1 -C ₄₎ phenyl alkyl, halo, _nitro, substituted with zero, one or two groups independently selected from _(C 1 -C ₄₎ alkoxy and cyano,
5 independently substituted with 0, 1, 2 or 3 groups selected from-(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro Or 6-membered heteroaryl, and
- _(C 1 -C _{4) alkyl,} 0 groups selected from _(C 1 -C ₄₎ alkoxy, cyano and halo, one, two or three heterocycle are independently substituted by a group Independently substituted with 0 or 1 group of choice,
-And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups,
-And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected independently from the group consisting of
And
When R ^1-3 and R ^1-4 , R ^1-3 and R ^1-5 , and R ^1-3 and R ^1-6 are bonded to the same nitrogen atom, the N to which they are bonded 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and piperidinyl (optionally substituted on N with (C ₁ -C ₄ ) alkyl) together with the atom May form}
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Where
Ar is

Selected from the group consisting of:
X is CH;
R ¹ is

Selected from the group consisting of {where,
R ^1-3 is H or (C ₁ -C ₄ ) alkyl;
R ^1-5 is
Indan-5-yl,
Phenyl substituted with one or two groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano;
5- or 6-membered heteroaryl, which is cyano, halo, nitro, (C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino , _(C 1 -C _{4) acyloxy, (C} 1 -C ₄₎ alkoxy, and zero, one or up to two _(C 1 -C ₄₎ is substituted with an alkoxy group _(C 2 -C ₄ ) substituted with 1 or 2 groups selected from 0, 1 or 2 groups optionally selected from alkoxy),
(C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl substituted with one or two groups selected from cyano and halo, and
(C ₁ -C ₆ ) alkyl, wherein (C ₁ -C ₆ ) alkyl is NH ₂ , (C ₁ -C ₄ ) alkoxy, (C ₂ -C ₄ ) alkoxy (this is 0, 1, 2 or 3 (C ₁ -C ₄ ) alkoxy and OH groups independently substituted and may be independently substituted with fluorine to the perfluoro level), carboxyl, ( C ₁ -C _{4) alkoxycarbonyl, (C} 1 -C ₄₎ alkylamino, _{aminocarbonyl, (C} 1 -C ₄₎ alkylsulfonyl, phenyl (which _{is, (C} 1 -C ₄₎ alkyl, halo, nitro, (C ₁ -C ₄ ) substituted with 0, 1 or 2 groups independently selected from alkoxy and cyano), 5-membered or 6-membered heteroaryl (which is (C _1- C ₄₎ alkyl , (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro independently substituted with 0, 1, 2 or 3 groups selected from) and heterocycles (which are , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, independently substituted with 0, 1, 2 or 3 groups selected from cyano and halo) And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected from the group consisting of
R ^1-6 is
H,
Indan-5-yl,
Phenyl substituted with 0, 1 or 2 groups independently selected from (C ₁ -C ₄ ) alkyl, halo, nitro, (C ₁ -C ₄ ) alkoxy and cyano;
5- or 6-membered heteroaryl, which is cyano, halo, nitro, (C ₁ -C ₄ ) alkyl (wherein the (C ₁ -C ₄ ) alkyl is (C ₁ -C ₄ ) alkylamino , _(C 1 -C _{4) acyloxy, (C} 1 -C ₄₎ alkoxy, and zero, one or up to two _(C 1 -C ₄₎ is substituted with an alkoxy group _(C 2 -C ₄ ) optionally substituted with 0, 1 or 2 groups selected from alkoxy), substituted with 0, 1 or 2 groups selected from
(C ₃ -C ₆ ) cycloalkyl, substituted with 0, 1 or 2 groups selected from (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano and halo, and,
(C ₁ -C ₆ ) alkyl, wherein (C ₁ -C ₆ ) alkyl is NH ₂ , (C ₁ -C ₄ ) alkoxy, (C ₂ -C ₄ ) alkoxy (this is 0, 1, 2 or 3 (C ₁ -C ₄ ) alkoxy and OH groups independently substituted and may be independently substituted with fluorine to the perfluoro level), carboxyl, ( C ₁ -C _{4) alkoxycarbonyl, (C} 1 -C ₄₎ alkylamino, _{aminocarbonyl, (C} 1 -C ₄₎ alkylsulfonyl, phenyl (which _{is, (C} 1 -C ₄₎ alkyl, halo, nitro, (C ₁ -C ₄ ) substituted with 0, 1 or 2 groups independently selected from alkoxy and cyano), 5-membered or 6-membered heteroaryl (which is (C _1- C ₄₎ alkyl , (C ₁ -C ₄ ) alkoxy, cyano, halo and nitro independently substituted with 0, 1, 2 or 3 groups selected from) and heterocycles (which are , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, independently substituted with 0, 1, 2 or 3 groups selected from cyano and halo) Independently substituted with 0 or 1 group, and the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups. And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
Selected from the group consisting of
And
When R ^1-3 and R ^1-5 , and R ^1-3 and R ^1-6 are bonded to the same nitrogen atom, they are combined with the N atom to which they are bonded to form pyrrolidinyl, morpholinyl , May form a 5- or 6-membered saturated heterocyclic ring selected from thiomorpholinyl and piperidinyl (optionally substituted on N with (C ₁ -C ₄ ) alkyl)},
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Where
Ar is

