JP2007051121A - Pyrimidine compounds that inhibit prostaglandin D synthase - Google Patents

Abstract

式中 R¹は置換基を有していてもよい５員もしくは６員の含窒素不飽和複素環基、又は置換基を有していてもよいフェニル基を表し、R²は環構造中に窒素原子、酸素原子及び硫黄原子からなる群から選ばれる１〜３個の複素原子を含む不飽和複素環基、又はフェニル基を表し、R²で表される不飽和複素環基は０〜２個のR³-(CH₂)_m-基を有しており、R²で表されるフェニル基は、その３位及び４位の一方又は両方にR³-(CH₂)_m-基を有しており、ｍは０〜４を示し、R³はハロゲン原子、シアノ基、ニトロ基、複素環基等を示す。
【選択図】なしA novel compound having a high inhibitory effect on prostaglandin D synthase is provided.
A pyrimidine compound represented by general formula (I) or a salt thereof, and a hematopoietic prostaglandin D synthase inhibitor containing the same as an active ingredient.

In the formula, R ¹ represents an optionally substituted 5- or 6-membered nitrogen-containing unsaturated heterocyclic group, or an optionally substituted phenyl group, and R ² represents a ring structure. An unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or a phenyl group, and an unsaturated heterocyclic group represented by R ² is 0 to 2 number of _{^{R 3 - (CH 2) m}} - has a group, a phenyl group represented by R ^2, one or both of the 3-position and 4-position R ³ - group - (CH _{2) m} And m represents 0 to 4, and R ³ represents a halogen atom, a cyano group, a nitro group, a heterocyclic group, or the like.
[Selection figure] None

Description

  The present invention relates to a pyrimidine compound or a salt thereof, and a medicine containing these as an active ingredient, particularly an agent for preventing and / or treating allergic disease, inflammatory disease due to hematopoietic prostaglandin D synthase inhibitory action, Alzheimer's disease or brain injury. And a novel pyrimidine compound or salt, and a pharmaceutical comprising the same as an active ingredient.

  A series of lipid mediators collectively called eicosanoids, such as prostaglandins and leukotrienes, are synthesized by an arachidonic acid cascade starting from arachidonic acid cleaved from membrane phospholipids in response to various stimuli. In particular, prostanoids are a type of arachidonic acid metabolite synthesized by using prostaglandin H2 produced by cyclooxygenase in the arachidonic acid cascade as an intermediate, and prostaglandin in addition to prostaglandin D2 through such biosynthetic pathway It is known that E2, prostaglandin F2α, prostaglandin I2, thromboxane A2, and the like are synthesized.

  Prostanoids act as locally active hormone-like chemical mediators and are generally synthesized in response to local tissue damage, stimulation with hormones / bacterial peptides / antigens, and stimulation with inflammatory mediators such as cytokines. The produced prostanoids bind to specific receptors expressed on the cell surface, thereby producing a wide variety of effects in many tissues, and regulating in vivo functions such as gastric acid secretion and blood flow. Others are known to affect many inflammatory responses as well as immune system function.

  Synthetic enzymes that produce prostaglandin D2 are called prostaglandin D synthases, and two types of hematopoietic enzymes and lipocalin-type enzymes are known.

  Hematopoietic enzymes in humans are distributed mainly in the placenta, lungs, embryonic liver, lymph nodes, brain, heart, thymus, bone marrow and spleen. At the cellular level, it is expressed in many antigen-presenting cells such as microglia cells, bone marrow megakaryocytes, Langerhans cells in the skin; Kupffer cells in the liver; macrophages; It has been reported.

  On the other hand, lipocalin-type enzyme is mainly distributed in the central nervous system of the brain and spinal cord, heart, testicular epithelium, and testis, and prostaglandin D2 produced by lipocalin-type enzyme functions as a humoral regulator of sleep, It is known that not only has a cranial nervous system regulation function by a arachnoid membrane, a pain regulation function typified by allodynia, and a spermatogenesis regulation function, but also a lipocalin type enzyme itself functions as a transport protein for a fat-soluble low molecular weight compound.

  Two types of specific receptors for prostaglandin D2 are known, DP1 and DP2 (sometimes referred to as CRTH2). DP1 is a bone marrow, brain, retina, digestive organ tissue, airway epithelial cell DP2 is expressed in cells such as bone marrow, brain, thymus, heart, Th2 cells, eosinophils, basophils, monocytes, etc. Has been reported. Prostaglandin D2 produced locally by hematopoietic enzymes by various stimuli binds to these receptors, thereby inhibiting platelet aggregation, vasodilation, vascular permeability, mucus production, Airway smooth muscle contraction, antigen-presenting cells; Th2 cells; migratory / activating effects of eosinophils, etc. are shown, and in particular, it is considered to be involved in the onset and exacerbation of allergic diseases and inflammatory diseases.

  In allergic diseases such as bronchial asthma and allergic rhinitis, the arachidonic acid cascade is activated and various inflammatory mediators are released mainly in mast cells activated by binding of antigen-immunoglobulin E complex. And is thought to play an important role in the induction of allergic symptoms. Among them, prostaglandin D2 is an inflammatory mediator that is produced and released in the largest amount, and is detected at a high concentration in bronchoalveolar lavage fluid of asthmatic patients (Non-patent Documents 1 and 2). Furthermore, it has been reported that airway contraction is observed in inhaled prostaglandin D2 in asthmatic patients compared to healthy individuals (Non-patent Document 3). In addition, the expression of hematopoietic enzymes in mast cells and inflammatory cells is high in the nasal mucosa of patients with allergic rhinitis or in the nasal cavity of patients with chronic sinusitis, eosinophils infiltrated with DP1 and DP2, DP2 is expressed in T cells (Non-patent Document 4), and the DP2-positive rate of skin lymphocyte homing antigen-positive cells (CLA) is high depending on the severity of patients with atopic dermatitis (Non-patent Document 4) Reference 5), it is considered that prostaglandin D2 derived from hematopoietic enzymes plays an important role in the onset and exacerbation of allergic diseases (Non-Patent Documents 6 to 8).

  In recent years, allergic reaction is promoted in mice overexpressing prostaglandin D synthase (Non-patent Document 9), whereas knockout mice of prostaglandin D2 receptor do not show allergic reaction. It has been reported (Non-Patent Document 10). In addition, it has been reported that hematopoietic enzyme-deficient mice have slight expansion of muscle necrosis and traumatic brain injury.

  Therefore, prostaglandin D2 produced by two types of enzymes, hematopoietic enzyme and lipocalin type enzyme, is involved in the onset of various diseases such as allergic diseases, functions as exacerbation factors, and in vivo regulatory mechanisms. Therefore, improving the production abnormality is considered to be extremely effective as a medicine for various diseases.

  For example, HQL-79 (4-benzhydryloxy-1- {3- (1H-tetrazol-5-yl) -propyl} piperidine) has been reported as a hematopoietic enzyme inhibitor (non-patent document). 11 and 12). HQL-79 is a compound having histamine H1 antagonism, and has been reported to suppress airway inflammatory pathologies such as eosinophil infiltration into the respiratory tract and delayed asthmatic reaction in an asthma pathological model. Not enough. In addition, there are other disclosures relating to the provision of prostaglandin D synthase inhibitors (Patent Documents 6 and 7). Although the enzyme inhibitory activity exceeds HQL-79, the activity is still sufficient. I can not say.

  Anti-allergic agents currently used for the purpose of preventing or treating allergic diseases include antihistamines, chemical mediator release inhibitors, leukotriene receptor antagonists, thromboxane A2 synthesis inhibitors and receptor antagonists, Th2 cytokine inhibition Agents, immunosuppressants, etc. are used (Non-patent Document 13). However, these anti-allergic agents are problematic and easy to use, such as those with inadequate efficacy, central side effects such as drowsiness and sedation, digestive symptoms such as diarrhea, and side effects such as immunosuppression Absent. Steroids are drugs that are used in the treatment of many inflammatory diseases as well as allergic diseases because of their powerful anti-inflammatory effects, but they are easily infectious, have adverse effects on bones, growth disorders, and rebound after discontinuation of administration. It is not an easy-to-use drug due to the phenomenon.

  On the other hand, an inhibitor of prostaglandin D synthase is a pharmaceutical agent useful as a prophylactic and / or therapeutic agent for allergic diseases or inflammatory diseases involving prostaglandin D2 produced by a hematopoietic enzyme or a metabolite thereof. Can be expected.

  Conventionally, pyrimidine compounds have been widely studied as useful compounds for medicines and the like.

  For example, Patent Document 1 (Japanese Patent Application Laid-Open No. 2000-226372) describes a wide range of amide compounds having a phenoxypyrimidine compound as a pest control agent.

  Patent Document 2 (Japanese Patent Publication No. 9-510471) describes a wide range of anthranilic acid compounds as antifungal agents, and discloses 2-phenoxy-N-phenyl-5-pyrimidinecarboxamide compounds having a substituent. Has been.

  Patent Document 3 (International Publication WO2001-83460) describes a very wide range of cyclic compounds as PDE (IV) inhibitors.

  Patent Document 4 (Japanese Patent Publication No. 2003-522165) describes a pyrimidine compound useful as a PDE (IV) inhibitor.

Patent Document 5 (Japanese Patent Laid-Open No. 2001-89412) describes a benzene derivative having collagen synthesis inhibitory activity.
JP 2000-226372 A Japanese National Patent Publication No. 9-510471 International Publication No. WO2001-83460 Special table 2003-522165 gazette JP 2001-89412 A Japanese Patent Laid-Open No. 2004-2248 JP 2004-51600 A J. Immumol., 129, 1627-1631 (1982) N. Eng. J. Med., 315, 800-804 (1986) N. Eng., J. Med., 311, 209-213 (1984) Prostaglandins & other Lipid Med. 73, 87-101 (2004) J. Invest. Dermatol. 119, 609-616 (2002) J. Immunol., 143, 2982-2989 (1989) J. Biol. Chem., 265, 371-375 (1990) J. Biol. Chem., 270, 3239-3246 (1995)) J. Immunol., 168, 443-449 (2002) Science, 287, 2013-2017 (2000) Jpn. J. Pharmacol., 78, 1-10 (1998) Jpn. J. Pharmacol., 78, 11-22 (1998) “Clinics and Research” Vol. 79, No. 2, pp. 30-33 (February 2002)

  The main object of the present invention is to provide a novel compound having a high effect of inhibiting a prostaglandin D synthase, particularly a hematopoietic prostaglandin D synthase, at a low dose.

  Further, the incidental problem of the present invention is based on the inhibitory action of prostaglandin D synthase, and is effective for the prevention / treatment of prostaglandin D2 derived from the enzyme or its metabolite-mediated disease, with less side effects. It is to provide a highly safe medicine.

  As a result of intensive studies on compounds having a prostaglandin D synthase inhibitory activity, the present inventors have found that a novel pyrimidine compound represented by the following general formula (I) is extremely superior to prostaglandin D synthase. The present invention has been completed through further investigations.

  That is, according to the present invention, a pyrimidine compound represented by the following general formula (I) or a salt thereof, a hematopoietic prostaglandin D synthase inhibitor containing the same as an active ingredient, and the like are provided.

[Claim 1]
The following general formula (I)

[Where
R ¹ represents a 5- or 6-membered nitrogen-containing unsaturated heterocyclic group which may have a substituent, or a phenyl group which may have a substituent,
R ² represents an unsaturated heterocyclic group or a phenyl group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure;
The unsaturated heterocyclic group represented by R ² has 0 to 2 R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ represents a halogen atom, a cyano group, a nitro group, a saturated or unsaturated heterocyclic ring which may have a substituent, —NR ⁴ R ⁵ group, — (C═O) —R ⁶ group, —OR ⁷ Group, or -SR ⁸ group,
R ⁴ and R ⁵ are the same or different and each have a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a substituent. An optionally substituted amino group, a saturated or unsaturated heterocyclic group which may have a substituent, an aryl group having 6 to 14 carbon atoms which may have a substituent or a carbonyl group having a substituent; Or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are each one or two selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. May form a saturated or unsaturated cyclic amino group which may have one hetero atom, the cyclic amino group may have a substituent,
R ⁶ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkenyl group having 2 to 6 carbon atoms, or a carbonyl group having a substituent. Represents
R ⁸ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms,
R ⁹ and R ¹⁰ are the same or different and are each a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon atom having 1 to 6 carbon atoms. Or an amino group which may have a substituent, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, are each one or two selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. A saturated or unsaturated cyclic amino group which may have one hetero atom may be formed, and the cyclic amino group may have a substituent. ]
Or a salt thereof (wherein R ¹ is a phenyl group substituted with a halogen atom, and R ² is a phenyl group substituted with a halogen atom) except for).

[Section 2]
R ¹ is 1 selected from the group consisting of an optionally substituted pyridyl group, or a halogen atom, a cyano group and a C 1-6 alkyl group optionally substituted with a halogen atom as a substituent. Represents a phenyl group optionally having one group;
R ² is a monocyclic or bicyclic unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in the ring structure, or phenyl Represents a group,
The unsaturated heterocyclic group represented by R ² has 0 to 2 R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is a halogen atom, a cyano group, a nitro group, an optionally substituted monocyclic saturated or unsaturated heterocyclic group, —NR ⁴ R ⁵ group, — (C═O) —R ⁶ group , -OR ⁷ group or -SR ⁸ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and the other of R ⁴ and R ⁵ has a hydrogen atom or a substituent. An optionally substituted alkyl group having 1 to 6 carbon atoms, a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent, and a phenyl group which may have a substituent Or a carbonyl group having a substituent, or
R ⁴ and R ⁵ , together with the adjacent nitrogen atom, are each in the ring structure one complex selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. ^May form a monocyclic or bicyclic saturated cyclic amino group which may have atoms, or R ⁴ and R ⁵ together with the adjacent nitrogen atom in the ring structure In addition to the adjacent nitrogen atom, the monocyclic or bicyclic unsaturated ring optionally having one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom An amino group may be formed, and the saturated or unsaturated cyclic amino group may have one or two substituents;
R ⁶ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an alkenyl group having 2 to 6 carbon atoms, a (C1-C6 alkyl) carbonyl group or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is a halogen atom, a hydroxyl group, An alkoxy group having 1 to 6 carbon atoms, a —NR ¹¹ R ¹² group, a phenyl group which may have a substituent, a pyridyl group which may have a substituent, and — (C═O) —R ^13. May have one or two groups selected from the group consisting of:
R ⁸ represents a C 1-3 alkyl group which may have a 5-membered or 6-membered monocyclic amino group as a substituent,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 3 carbon atoms, and the other of R ⁹ and R ¹⁰ is a hydrogen atom, an amino group, or a substituted group. Represents an alkyl group having 1 to 6 carbon atoms which may have a group, or an alkoxy group having 1 to 3 carbon atoms which may have a substituent, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, are each one ring selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. It may form a 5-membered or 6-membered monocyclic saturated cyclic amino group which may have a hetero atom, or R ⁹ and R ¹⁰ are each taken together with an adjacent nitrogen atom. In addition to the adjacent nitrogen atom, the ring structure may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. May form a monocyclic unsaturated cyclic amino group, the saturated or unsaturated cyclic amino group may have one substituent,
R ¹¹ and R ^12, one of which represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a phenyl group, the other of R ¹¹ and R ¹² is a hydrogen atom, a phenyl group Yes An alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a 5-membered or 6-membered monocyclic saturated or unsaturated heterocyclic group, or a (C1-C6 alkyl) carbonyl group. Represent or
R ¹¹ and R ¹² , together with the adjacent nitrogen atom, are each one ring selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group [which may have a hydroxyl group] which may have a hetero atom, or R ¹¹ and R ¹² each have an adjacent nitrogen atom and Together, the ring structure may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. May form a formula unsaturated cyclic amino group [may have a methyl group]
R ¹³ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group (R ⁹ and R ¹⁰ are the same as above). 1. A pyrimidine compound or a salt thereof according to ¹ , wherein R ¹ is a phenyl group substituted with a halogen atom and R ² is a phenyl group substituted with a halogen atom. except).

[Section 3]
R ¹ is a pyridyl group, or a halogen atom, a cyano group, or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom as a substituent at either the 2-position or the 3-position Represents a phenyl group optionally having one group selected from the group consisting of:
R ² is an unsaturated heterocyclic group selected from the group consisting of a pyridyl group, a pyrimidinyl group, a pyrrolyl group, an indolyl group, and a benzofuranyl group, or represents a phenyl group,
The unsaturated heterocyclic group represented by R ² has one or two R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is a monocyclic saturated or unsaturated heterocyclic group optionally having a chlorine atom, a nitro group, a C 1-6 alkyl group or an oxo group as a substituent, —NR ⁴ R ⁵ Represents a group,-(C = O) -R ⁶ group, -OR ⁷ group, or -SR ⁸ group,
R ⁴ and R ^5, one of which represents a hydrogen atom, or a substituent one has to have also a good 1 to 6 carbon atoms alkyl group, the other of R ⁴ and R ⁵ are hydrogen atom, a substituted An alkyl group having 1 to 6 carbon atoms which may have one group, a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have one substituent, and 1 substituent. Represents a phenyl group which may have one carbonyl group or one substituent, or
R ⁴ and R ⁵ , together with the adjacent nitrogen atom, are each in the ring structure one complex selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group which may have an atom, or R ⁴ and R ⁵ , together with the adjacent nitrogen atom, form a ring 5-membered monocyclic ring which may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as a constituent atom in addition to the adjacent nitrogen atom in the structure An unsaturated cyclic amino group may be formed, the saturated cyclic amino group or the unsaturated cyclic amino group may have one or two substituents;
R ⁶ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an allyl group, a tert-butylcarbonyl group, or an alkyl group having 1 to 6 carbon atoms. One selected from the group consisting of —NR ¹¹ R ¹² group, an optionally substituted phenyl group, an optionally substituted pyridyl group, and — (C═O) —R ^13; May have two groups,
R ⁸ represents a C 1-3 alkyl group which may have a morpholino group as a substituent,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other of R ⁹ and R ¹⁰ may have a hydrogen atom, an amino group, or a substituent. Represents an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms, or
R ⁹ and R ¹⁰ together with the adjacent nitrogen atom each have one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group, or R ⁹ and R ¹⁰ together with the adjacent nitrogen atom may be combined with the adjacent nitrogen atom in the ring structure. In addition, a 5- or 6-membered unsaturated cyclic amino group which may have 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom as a constituent atom may be formed. The saturated cyclic amino group or unsaturated cyclic amino group may have one substituent,
One of R ¹¹ and R ¹² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a phenyl group, and the other of R ¹¹ and R ¹² represents a hydrogen atom or a phenyl group. An optionally substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or
R ¹¹ and R ¹² together with the adjacent nitrogen atom each have one heterocyclic atom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group (which may have a hydroxyl group), or R ¹¹ and R ¹² may be combined with an adjacent nitrogen atom, respectively. In the ring structure, in addition to the adjacent nitrogen atom, a monocyclic unsaturated cyclic amino group optionally having one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom [ May have a methyl group],
R ¹³ represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group (R ⁹ and R ¹⁰ are as defined above), or a pyrimidine compound or a salt thereof according to item 1, wherein R ¹ is a phenyl group substituted with a halogen atom, and R ² is a phenyl group substituted with a halogen atom (except for the compound represented by the general formula (I)).

[Claim 4]
R ¹ represents a pyridyl group or a phenyl group,
R ² represents a 3-pyridyl group, an indolyl group or a phenyl group,
The 3-pyridyl group and indolyl group represented by R ^{2 have} one or two R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the 3-pyridyl group, indolyl group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m The groups may be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ represents a nitro group, a tetrahydropyridazinyl group or an imidazolyl group optionally having any of an alkyl group having 1 to 6 carbon atoms or an oxo group as a substituent, a —NR ⁴ R ⁵ group, — ( C = O) -R ⁶ group, or -OR ⁷ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
The other of R ⁴ and R ⁵ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a monocyclic or bicyclic unsaturated heterocyclic group or substituent having 1 or 2 nitrogen atoms as constituent atoms. Each of the carbonyl groups represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a mono- or di (C1-C6 alkyl) amino group, a (C1-C6 alkoxy) carbonyl group, a substituent. One selected from the group consisting of a 5-membered or 6-membered monocyclic saturated or unsaturated heterocyclic group which may have 1 and a phenyl group which may have 1 sulfamoyl group as a substituent May have a group of
The carbonyl group having one substituent is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a carbon number which may have 1 to 3 substituents as the substituent. 1 to 6 alkoxy groups and one group selected from the group consisting of monocyclic saturated or unsaturated heterocyclic rings, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom each have one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group, or R ⁴ and R ⁵ together with the adjacent nitrogen atom may form a ring structure. In addition to the adjacent nitrogen atom, a 5-membered monocyclic unsaturated cyclic amino group which may have one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom is formed. The saturated cyclic amino group or the unsaturated cyclic amino group may have one or two substituents,
R ⁶ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a (C1-C6 alkyl) carbonyl group, and the alkyl group has a fluorine atom, hydroxyl group, carbon as a substituent. A C 1-3 alkoxy group, a carboxyl group, a (C1-C6 alkoxy) carbonyl group, a carbonyl group having a 5-membered or 6-membered monocyclic saturated heterocyclic group, an optionally substituted 5-membered or It may have any one or two groups of a 6-membered monocyclic unsaturated heterocyclic group and —NR ¹¹ R ¹² group,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁹ and R ¹⁰ represents a hydrogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or a pyridyl group, and the alkyl group is substituted with a hydroxyl group as a substituent. An optionally substituted alkoxy group having 1 to 6 carbon atoms, a mono- or di (C1-C6 alkyl) amino group, an optionally substituted 5- or 6-membered monocyclic unsaturated heterocyclic group, substituted May have either a 5-membered or 6-membered saturated cyclic amino group which may have a group, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, each have a hetero atom of either a nitrogen atom or an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a saturated cyclic amino group, or R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, may be added to the adjacent nitrogen atom in the ring structure in addition to 1 An unsaturated cyclic amino group which may have one or two nitrogen atoms may be formed, and the saturated cyclic amino group or the unsaturated cyclic amino group may have a substituent. ,
One of R ¹¹ and R ¹² represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other of R ¹¹ and R ¹² may have a hydrogen atom or a phenyl group. Represents 1 to 3 alkyl groups, or
R ¹¹ and R ¹² , together with the adjacent nitrogen atom, each have a hetero atom of any one of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group [which may have a hydroxyl group], or R ¹¹ and R ¹² may be combined with an adjacent nitrogen atom, respectively. The ring structure may have one or two heteroatoms selected from the group consisting of nitrogen atoms and oxygen atoms in addition to the adjacent nitrogen atoms. Item 2. The pyrimidine compound or a salt thereof according to Item 1, which may form a monocyclic unsaturated cyclic amino group [which may have a methyl group].