Selected from the group consisting of:
X is CH;
R ¹ is

Selected from the group consisting of {where,
R ^1-3 is H;
R ^1-5 is (C ₁ -C ₆ ) alkyl, wherein (C ₁ -C ₆ ) alkyl is (C ₁ -C ₄ ) alkoxy, (C ₂ -C ₄ ) alkoxy (this Are independently substituted with 0, 1 or 2 (C ₁ -C ₄ ) alkoxy and OH groups, and may be independently substituted with fluorine to the perfluoro level) And the (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and And the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro,
R ^1-6 is selected from the group consisting of H and (C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is (C ₁ -C ₄ ) alkoxy, (C _2- C ₄ ) alkoxy (which is independently substituted with 0, 1, 2 or 3 (C ₁ -C ₄ ) alkoxy and OH groups and independently substituted with fluorine to the perfluoro level. And (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH, which may be independently substituted with 0 or 1 group selected from Or independently substituted with a halo group, and the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro},
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Where
Ar is

Selected from the group consisting of:
X is CH;
R ¹ is

Selected from the group consisting of {where,
R ^1-3 is H;
R ^1-6 is selected from the group consisting of H and (C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is (C ₁ -C ₄ ) alkoxy, (C _2- C ₄ ) alkoxy (which is independently substituted with 0, 1, 2 or 3 (C ₁ -C ₄ ) alkoxy and OH groups and independently substituted with fluorine to the perfluoro level. And (C ₁ -C ₆ ) alkyl is independently substituted with 0, 1 or 2 OH, which may be independently substituted with 0 or 1 group selected from Or independently substituted with a halo group, and the (C ₁ -C ₆ ) alkyl may be independently substituted with fluorine to the level of perfluoro},
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. A method for producing the compound of claim 1, comprising:
(A) Formula (VI) with or without first hydrolyzing the ester group -COOR '

(Wherein X and R ¹ have the meanings given in claim 1 and R ′ is lower alkyl)
A compound of formula Ar—NH ₂ (VIII)
(Wherein Ar has the meaning of claim 1)
Or react with a compound of
(B) Formula (IX)

(Wherein Ar has the meaning of claim 1)
A compound of formula (IV)

(Wherein X and R ¹ have the meaning of claim 1)
Or subsequently reducing the resulting compound; or
(C) a compound of formula (IX) (wherein Ar has the meaning of claim 1)

(Wherein lg represents a leaving group)
Or react with a compound of
(D) Formula (IIa)

(Wherein X and R ¹ have the meanings given in claim 1 and R ′ is lower alkyl)
A compound of formula (VIII)
ArNH ₂ (VIII)
(Wherein Ar has the meaning of claim 1)
Or in the presence of (R ′) ₃ Al where R ′ is lower alkyl; or
(E) first hydrolyzing the ester group -COOR 'of the compound of formula (IIa) above, followed by reacting the resulting compound with the compound of formula (VIII) above.
Including methods.   2. A compound according to claim 1 for the treatment or prevention of a disorder.   A pharmaceutical composition comprising the compound of claim 1.   9. The pharmaceutical composition according to claim 8, further comprising at least one pharmaceutically acceptable carrier or adjuvant.   10. A pharmaceutical composition according to claim 8 or claim 9 for the treatment or prevention of cancer.   10. A method for producing a pharmaceutical composition according to claim 9, wherein at least one compound according to claim 1 is combined with at least one pharmaceutically acceptable carrier or excipient and the resulting combination A form suitable for the pharmaceutical composition.   Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease.   Use according to claim 12, wherein the disease is cancer.   A method of treating a disease or condition in a mammal comprising administering to a mammal in need thereof an effective amount of the compound of claim 1.   15. A method according to claim 14, wherein the disease or condition is cancer.