[Section 5]
R ¹ represents a 3-pyridyl group or a phenyl group,
R ² is, R ³ in the 6-position - (CH _{2) m} - 3- pyridyl groups having group, at the 2-position _{^{R 3 - (CH 2) m}} - any indolyl group, or a 3- or 4-position with a group Represents a phenyl group having a R ^3- (CH ₂ ) _m -group,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is 2-methyl-1-imidazolyl group, 3-oxo-2,3,4,5-tetrahydropyridazinyl group, -NR ⁴ R ⁵ group,-(C = O) -R ⁶ group, or an -OR ⁷ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁴ and R ⁵ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a monocyclic or bicyclic unsaturated heterocyclic group having one nitrogen atom as a constituent atom, a tert-butoxycarbonyl group, cyclopropyl Represents a carbonyl group, an ethoxyethylcarbonyl group, a 3-acetoxy-2,2-dimethylpropionyl group, a thiophenecarbonyl group or a furylcarbonyl group, the alkyl group as a substituent having 1 to 3 carbon atoms, mono or di ( C1-C6 alkyl) 1 group selected from the group consisting of amino group, ethoxycarbonyl group, morpholino group, pyrrolidinyl group optionally having oxo group, pyridyl group, imidazolyl group, and 4-sulfamoylphenyl group May have a group, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, imidazolyl group, pyrazolyl group, pyrazolinyl group, thiazolinyl group, 1,2,3-triazolyl group, And any of the 1,2,4-triazolyl cyclic amino groups, the cyclic amino group may have a substituent,
R ⁶ represents a hydrogen atom, a hydroxyl group, an ethoxy group, a tert-butoxy group, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and the alkyl group is substituted with a hydroxyl group, a methoxy group, a benzylmethylamino group, a carboxyl group, a tert-butoxycarbonyl group, a morpholinocarbonyl group, 2 -Methylimidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, pyrrolyl group, pyrrolidinyl group, morpholino group, 4-hydroxypiperidinyl group, or pyridyl group You may have
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁹ and R ^{10 represents} a hydrogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, and the alkyl group has a hydroxyethoxy group, a dimethylamino group as a substituent, Or may have one group selected from the group consisting of a pyrrolidinyl group, a morpholino group and a pyridyl group, which may have an oxo group, or
The pyrimidine compound or a salt thereof according to Item 1, wherein R ⁹ and R ¹⁰ together with the adjacent nitrogen atom represent a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, or pyrazolinyl group.

[Claim 6]
R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position or a 3-pyridyl group having an R ³ — (CH ₂ ) _m — group at the 6-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ represents -NR ⁴ R ⁵ group, or -OR ⁷ group,
R ⁴ and R ⁵ each represents a hydrogen atom or a methyl group, and the other represents a hydrogen atom, a methoxypropyl group, a dimethylaminoethyl group, an ethoxycarbonylethyl group, a morpholinoethyl group, a 2-oxopyrrolidinylpropyl group, Pyridylethyl group, imidazolylpropyl group, 4-sulfamoylphenylethyl group, tert-butoxycarbonyl group, cyclopropylcarbonyl group, ethoxyethylcarbonyl group, 3-acetoxy-2,2-dimethylpropionyl group, thiophenecarbonyl group or furyl Represents any of the carbonyl groups, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are pyrrolidinyl group optionally having oxo group, piperidinyl group having substituent, piperazinyl group having substituent, morpholino group, carbon as substituent An imidazolyl group optionally having an alkyl group of 1 to 6, a hydroxyl group as a substituent, a pyrazolyl group optionally having one or both of a methyl group, a pyrazolinyl group, a thiazolidinyl group, 1,2, Represents either a 3-triazolyl group or a 1,2,4-triazolyl group,
R ⁷ is a hydrogen atom, isobutyl group, hydroxypropyl group, carboxymethyl group, tert-butoxycarbonylmethyl group, pyrrolidinylpropyl group, 4-hydroxypiperidinylpropyl group, morpholinoethyl group, pyrrolylpropyl group, 2 -Represents any one of a methylimidazolylethyl group, a 1,2,3-triazolylethyl group, a 1,2,4-triazolylethyl group, or a morpholinocarbonylmethyl group,
Item 4. The pyrimidine compound or a salt thereof according to Item 1.

[Claim 7]
R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ represents -NR ⁴ R ⁵ group, or -OR ⁷ group,
R ⁴ and R ⁵ each represents a hydrogen atom or a methyl group, and the other represents a hydrogen atom, a methoxypropyl group, a 4-sulfamoylphenylethyl group, a tert-butoxycarbonyl group, a cyclopropylcarbonyl group, an ethoxyethylcarbonyl group. Represents a group, 3-acetoxy-2,2-dimethylpropionyl group, thiophenecarbonyl group or furylcarbonyl group, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are pyrrolidinyl group optionally having oxo group, piperidinyl group having substituent, piperazinyl group having substituent, morpholino group, carbon as substituent An imidazolyl group optionally having an alkyl group of 1 to 6, a hydroxyl group as a substituent, a pyrazolyl group optionally having one or both of a methyl group, a pyrazolinyl group, a thiazolidinyl group, 1,2, Represents either a 3-triazolyl group or a 1,2,4-triazolyl group,
R ⁷ is a hydrogen atom, isobutyl group, hydroxypropyl group, carboxymethyl group, tert-butoxycarbonylmethyl group, pyrrolidinylpropyl group, 4-hydroxypiperidinylpropyl group, morpholinoethyl group, pyrrolylpropyl group, 2 -Represents any one of a methylimidazolylethyl group, a 1,2,3-triazolylethyl group, a 1,2,4-triazolylethyl group, or a morpholinocarbonylmethyl group,
Item 4. The pyrimidine compound or a salt thereof according to Item 1.

[Section 8]
R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ represents a pyrrolidinyl group, a piperidinyl group having a substituent at the 4-position, a piperazinyl group having a substituent at the 4-position, a morpholino group, a 2-methylimidazolyl group, or a 1,2,4-triazolyl group,
Item 4. The pyrimidine compound or a salt thereof according to Item 1.

[Claim 9]
2-phenoxy-N- (4- (1,2,4-triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (2- (2-methylimidazol-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4-tert-butoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4-carboxylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4- (1-pyrrolidinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4- (4-morpholinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4- (N-methoxy-N-methyl) -carboxamidopiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (3- (4-hydroxypiperidin-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide,
2- (3-pyridyloxy) -N- (4- (4-hydroxypiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide, or 2- (3-pyridyloxy) -N- (4- ( Item 2. The pyrimidine compound or a salt thereof according to Item 1, which is 2- (morpholin-4-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide.

[Section 10]
Item 10. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

[Section 11]
Item 10. A prostaglandin D synthase inhibitor comprising an effective amount of the compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

[Claim 12]
Item 10. A disease involving prostaglandin D2 or a metabolite thereof, comprising an effective amount of the compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. Prophylactic or therapeutic agent.

[Claim 13]
Item 13. The preventive or therapeutic agent according to item 12, wherein the disease involving prostaglandin D2 or a metabolite thereof is any of allergic disease, inflammatory disease, Alzheimer's disease, and brain injury.

[Section 14]
Item 10. A prophylactic or therapeutic agent for allergic diseases, comprising an effective amount of the compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

[Section 15]
Item 10. A prophylactic or therapeutic agent for inflammatory diseases, comprising an effective amount of the compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

[Section 16]
Item 10. A prophylactic and / or therapeutic agent for Alzheimer's disease or brain injury, comprising an effective amount of the compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

  According to the present invention, there is provided a novel pyrimidine compound represented by the above general formula (I) or a salt thereof useful as a prostaglandin D synthase inhibitor, particularly a hematopoietic enzyme inhibitor.

  The pyrimidine compound of the present invention or a salt thereof has excellent prostaglandin D synthase inhibitory activity, and is superior to, for example, HQL-79, which has been conventionally known as a hematopoietic enzyme inhibitor. It has vessel-type prostaglandin D synthase inhibitory activity (see Experimental Example 1 described later).

  Therefore, the pyrimidine compound of the present invention or a salt thereof is based on its excellent prostaglandin D synthase inhibitory activity, such as a disease involving prostaglandin D2 or a metabolite thereof, such as allergic diseases or inflammatory diseases. It is useful as a prophylactic and / or therapeutic agent, an exacerbation inhibitor of Alzheimer's disease and brain damage, and other useful effects can be expected.

Pyrimidine Compound of the Present Invention The pyrimidine compound of the present invention has the following general formula (I)

[Where
R ¹ represents a 5- or 6-membered nitrogen-containing unsaturated heterocyclic group which may have a substituent, or a phenyl group which may have a substituent,
R ² represents an unsaturated heterocyclic group or a phenyl group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure;
The unsaturated heterocyclic group represented by R ² has 0 to 2 R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is a halogen atom, a cyano group, a nitro group, a saturated or unsaturated heterocyclic ring which may have a substituent, -NR ⁴ R ⁵ group,-(C = O) -R ⁶ group, -OR ⁷ group Or represents -SR ⁸ group,
R ⁴ and R ⁵ are the same or different and each have a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a substituent. An optionally substituted amino group, a saturated or unsaturated heterocyclic group which may have a substituent, an aryl group having 6 to 14 carbon atoms which may have a substituent or a carbonyl group having a substituent; Or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are each one or two selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. May form a saturated or unsaturated cyclic amino group which may have one hetero atom, the cyclic amino group may have a substituent,
R ⁶ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkenyl group having 2 to 6 carbon atoms, or a carbonyl group having a substituent. Represents
R ⁸ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms,
R ⁹ and R ¹⁰ are the same or different and are each a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon atom having 1 to 6 carbon atoms. Or an amino group which may have a substituent, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, are each one or two selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. A saturated or unsaturated cyclic amino group which may have one hetero atom may be formed, and the cyclic amino group may have a substituent. ]
The pyrimidine compound represented by these, or its salt. However, the compound represented by the general formula (I) in which R ¹ is a phenyl group substituted with a halogen atom and R ² is a phenyl group substituted with a halogen atom is excluded.

  The pyrimidine compound represented by the above general formula (I) of the present invention is a novel compound and is not specifically described in the prior art document.

  For example, Patent Document 1 (Japanese Patent Application Laid-Open No. 2000-226372) describes a wide range of amide compounds having a phenoxypyrimidine compound as a pest control agent. However, except that 2- (4-bromophenoxy) -N- (4-chlorophenyl) -5-pyrimidinecarboxamide is disclosed as Compound No. 1-91 in Table 1 of paragraph 0117 of Patent Document 1, pyrimidine is disclosed. Phenoxypyrimidine compounds having substituents at the 4-position and 6-position of the ring are disclosed, but no specific disclosure of the pyrimidine compounds of the present invention is made.

  Patent Document 2 (Japanese Patent Publication No. 9-510471) describes a wide range of anthranilic acid compounds as antifungal agents, and discloses 2-phenoxy-N-phenyl-5-pyrimidinecarboxamide compounds having a substituent. Has been. However, these compounds all have a substituent at the 2-position of the N-phenyl group and are different from the compounds of the present invention having substituents at the 3-position and 4-position of the N-phenyl group.

  Patent Document 3 (International Publication WO2001-83460) describes a very wide range of cyclic compounds as PDE (IV) inhibitors. However, in Patent Document 3, when the cyclic compound is a pyrimidine compound, compounds having a substituent at the 4-position of the pyrimidine ring are described, and these compounds have a hydrogen atom at the 4-position of the pyrimidine ring. It is clearly different from certain compounds of the present invention.

  Further, a pyrimidine compound described as a PDE (IV) inhibitor in Patent Document 4 (Japanese Patent Publication No. 2003-522165) is a compound having a substituent at the 4-position of the pyrimidine ring, and the 4-position of the pyrimidine ring is This is clearly different from the compound of the present invention which is a hydrogen atom.

  Patent Document 5 (Japanese Patent Application Laid-Open No. 2001-89412) describes a benzene derivative having collagen synthesis inhibitory activity. However, as the pyrimidine compound, a compound in which the amide bond (—NH—CO—) of the compound of the present invention is in the reverse order (that is, —CO—NH—), or a compound in which a urea bond is substituted is used. It is only disclosed, and the pyrimidine compound of the present invention is not specifically disclosed.

The compounds of the present invention typically have the general formula (I)
R ¹ is selected from the group consisting of a pyridyl group which may have a substituent, or a halogen atom, a cyano group and a C 1-6 alkyl group which may be substituted with a halogen atom as a substituent. Represents a phenyl group optionally having one group;
R ² is a monocyclic or bicyclic unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in the ring structure, or phenyl Represents a group,
The unsaturated heterocyclic group represented by R ² has 0 to 2 R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is a halogen atom, a cyano group, a nitro group, an optionally substituted monocyclic saturated or unsaturated heterocyclic group, —NR ⁴ R ⁵ group, — (C═O) —R ⁶ group , -OR ⁷ group or -SR ⁸ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and the other of R ⁴ and R ⁵ has a hydrogen atom or a substituent. An optionally substituted alkyl group having 1 to 6 carbon atoms, a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent, and a phenyl group which may have a substituent Or a carbonyl group having a substituent, or
R ⁴ and R ⁵ , together with the adjacent nitrogen atom, are each in the ring structure one complex selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. ^May form a monocyclic or bicyclic saturated cyclic amino group which may have atoms, or R ⁴ and R ⁵ together with the adjacent nitrogen atom in the ring structure In addition to the adjacent nitrogen atom, the monocyclic or bicyclic unsaturated ring optionally having one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom An amino group may be formed, and the saturated or unsaturated cyclic amino group may have one or two substituents;
R ⁶ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an alkenyl group having 2 to 6 carbon atoms, a (C1-C6 alkyl) carbonyl group or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is a halogen atom, a hydroxyl group, An alkoxy group having 1 to 6 carbon atoms, a —NR ¹¹ R ¹² group, a phenyl group which may have a substituent, a pyridyl group which may have a substituent, and — (C═O) —R ^13. May have one or two groups selected from the group consisting of:
R ⁸ represents a C 1-3 alkyl group which may have a 5-membered or 6-membered monocyclic amino group as a substituent,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 3 carbon atoms, and the other of R ⁹ and R ¹⁰ is a hydrogen atom, an amino group, or a substituted group. Represents an alkyl group having 1 to 6 carbon atoms which may have a group, or an alkoxy group having 1 to 3 carbon atoms which may have a substituent, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, are each one ring selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. It may form a 5-membered or 6-membered monocyclic saturated cyclic amino group which may have a hetero atom, or R ⁹ and R ¹⁰ are each taken together with an adjacent nitrogen atom. In addition to the adjacent nitrogen atom, the ring structure may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. May form a monocyclic unsaturated cyclic amino group, the saturated or unsaturated cyclic amino group may have one substituent,
R ¹¹ and R ^12, one of which represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a phenyl group, the other of R ¹¹ and R ¹² is a hydrogen atom, a phenyl group Yes An alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a 5-membered or 6-membered monocyclic saturated or unsaturated heterocyclic group, or a (C1-C6 alkyl) carbonyl group. Represent or
R ¹¹ and R ¹² , together with the adjacent nitrogen atom, are each one ring selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group [which may have a hydroxyl group] which may have a hetero atom, or R ¹¹ and R ¹² each have an adjacent nitrogen atom and Together, the ring structure may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. May form a formula unsaturated cyclic amino group [may have a methyl group]
R ¹³ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group (where R ⁹ and R ¹⁰ are the same as above). A compound or a salt thereof. (However, the compound represented by the general formula (I) in which R ¹ is a phenyl group substituted with a halogen atom and R ² is a phenyl group substituted with a halogen atom is excluded).

Furthermore, the compound of the present invention is represented by the general formula (1):
R ¹ is a pyridyl group, or a halogen atom, a cyano group, or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom as a substituent at either the 2-position or the 3-position Represents a phenyl group optionally having one group selected from the group consisting of:
R ² is an unsaturated heterocyclic group selected from the group consisting of a pyridyl group, a pyrimidinyl group, a pyrrolyl group, an indolyl group, and a benzofuranyl group, or represents a phenyl group,
The unsaturated heterocyclic group represented by R ² has one or two R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is a monocyclic saturated or unsaturated heterocyclic group optionally having a chlorine atom, a nitro group, a C 1-6 alkyl group or an oxo group as a substituent, —NR ⁴ R ⁵ Represents a group,-(C = O) -R ⁶ group, -OR ⁷ group, or -SR ⁸ group,
R ⁴ and R ^5, one of which represents a hydrogen atom, or a substituent one has to have also a good 1 to 6 carbon atoms alkyl group, the other of R ⁴ and R ⁵ are hydrogen atom, a substituted An alkyl group having 1 to 6 carbon atoms which may have one group, a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have one substituent, and 1 substituent. Represents a phenyl group which may have one carbonyl group or one substituent, or
R ⁴ and R ⁵ , together with the adjacent nitrogen atom, are each in the ring structure one complex selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group which may have an atom, or R ⁴ and R ⁵ , together with the adjacent nitrogen atom, form a ring 5-membered monocyclic ring which may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as a constituent atom in addition to the adjacent nitrogen atom in the structure An unsaturated cyclic amino group may be formed, the saturated cyclic amino group or the unsaturated cyclic amino group may have one or two substituents;
R ⁶ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an allyl group, a tert-butylcarbonyl group, or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is a halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms as a substituent, One selected from the group consisting of —NR ¹¹ R ¹² group, an optionally substituted phenyl group, an optionally substituted pyridyl group, and — (C═O) —R ^13; May have two groups,
R ⁸ represents a C 1-3 alkyl group which may have a morpholino group as a substituent,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other of R ⁹ and R ¹⁰ may have a hydrogen atom, an amino group, or a substituent. Represents an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms, or
R ⁹ and R ¹⁰ together with the adjacent nitrogen atom each have one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group, or R ⁹ and R ¹⁰ together with the adjacent nitrogen atom may be combined with the adjacent nitrogen atom in the ring structure. In addition, a 5- or 6-membered unsaturated cyclic amino group which may have 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom as a constituent atom may be formed. The saturated cyclic amino group or unsaturated cyclic amino group may have one substituent,
One of R ¹¹ and R ¹² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a phenyl group, and the other of R ¹¹ and R ¹² represents a hydrogen atom or a phenyl group. An optionally substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or
R ¹¹ and R ¹² together with the adjacent nitrogen atom each have one heterocyclic atom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group (which may have a hydroxyl group), or R ¹¹ and R ¹² may be combined with an adjacent nitrogen atom, respectively. In the ring structure, in addition to the adjacent nitrogen atom, a monocyclic unsaturated cyclic amino group optionally having one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom [ May have a methyl group],
R ¹³ is a pyrimidine compound or a salt thereof representing a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group (R ⁹ and R ¹⁰ are as defined above). (However, R ¹ is a phenyl group substituted with a halogen atom, and R ² is a phenyl group substituted with a halogen atom, except for the compound represented by the general formula (I)).

Further, the compound according to a preferred embodiment of the present invention is represented by the general formula (I):
R ¹ represents a pyridyl group or a phenyl group,
R ² represents a 3-pyridyl group, an indolyl group or a phenyl group,
The 3-pyridyl group and indolyl group represented by R ^{2 have} one or two R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the 3-pyridyl group, indolyl group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m The groups may be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ represents a nitro group, a tetrahydropyridazinyl group or an imidazolyl group optionally having any of an alkyl group having 1 to 6 carbon atoms or an oxo group as a substituent, a —NR ⁴ R ⁵ group, — ( C = O) -R ⁶ group, or -OR ⁷ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
The other of R ⁴ and R ⁵ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a monocyclic or bicyclic unsaturated heterocyclic group or substituent having 1 or 2 nitrogen atoms as constituent atoms. Each of the carbonyl groups represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a mono- or di (C1-C6 alkyl) amino group, a (C1-C6 alkoxy) carbonyl group, a substituent. One selected from the group consisting of a 5-membered or 6-membered monocyclic saturated or unsaturated heterocyclic group which may have 1 and a phenyl group which may have 1 sulfamoyl group as a substituent May have a group of
The carbonyl group having one substituent is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a carbon number which may have 1 to 3 substituents as the substituent. 1 to 6 alkoxy groups and one group selected from the group consisting of monocyclic saturated or unsaturated heterocyclic rings, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom each have one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group, or R ⁴ and R ⁵ together with the adjacent nitrogen atom may form a ring structure. A 5-membered monocyclic unsaturated cyclic amino group optionally having one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom And the saturated cyclic amino group or unsaturated cyclic amino group may have one or two substituents,
R ⁶ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a (C1-C6 alkyl) carbonyl group, and the alkyl group has a fluorine atom, hydroxyl group, carbon as a substituent. A C 1-3 alkoxy group, a carboxyl group, a (C1-C6 alkoxy) carbonyl group, a carbonyl group having a 5-membered or 6-membered monocyclic saturated heterocyclic group, an optionally substituted 5-membered or It may have one or two groups of a 6-membered monocyclic unsaturated heterocyclic group or a —NR ¹¹ R ¹² group,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁹ and R ¹⁰ represents a hydrogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or a pyridyl group, and the alkyl group has a hydroxyl group as a substituent. Optionally substituted alkoxy group having 1 to 6 carbon atoms, mono- or di (C1-C6 alkyl) amino group, optionally substituted 5-membered or 6-membered monocyclic unsaturated heterocyclic group Or a 5- or 6-membered saturated cyclic amino group that may have a substituent, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, each have a hetero atom of either a nitrogen atom or an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a saturated cyclic amino group, or R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, may be added to the adjacent nitrogen atom in the ring structure in addition to 1 An unsaturated cyclic amino group which may have one or two nitrogen atoms may be formed, and the saturated cyclic amino group or the unsaturated cyclic amino group may have a substituent. ,
One of R ¹¹ and R ¹² represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other of R ¹¹ and R ¹² may have a hydrogen atom or a phenyl group. Represents 1 to 3 alkyl groups, or
R ¹¹ and R ¹² , together with the adjacent nitrogen atom, each have a hetero atom of any one of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group [which may have a hydroxyl group], or R ¹¹ and R ¹² may be combined with an adjacent nitrogen atom, respectively. The ring structure may have one or two heteroatoms selected from the group consisting of nitrogen atoms and oxygen atoms in addition to the adjacent nitrogen atoms. May form a monocyclic unsaturated cyclic amino group [which may have a methyl group],
It is a pyrimidine compound or a salt thereof.

  The compounds represented by formula (I) and the compounds represented by other formulas will be further described below.

  In the present specification, when “may have a substituent” for a certain structure, it may have one or more “substituents” at chemically possible positions on the structure. It means that there is. Further, in this specification, when “having a substituent” for a certain structure, it means that it has one or more “substituents” at chemically possible positions on the structure. means.

There are no particular limitations on the type of substituents present in the structure (or which may be present), the number of substituents, and the position of substitution, and when two or more substituents are present, they are the same. Or different. Examples of the “substituent” include a halogen atom, a hydroxyl group, an oxo group, a cyano group, a nitro group, an amino group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and the number of carbon atoms. An alkenyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an acyl group, a saturated or unsaturated heterocyclic group, a —NR ¹¹ R ¹² group, a — (C═O) —R ¹³ group, and a carbon number of 6 to 14 Aryl groups, sulfamoyl groups and the like, and the number of the substituents is typically 1 to 3.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  “C1-C6 alkyl group” refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and n-butyl groups. , Isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and the like.

  Examples of the “C3-C7 cycloalkyl group” include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.

  Examples of the “alkenyl group having 2 to 6 carbon atoms” include ethenyl group, allyl group, butenyl group, butadienyl group, hexatrienyl group and the like.

  “Alkoxy group having 1 to 6 carbon atoms” refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group. Group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, n-hexyloxy group and the like.

  The “acyl group” includes an aliphatic or aromatic carbonyl group. Examples of the aliphatic carbonyl group include an acetyl group, a propionyl group, a butyroyl group, an isobutyroyl group, a pivaloyl group, a pentanoyl group, a hexanoyl group, and a cyclopropylcarbonyl group. Group, acryloyl group, propioyl group, methacryloyl group, crotonoyl group and the like. Examples of the aromatic substituted carbonyl group include benzoyl group, toluyl group, naphthylcarbonyl group, furoyl group, thienoyl group, nicotinoyl group, isonicotinoyl group, pyrrolidinone. Groups and the like. Preferred acyl groups are formyl group, acetyl group, propionyl group, cyclopropyloyl group, furoyl group, theroyl group, nicotinoyl group, and isonicotinoyl group.

  Examples of the “saturated or unsaturated heterocycle” include pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, homopiperidinyl group, imidazolyl group, thienyl group, furyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl Group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, pyridazyl group, indolyl group, isoindolyl group, indazolyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, benzofuranyl group, Dihydrobenzofuranyl group, benzimidazolyl group, benzoxazole group, benzothiazolyl group, purinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalyl group, 2,3,4,5-tetrahydropyrida Group and the like.

R ¹¹ and R ¹² of the “—NR ¹¹ R ¹² group” are the same or different from each other, and may have, for example, a hydrogen atom, a hydroxyl group, a phenyl group, a C 1-6 alkyl group, a carbon Number 1-6 alkoxy group, amino group, mono or di (C1-C6 alkyl) amino group, (C1-C6 alkyl) (C1-C6 alkoxy) amino group, (C1-C6 alkoxy) carbonyl group, mono or di (C1-C6 alkyl) aminocarbonyl group, saturated or unsaturated heterocyclic group, aryl group having 6 to 14 carbon atoms and the like.

The “—NR ¹¹ R ¹² group” means a saturated cyclic amino group which may have a hydroxyl group or an unsaturated cyclic amino group which may have a methyl group (in particular, the adjacent nitrogen atom, 5 or 6-membered saturated or unsaturated cyclic amino group which may have 1 or 2 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom For example, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholino group, a thiomorpholino group, an imidazolyl group, a pyrrolyl group, a homopiperidinyl group, an imidazolidinyl group, an oxazolidinyl group, a thiazolidinyl group, an imidazolidinyl group, Group, pyrazolinyl group, pyrazolyl group, triazolyl group and the like.

The R ¹³ in the - "(C = O) -R ¹³ group", for example, a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, saturated or unsaturated heterocyclic group And an aryl group having 6 to 14 carbon atoms.

  Examples of the “C6-C14 aryl group” include phenyl group, naphthyl group, anthracene group and the like.

  “Mono or di (C1-C6 alkyl) amino group” means an amino group having a linear or branched alkyl group having 1 to 6 carbon atoms as one or two substituents, such as a methylamino group Ethylamino group, n-propylamino group, n-hexylamino group, dimethylamino group, methylethylamino group, ethylisobutylamino group, benzylmethylamino group, and the like.

  “(C1-C6 alkyl) (C1-C6 alkoxy) amino group” means a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkoxy group having 1 to 6 carbon atoms. An amino group having each group as a substituent is exemplified, and examples thereof include a methylmethoxyamino group, an ethylmethoxyamino group, an n-propylethoxyamino group, and an n-hexylethoxyamino group.

  The “(C1-C6 alkyl) carbonyl group” is a carbonyl group having one linear or branched alkyl group having 1 to 6 carbon atoms as a substituent, such as an acetyl group, a propionyl group, a butyroyl group, etc. Is mentioned.

  Examples of the “(C1-C6 alkoxy) carbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, Examples thereof include tert-butoxycarbonyl group, n-pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, n-hexyloxycarbonyl group and the like.

  Examples of the “mono or di (C1-C6 alkyl) aminocarbonyl group” include a methylaminocarbonyl group, an ethylaminocarbonyl group, an n-propylaminocarbonyl group, an isopropylaminocarbonyl group, an n-butylaminocarbonyl group, and an isobutylaminocarbonyl group. Group, sec-butylaminocarbonyl group, tert-butylaminocarbonyl group, n-pentylaminocarbonyl group, isopentylaminocarbonyl group, neopentylaminocarbonyl group, n-hexylaminocarbonyl, dimethylaminocarbonyl group, methylethylaminocarbonyl Group, ethylisobutylaminocarbonyl group and the like.

In the general formula (I), “5-membered or 6-membered nitrogen-containing unsaturated heterocycle” of “optionally substituted 5- or 6-membered nitrogen-containing unsaturated heterocyclic group” represented by R ¹ Examples of the `` ring group '' include imidazolyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, pyridazyl group and the like. A pyridyl group is preferable. In addition, examples of the substituent of the “optionally substituted 5- or 6-membered nitrogen-containing unsaturated heterocyclic group” include the above-mentioned substituents, but preferably a halogen atom, a cyano group, carbon It is an alkyl group having 1 to 6, more preferably a chlorine atom, a fluorine atom, or a methyl group, and the number is typically one.

In the general formula (I), represented by R ² is an “unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure”. For example, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, imidazolinyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyridazinyl Group, indole group, isoindole group, indazole group, benzofuranyl group, benzoimidazole group, benzoxazole group, benzothiazole group, phthalimidyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalyl group, etc. Consists of nitrogen and oxygen atoms in the structure Monocyclic or bicyclic unsaturated heterocycles containing 1 to 3 heteroatoms selected from: 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring structure 5-membered or 6-membered monocyclic unsaturated heterocyclic group or a bicyclic unsaturated heterocyclic group in which the monocyclic unsaturated heterocyclic group and a benzene ring or a pyrimidine ring are condensed, more preferably A pyridyl group, a pyrimidinyl group, a pyrrolyl group, an indolyl group, and a benzofuranyl group are preferable, and a pyridyl group and an indolyl group are particularly preferable.

In the general formula (I), examples of the “halogen atom” represented by R ³ include the above-described halogen atoms, preferably a chlorine atom.

In the general formula (I), the “saturated or unsaturated heterocycle” of the “saturated or unsaturated heterocycle optionally having a substituent” represented by R ³ includes the above-mentioned saturated or unsaturated heterocycle And is preferably a monocyclic saturated or unsaturated heterocyclic ring, more preferably a 2,3,4,5-tetrahydropyridazinyl group or an imidazolyl group. Examples of the substituent of the “saturated or unsaturated heterocyclic ring optionally having substituent” include the above-mentioned substituents, preferably an alkyl group having 1 to 6 carbon atoms and an oxo group, more preferably Is a methyl group or an oxo group, and the number thereof is typically one.

Examples of the “alkyl group having 1 to 6 carbon atoms” of the “optionally substituted alkyl group having 1 to 6 carbon atoms” represented by R ⁴ and R ⁵ include the above-described alkyl groups, Preferably it is a C1-C3 alkyl group, More preferably, they are a methyl group, an ethyl group, and n-propyl group. Moreover, as a substituent of "the C1-C6 alkyl group which may have a substituent", the above-mentioned substituent is illustrated, Preferably a hydroxyl group, a C1-C6 alkoxy group, mono or Di (C1-C6 alkyl) amino group, (C1-C6 alkoxy) carbonyl group, saturated or unsaturated cyclic amino group, monocyclic saturated or unsaturated heterocyclic group, phenyl group [the heterocyclic group and phenyl group are substituted And may be a hydroxyl group, a methoxy group, a dimethylamino group, an ethoxycarbonyl group, a morpholino group, a pyrrolidinyl group, a pyridyl group, an imidazolyl group, or a phenyl group.

The “alkoxy group having 1 to 6 carbon atoms” represented by R ⁴ and R ⁵ is exemplified by the above-mentioned alkoxy group, preferably a methoxy group or an ethoxy group.

Examples of the substituent of the “optionally substituted amino group” represented by R ⁴ and R ⁵ include the above-mentioned substituents, and the number thereof is typically one.

Examples of the “saturated or unsaturated heterocycle” of the “saturated or unsaturated heterocycle optionally having a substituent” represented by R ⁴ and R ⁵ include the above-mentioned saturated or unsaturated heterocycle, Preferred is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring, more preferred is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having one or two nitrogen atoms as constituent atoms. Particularly preferred is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having one nitrogen atom as a constituent atom, particularly a pyridyl group or an indolyl group. Further, examples of the substituent of “saturated or unsaturated heterocyclic ring optionally having substituent (s)” include the above-mentioned substituents, and the number thereof is typically one.

The “aryl group having 6 to 14 carbon atoms” of the “optionally substituted aryl group having 6 to 14 carbon atoms” represented by R ⁴ and R ⁵ is the above-mentioned 6 to 14 carbon atoms. An aryl group is exemplified, and a phenyl group is preferable. Examples of the substituent of the “optionally substituted aryl group having 6 to 14 carbon atoms” include the above-mentioned substituents, preferably a sulfamoyl group, and the number is typically one. It is.

Examples of the substituent of the “carbonyl group having a substituent” represented by R ⁴ and R ⁵ include the above-mentioned substituents, preferably an alkyl group having 1 to 6 carbon atoms and a cycloalkyl having 3 to 7 carbon atoms. Group, a C 1-6 alkoxy group, a monocyclic saturated or unsaturated heterocyclic group [the alkyl group may have 1 to 3 substituents], more preferably an ethyl group, tert -Butyl group, cyclopropyl group, tert-butoxy group, thienyl group, furyl group [ethyl group, tert-butyl group is an alkoxy group having 1 to 6 carbon atoms, acyloxy group, particularly methoxy group, ethoxy group as substituents May have one acetoxy group], and the number is typically one.

R ⁴ and R ⁵ may be formed together with an adjacent nitrogen atom. In the ring structure, in addition to the adjacent nitrogen atom, 1 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Examples of the “saturated or unsaturated cyclic amino ring” of “saturated or unsaturated cyclic amino ring optionally having 1 or 2 heteroatoms” include, for example, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group Thiomorpholino group, homopiperidinyl group, imidazolyl group, pyrrolyl group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, pyrazolidinyl group, imidazolinyl group, pyrazolinyl group, triazolyl group, etc., preferably monocyclic or bicyclic saturated or An unsaturated cyclic amino group, more preferably a monocyclic saturated or unsaturated cyclic amino group, and particularly preferred. Or pyrrolidinyl, piperidinyl, piperazinyl, morpholino, imidazolyl, pyrazolyl, pyrazolinyl, thiazolidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl.

Further, R ⁴ and good "ring structure be formed together with the nitrogen atom to which R ⁵ is adjacent, in addition to said adjacent nitrogen atom, selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom Examples of the substituent which the saturated or unsaturated cyclic amino ring optionally having 1 or 2 heteroatoms may have include the above-mentioned substituents, preferably a hydroxyl group, oxo Group, an alkyl group having 1 to 6 carbon atoms [the alkyl group may have a substituent], a carboxyl group, (C1-C6 alkyl) carbonyl group [the C1-C6 alkyl is a substituent such as acetoxy May have one group, one hydroxyl group, etc.], (C1-C6 alkoxy) carbonyl group, a carbonyl group substituted with a saturated or unsaturated cyclic amino group, (C1-C6 alkyl) (C1-C6 alkoxy) A carbonyl group substituted with an amino group, a saturated or unsaturated heterocyclic ring More preferably, a hydroxyl group, an oxo group, a methyl group [which may have a hydroxyl group or a methoxy group as a substituent], a carboxyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a hydroxymethylcarbonyl group, an acetoxyacetyl Group, pyrrolidinylcarbonyl group, morpholinocarbonyl group, pyrazolinylcarbonyl group, N-methoxy-N-methylaminocarbonyl group, pyrimidyl group, the number of which is typically one or two, especially one It is.

Examples of the “alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R ⁶ include the above-mentioned alkoxy groups, preferably methoxy Group, ethoxy group, n-propoxy group, isopropoxy group, tert-butoxy group. Moreover, as a substituent of "the C1-C6 alkoxy group which may have a substituent", the above-mentioned substituent is illustrated and the number is typically one.

Examples of the “alkyl group having 1 to 6 carbon atoms” of the “optionally substituted alkyl group having 1 to 6 carbon atoms” represented by R ⁷ include the alkyl groups described above, preferably It is a C1-C4 alkyl group, More preferably, they are a methyl group, an ethyl group, n-propyl group, isopropyl group, and an isobutyl group. Moreover, as a substituent of "the C1-C6 alkyl group which may have a substituent", the above-mentioned substituent is illustrated, Preferably a halogen atom, a hydroxyl group, a C1-C6 alkoxy group -NR ¹¹ R ¹² group, optionally substituted phenyl group, optionally substituted pyridyl group,-(C = O) -R ¹³ group, more preferably a fluorine atom A hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, a carboxyl group, a (C1-C6 alkoxy) carbonyl group, a carbonyl group having a 5-membered or 6-membered monocyclic saturated heterocyclic group, and a substituent. A 5- or 6-membered monocyclic unsaturated heterocyclic group, —NR ¹¹ R ¹² group, particularly preferably a fluorine atom, a hydroxyl group, a methoxy group, a benzylmethylamino group (Example 107), a carboxyl group Group, tert-butoxycarbonyl group, morpholinocar Nyl, 2-methylimidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrrolyl, pyrrolidinyl, morpholino, 4-hydroxypiperidinyl, pyridyl, morpholinocarbonylpyridyl The number of groups is typically one.

Examples of the “alkenyl group having 2 to 6 carbon atoms” of the “optionally substituted alkenyl group having 2 to 6 carbon atoms” represented by R ⁷ include the above-mentioned alkenyl groups, preferably allyl. It is a group. Further, examples of the substituent that the “optionally substituted alkenyl group having 2 to 6 carbon atoms” may have include the above-mentioned substituents, and the number thereof is typically 1 It is.

As the “carbonyl group having a substituent” represented by R ⁷ , the above-mentioned (C1-C6 alkyl) carbonyl group, (C1-C6 alkoxy) carbonyl group, mono- or di (C1-C6 alkyl) aminocarbonyl group may be used. Exemplified, preferably a (C1-C6 alkyl) carbonyl group, and more preferably a tert-butylcarbonyl group.

Examples of the “alkyl group having 1 to 6 carbon atoms” of the “optionally substituted alkyl group having 1 to 6 carbon atoms” represented by R ⁸ include the above-mentioned alkyl groups, preferably carbon. It is a C 1-3 alkyl group, and more preferably an ethyl group. Examples of the substituent of the “optionally substituted alkyl group having 1 to 6 carbon atoms” include the above-mentioned substituents, preferably a 5-membered or 6-membered monocyclic cyclic amino group. More preferably, it is a morpholino group, and the number is typically one.

Examples of the “alkyl group having 1 to 6 carbon atoms” of the “optionally substituted alkyl group having 1 to 6 carbon atoms” represented by R ⁹ and R ¹⁰ include the above-described alkyl groups, Preferably it is a C1-C3 alkyl group, More preferably, they are a methyl group, an ethyl group, and n-propyl group. Further, examples of the substituent of the “optionally substituted alkyl group having 1 to 6 carbon atoms” include the above-mentioned substituents, preferably an alkoxy group having 1 to 6 carbon atoms [the alkoxy group is substituted. A mono- or di (C1-C6 alkyl) amino group (Example 6, Example 122), a 5-membered or 6-membered monocyclic unsaturated heterocyclic group [the heterocyclic group] May have a substituent] is a 5-membered or 6-membered saturated cyclic amino group [the cyclic amino group may have a substituent], more preferably a hydroxyl group is substituted. An optionally substituted alkyl group having 1 to 6 carbon atoms, a di (C1-C6 alkyl) amino group, a 6-membered monocyclic unsaturated heterocyclic group, and an optionally substituted 5-membered or 6-membered saturated group Cyclic amino group, particularly preferably hydroxyethoxy group (Example 15), dimethylamino group (Example 6), pyridyl group ( Example 9), which may have an oxo group (Example 8), morpholino group (Example 7), and the number of these substituents is typically 1 to 3, particularly 1. is there.

Examples of the “alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R ⁹ and R ¹⁰ include the above-mentioned alkoxy groups, Preferably it is a C1-C3 alkoxy group, More preferably, they are a methoxy group, an ethoxy group, n-propoxy group, and an isopropoxy group. Examples of the substituent of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” include the above-described substituents, and the number thereof is typically one.

Examples of the substituent of the “amino group optionally having substituent (s)” represented by R ⁹ and R ¹⁰ include the above-mentioned substituents, and the number thereof is typically 1 or 2, particularly One.

R ⁹ and R ¹⁰ may be formed together with an adjacent nitrogen atom. “In the ring structure, in addition to the adjacent nitrogen atom, 1 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom” Examples of the “saturated or unsaturated cyclic amino group optionally having one or two heteroatoms” include the above-mentioned saturated or unsaturated cyclic amino groups, preferably 5-membered or 6-membered monocyclic saturated Cyclic amino group [for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, pyrazolidinyl group, homopiperidinyl group, pyrrolidinyl group, etc.], or 5-membered or 6-membered A monocyclic unsaturated cyclic amino group [for example, an imidazolyl group, a pyrrolyl group, an imidazolinyl group, a pyrazolinyl group, a triazolyl group, etc. More preferably, together with the adjacent nitrogen atom, in the ring structure, in addition to the adjacent nitrogen atom, a single heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom Represents a monocyclic saturated cyclic amino group which may have, or R ⁹ and R ¹⁰ together with the adjacent nitrogen atom, in addition to the adjacent nitrogen atom in the ring structure A 5- or 6-membered unsaturated cyclic amino group optionally having 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom, particularly preferably a pyrrolidinyl group or piperidinyl group A group, a morpholino group, and a pyrazolinyl group. “Along with the adjacent nitrogen atom, the ring structure has one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. Examples of the substituent which the “saturated or unsaturated cyclic amino group optionally having” may have include the above-mentioned substituents, and the number thereof is typically 1 to 3, particularly 1.

Examples of the “alkyl group having 1 to 6 carbon atoms” of the “alkyl group having 1 to 6 carbon atoms which may have a phenyl group” represented by R ¹¹ and R ¹² include the above-described alkyl groups, Preferably it is a C1-C3 alkyl group, More preferably, they are a methyl group, an ethyl group, n-propyl group, and an isopropyl group.

Examples of the “C1-C6 alkoxy group” of the “C1-C6 alkoxy group” represented by R ¹¹ and R ¹² include the above-mentioned alkoxy groups, preferably C 1-3 alkoxy. More preferably a methoxy group, an ethoxy group, an n-propoxy group or an isopropoxy group.

Examples of the “5-membered or 6-membered monocyclic saturated or unsaturated heterocyclic ring” represented by R ¹¹ and R ¹² include the above-mentioned 5-membered or 6-membered monocyclic saturated or unsaturated heterocyclic ring. .

Examples of the “(C1-C6 alkyl) carbonyl group” represented by R ¹¹ and R ¹² include the above-mentioned (C1-C6 alkyl) carbonyl group, preferably a tert-butylcarbonyl group.

R ¹¹ and R ¹² may be formed together with an adjacent nitrogen atom “in the ring structure, in addition to the adjacent nitrogen atom, 1 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom” Examples of the “monocyclic saturated cyclic amino group” of the “monocyclic saturated cyclic amino group optionally having a single hetero atom” include, for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, homopiperidinyl Group, homopiperazinyl group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, pyrazolidinyl group and the like, preferably together with the adjacent nitrogen atom, in addition to the adjacent nitrogen atom, a nitrogen atom and A monocyclic saturated cyclic amino group [may have a hydroxyl group] which may have one heteroatom selected from the group consisting of oxygen atoms A Yes], more preferably a saturated cyclic amino group of 5-membered or 6-membered.

R ¹¹ and R ¹² may be formed together with an adjacent nitrogen atom. “In the ring structure, in addition to the adjacent nitrogen atom, 1 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom” As the “monocyclic unsaturated cyclic amino group” of the “monocyclic unsaturated cyclic amino group optionally having two or two heteroatoms”, for example, an imidazolyl group, a pyrrolyl group, an imidazolinyl group, a pyrazolinyl group, A triazolyl group, and the like, preferably together with the adjacent nitrogen atom, in the ring structure, in addition to the adjacent nitrogen atom, one or two selected from the group consisting of a nitrogen atom and an oxygen atom It is a monocyclic unsaturated cyclic amino group [which may have a methyl group] which may have a hetero atom, and more preferably a 5-membered or 6-membered unsaturated cyclic amino group.

Examples of the “alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R ¹³ include the above-mentioned alkoxy groups, preferably tert -Butoxy group. Examples of the substituent of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” include the above-described substituents, and the number thereof is typically one.

  Among the compounds represented by the general formula (I) of the present invention, the following compounds are more preferable.

(A) In the general formula (I),
R ¹ represents a 3-pyridyl group or a phenyl group,
R ² is, R ³ in the 6-position - (CH _{2) m} - 3- pyridyl groups having group, at the 2-position _{^{R 3 - (CH 2) m}} - any indolyl group, or a 3- or 4-position with a group Represents a phenyl group having a R ^3- (CH ₂ ) _m -group,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is 2-methyl-1-imidazolyl group, 3-oxo-2,3,4,5-tetrahydropyridazinyl group, -NR ⁴ R ⁵ group,-(C = O) -R ⁶ group, or an -OR ⁷ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁴ and R ⁵ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, and a monocyclic or bicyclic unsaturated heterocyclic group having one nitrogen atom as a constituent atom (particularly pyridyl group, indolyl group) Tert-butoxycarbonyl group, cyclopropylcarbonyl group, ethoxyethylcarbonyl group, 3-acetoxy-2,2-dimethylpropionyl group, thiophenecarbonyl group or furylcarbonyl group, and the alkyl group has 1 carbon atom as a substituent. ~ 3 alkoxy groups, mono or di (C1-C6 alkyl) amino group, ethoxycarbonyl group, morpholino group, pyrrolidinyl group optionally having an oxo group, pyridyl group, imidazolyl group, and 4-sulfamoylphenyl May have one group selected from the group consisting of groups, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, imidazolyl group, pyrazolyl group, pyrazolinyl group, thiazolinyl group, 1,2,3-triazolyl group, Or a cyclic amino group of any one of 1,2,4-triazolyl groups, and the cyclic amino group is a substituent (in particular, a hydroxyl group, an oxo group, a hydroxymethyl group, a methoxymethyl group, a carboxyl group, an ethoxycarbonyl group, One selected from tert-butoxycarbonyl group, hydroxymethylcarbonyl group, acetoxyacetyl group, pyrrolidinylcarbonyl group, morpholinocarbonyl group, pyrazolinylcarbonyl group, N-methoxy-N-methylaminocarbonyl group, and pyrimidyl group May have a substituent of
R ⁶ represents a hydrogen atom, a hydroxyl group, an ethoxy group, a tert-butoxy group, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and the alkyl group is substituted with a hydroxyl group, a methoxy group, a benzylmethylamino group, a carboxyl group, a tert-butoxycarbonyl group, a morpholinocarbonyl group, 2 -Methylimidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, pyrrolyl group, pyrrolidinyl group, morpholino group, 4-hydroxypiperidinyl group, or pyridyl group You may have
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁹ and R ^{10 represents} a hydrogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is a hydroxyethoxy group or a dimethylamino group as a substituent. , May have one group selected from the group consisting of a pyrrolidinyl group, a morpholino group, and a pyridyl group, which may have one oxo group, or
A pyrimidine compound or a salt thereof, wherein R ⁹ and R ¹⁰ together with an adjacent nitrogen atom represent a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, or pyrazolinyl group.

(B) In the general formula (I),
R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position or a 3-pyridyl group having an R ³ — (CH ₂ ) _m — group at the 6-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ represents -NR ⁴ R ⁵ group, or -OR ⁷ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or a methyl group, and the other represents a hydrogen atom, a methoxypropyl group (Example 21), a dimethylaminoethyl group (Example 100), an ethoxycarbonylethyl group, a morpholinoethyl group. 2-oxopyrrolidinylpropyl group, pyridylethyl group, imidazolylpropyl group, 4-sulfamoylphenylethyl group, tert-butoxycarbonyl group, cyclopropylcarbonyl group, ethoxyethylcarbonyl group, 3-acetoxy-2,2 -Represents either a dimethylpropionyl group, a thiophenecarbonyl group or a furylcarbonyl group, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom may be a pyrrolidinyl group (Example 27) which may have one oxo group, a substituent (for example, hydroxyl group, hydroxymethyl group, methoxymethyl). One selected from the group consisting of a group, carboxyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, pyrrolidinylcarbonyl group, morpholinocarbonyl group, pyrazolinylcarbonyl group, and N-methoxy-N-methylaminocarbonyl group A piperidinyl group having a substituent, a piperazinyl group having a substituent (for example, one selected from the group consisting of an acetoxyacetyl group, a hydroxymethylcarbonyl group, and a pyrimidyl group), a morpholino group (Example 52), and a carbon number as a substituent An imidazolyl group optionally having 1 to 6 alkyl groups, a hydroxyl group as a substituent, methyl A pyrazolyl group (Example 69, Example 71), a pyrazolinyl group (Example 70), a thiazolidinyl group, a 1,2,3-triazolyl group, or a 1,2,4 -Represents any of the triazolyl groups,
R ⁷ is a hydrogen atom, isobutyl group, hydroxypropyl group, carboxymethyl group, tert-butoxycarbonylmethyl group, pyrrolidinylpropyl group, 4-hydroxypiperidinylpropyl group, morpholinoethyl group, pyrrolylpropyl group, 2 -A pyrimidine compound or a salt thereof representing any one of a methylimidazolylethyl group, a 1,2,3-triazolylethyl group, a 1,2,4-triazolylethyl group, or a morpholinocarbonylmethyl group.

(C) In general formula (I),
R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ represents -NR ⁴ R ⁵ group, or -OR ⁷ group,
R ⁴ and R ⁵ each represents a hydrogen atom or a methyl group, and the other represents a hydrogen atom, a methoxypropyl group, a 4-sulfamoylphenylethyl group, a tert-butoxycarbonyl group, a cyclopropylcarbonyl group, an ethoxyethylcarbonyl group. Represents a group, 3-acetoxy-2,2-dimethylpropionyl group, thiophenecarbonyl group or furylcarbonyl group, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom may be a pyrrolidinyl group which may have one oxo group, a substituent (for example, a hydroxyl group, a hydroxymethyl group, a methoxymethyl group, a carboxyl group, A piperidinyl group having one selected from the group consisting of ethoxycarbonyl group, tert-butoxycarbonyl group, pyrrolidinylcarbonyl group, morpholinocarbonyl group, pyrazolinylcarbonyl group, and N-methoxy-N-methylaminocarbonyl group) A piperazinyl group having a substituent (for example, one selected from the group consisting of an acetoxyacetyl group, a hydroxymethylcarbonyl group, and a pyrimidyl group), a morpholino group, and an alkyl group having 1 to 6 carbon atoms as a substituent. May be an imidazolyl group, a hydroxyl group as a substituent, a methyl group, or both Which represents either a pyrazolyl group, a pyrazolinyl group, a thiazolidinyl group, a 1,2,3-triazolyl group, or a 1,2,4-triazolyl group,
R ⁷ is a hydrogen atom, isobutyl group, hydroxypropyl group, carboxymethyl group, tert-butoxycarbonylmethyl group, pyrrolidinylpropyl group, 4-hydroxypiperidinylpropyl group, morpholinoethyl group, pyrrolylpropyl group, 2 -A pyrimidine compound or a salt thereof representing any one of a methylimidazolylethyl group, a 1,2,3-triazolylethyl group, a 1,2,4-triazolylethyl group, or a morpholinocarbonylmethyl group.

(D) In general formula (I),
R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ is a pyrrolidinyl group, a substituent at the 4-position (eg, hydroxyl group, hydroxymethyl group, methoxymethyl group, carboxyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, pyrrolidinylcarbonyl group, morpholinocarbonyl group, pyra A piperidinyl group having a zolinylcarbonyl group and an N-methoxy-N-methylaminocarbonyl group selected from the group consisting of a substituent at the 4-position (for example, an acetoxyacetyl group, a hydroxymethylcarbonyl group, and a pyrimidyl group) A pyrimidine compound having a piperazinyl group, a morpholino group, a 2-methylimidazolyl group, or a 1,2,4-triazolyl group or a salt thereof having one selected from the group consisting of:

(E) Among the compounds represented by the above general formula (I), the following specific compounds or salts thereof can be mentioned in particular.
2-phenoxy-N- (4- (1,2,4-triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide2-phenoxy-N- (4- (2- (2-methylimidazole-1 -Yl) ethyl) phenyl) -5-pyrimidinecarboxamide, 2-phenoxy-N- (4- (4-tert-butoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide, 2-phenoxy-N- ( 4- (4-carboxylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide 2-phenoxy-N- (4- (4- (1-pyrrolidinylcarbonyl) -piperidin-1-yl) phenyl)- 5-Pyrimidinecarboxamide, 2-phenoxy-N- (4- (4- (4-morpholinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide, 2-phenoxy-N- (4- ( 4- (N-methoxy-N-methyl) -carboxamidopiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide 2-phenoxy-N- (4- (3- (4- Droxypiperidin-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide ・ 2- (3-pyridyloxy) -N- (4- (4-hydroxypiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide 2- (3-pyridyloxy) -N- (4- (2- (morpholin-4-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide.

  In addition, in the compound (I) useful as an active ingredient of the medicament of the present invention, when an asymmetric carbon is present, an optical isomer derived from the asymmetric carbon and other isomers may exist. The present invention includes all of these isomers separated or mixtures thereof.

  The compound (I) useful as an active ingredient of the medicament of the present invention also includes a pharmacologically acceptable prodrug. The pharmacologically acceptable prodrug means an amino group, a hydroxyl group, a carboxyl group, a carbonyl of the compound (I) which is an active ingredient of the pharmaceutical agent of the present invention under chemical conditions such as solvolysis or physiological conditions. It is a compound having a functional group that can be converted into a functional group such as a group. Representative functional groups that form prodrugs include groups described in “Development of Pharmaceuticals” (Yodogawa Shoten, 1990) Vol. 7 163-198.

  Furthermore, the compound (I) useful as an active ingredient of the medicament of the present invention may form an acid adduct salt or a salt with a base, and as long as such a salt is a pharmaceutically acceptable salt, the present invention Is included. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium, aluminum Examples thereof include salts and ammonium salts with organic bases such as methylamine, ethylamine, meglumine and ethanolamine, or basic amino acids such as lysine, arginine and ornithine.

  Furthermore, the present invention also includes compound (I) useful as an active ingredient of the medicament of the present invention and various hydrates and solvates and polymorphic substances of pharmaceutically acceptable salts thereof.

Production Method of the Compound of the Present Invention A typical production method of the compound represented by formula (I) will be described.

  [Method 1]

In the above reaction scheme 1, R ¹ and R ² are the same as above, R represents a protecting group for a carboxyl group or a hydrogen atom, and X represents a leaving functional group.

  In this production method, a pyrimidine compound represented by the formula (1a) and a phenolic compound represented by the formula (1b) or a hydroxyl group-containing nitrogen-containing unsaturated heterocyclic compound are condensed by a conventional method, and represented by the formula (2). The first step of making an ether derivative, when R is a carboxyl protecting group, the second step of obtaining a carboxylic acid derivative represented by the formula (3) by deesterification such as hydrolysis reaction, carboxylic acid derivative (3) Is a method comprising a third step of producing a compound represented by the general formula (I) by condensing with an amine compound represented by the formula (1c) by a conventional method.

<First step>
In the first step, X in the compound (1a) may be any as long as it is a leaving functional group, and examples thereof include a chlorine atom, a bromine atom, a methylsulfonyl group, a benzenesulfonyl group, and a p-toluenesulfonyl group. R in the compound (1a) may be any known ester protecting group, for example, an alkyl group having 1 to 6 carbon atoms, an allyl group, a phenyl group, a methoxymethyl group, a methylthiomethyl group, a tetrahydropyrani group. Group, benzyloxymethyl group, 2-trimethylsilylethyl group, benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, diphenylmethyl group, triphenylmethyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert- A butyl diphenylsilyl group etc. are mentioned.

  In a suitable solvent, 0.5 to 10 moles, preferably 0.8 to 2 moles of the phenolic compound represented by the formula (1b) or the hydroxyl group-containing nitrogen-containing unsaturated heterocycle per mole of the pyrimidine compound represented by the formula (1a) Using the compound, the reaction is carried out at 0 to 180 ° C., preferably 20 to 150 ° C. in the presence of 0.5 to 10 mol, preferably 0.8 to 3 mol of a base with respect to 1 mol of the pyrimidine compound represented by the formula (1a). Thus, an ether derivative represented by the formula (2) can be obtained.

  The suitable solvent is not particularly limited as long as it does not affect the reaction. For example, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination.

  Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate and the like, and organic bases such as pyridine and lutidine. , Collidine, 4- (N, N-dimethylamino) pyridine, triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7- En or the like can be used.

<Second step>
In the second step, the conversion of the derivative represented by formula (2) to the carboxylic acid derivative represented by formula (3) by deprotection of the ester group differs depending on the type of R. For example, R is a methyl group, ethyl In the case of a lower alkyl group such as a propyl group or a propyl group, 0.5 to 10 moles, preferably 1 to 5 moles of lithium hydroxide, water per 1 mole of the ester group of the derivative represented by the formula (2) in a suitable solvent The deprotection can be carried out by reacting at −30 ° C. to 150 ° C., preferably −10 ° C. to 100 ° C. in the presence of a base such as sodium oxide or potassium hydroxide.

  A suitable solvent is not particularly limited as long as it does not affect the reaction.For example, water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, N, N-dimethylformamide, N, N -Dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and the like can be mentioned, and these can be used alone or in combination.

<Third step>
In the third step, the amine derivative represented by the formula (1c) or a salt thereof and the carboxylic acid derivative represented by the formula (3) or a reactive derivative thereof are condensed by a conventional method to give a general formula (I) The indicated amide compound can be obtained.

  Examples of the salt of the amine derivative represented by the formula (1c) include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, carbonic acid, methanesulfonic acid, benzenesulfonate, p-toluenesulfonate, and the like. Examples include acid addition salts with organic acids.

  Examples of the reactive derivative of the compound (3) include normal esters such as methyl ester, ethyl ester and tert-butyl ester, acid halides such as acid chloride and acid bromide, acid azide, N-hydroxybenzotriazole, and N-hydroxys. Examples thereof include active esters with succinimide, p-nitrophenol and the like, symmetric acid anhydrides, mixed acid anhydrides with alkyl carbonate, p-toluenesulfonic acid and the like.

  When reacting the compound (3) with a free acid or without reacting the active ester or acid halide without isolation, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl azide, 1-ethyl-3 It is possible to use condensing agents such as-(3-dimethylaminopropyl) carbodiimide hydrochloride and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride. Is preferred.

  0.5 to 10 mol, preferably 0.8 to 2 mol of the carboxylic acid derivative represented by the formula (3) or a reactive derivative thereof is used with respect to 1 mol of the amine derivative represented by the formula (1c), and the above condensing agent is used. In this case, the amount used is 0.5 to 20 mol, preferably 0.8 to 3 mol, per 1 mol of the amine derivative represented by the formula (1c).

  The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, pyridine, etc., in a solvent inert to the reaction, it can be carried out at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  In the reaction, 0.5 to 20 mol, preferably 0.8 to 5 mol, of triethylamine, diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, N, N--, with respect to 1 mol of the amine derivative represented by the formula (1c). The reaction may proceed smoothly by carrying out the reaction in the presence of a base such as diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, lutidine and the like.

  Compound (I) of the present invention is obtained by performing the first to third steps.

  The pyrimidine compounds represented by the above formula (1a), the phenolic compounds represented by the formula (1b) or the hydroxyl group-containing nitrogen-containing unsaturated heterocyclic compounds, and the amine derivatives represented by the formula (1c) are known. Or can be prepared according to known methods.

  Further, the amine derivative represented by the formula (1c), that is, the amine derivative represented by the following formula (2d) can also be synthesized, for example, by the method shown in the following reaction process formula 2.

In the above reaction scheme 2, m is 0 to 4, R ^2a is a divalent residue obtained by removing one hydrogen atom from R ² , Z ¹ is a nitro group or protecting group-substituted amino group, X ¹ represents a leaving functional group, n represents 1 or 2, and A ¹ has the same meaning as R ³ .

That is, the ^{first step} of reacting the compound (2a) having a leaving functional group X ¹ with the amine compound or hydroxyl compound represented by the formula (2b), and the resulting derivative (2c) This is a method comprising a second step of obtaining an amine compound (2d) by reducing a group or deprotecting an amino-protecting group.

<First step>
In the first step, X ¹ of compound (2a) may be any known functional group such as a fluorine atom, chlorine atom, bromine atom, iodine atom, methylsulfonyl group, benzenesulfonyl group, p -Toluenesulfonyl group and the like.

  In an appropriate solvent, 0.5 to 10 mol, preferably 0.8 to 2 mol, of an amine compound or a hydroxyl compound represented by the formula (2b) is used per 1 mol of the compound represented by the formula (2a). The reaction is carried out at a temperature of −20 ° C. to 180 ° C., preferably 0 ° C. to 150 ° C., in the presence or absence of 0.5 to 10 mol, preferably 0.8 to 3 mol of a base, per 1 mol of the compound represented by The nitro compound represented by 2c) can be obtained.

  The suitable solvent is not particularly limited as long as it does not affect the reaction. For example, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination.

  Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like, and organic bases For example, pyridine, lutidine, collidine, 4- (N, N-dimethylamino) pyridine, triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0 ] Undec-7-ene, tert-butoxypotassium, etc. can be used.

<Second step>
For the reduction reaction when Z ¹ is a nitro group, any reaction condition can be used as long as it is a reaction that reduces the nitro group to convert it to an amino group. In view of the above, it is preferable to select the reaction conditions.

Examples of typical reduction methods include the following methods:
(A) In water, alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, or a mixed solvent thereof, 0.3 mol per mole of the nitro derivative represented by the formula (2c) -30 mol, preferably 0.5-20 mol ammonium salt such as ammonium chloride, hydrazine hydrate, etc., in the presence of 0.01-10 mol, preferably 0.03-5 mol reduced iron, tin chloride, iron chloride, etc. A method in which a metal having reducibility of 0 to 150 ° C., preferably 20 to 120 ° C. is allowed to act.

  (B) In alcohols, ethers, esters such as ethyl acetate and butyl acetate, organic acids such as formic acid and acetic acid, or a mixed solvent thereof, 0.001 to 1 per mole of the nitro derivative represented by the formula (2c) Molar, preferably 0.01-0.3 moles of palladium on carbon, platinum oxide, Raney nickel, etc. in the presence of reducing metals such as 0 to 120 ° C, preferably 20 to 100 ° C under normal or pressurized hydrogen gas action Or 0.5 to 20 mol, preferably 1 to 10 mol of formic acid, ammonium formate, cyclohexene or the like is used as a hydrogen source with respect to 1 mol of the nitro derivative represented by the formula (2c) instead of hydrogen gas.

Deprotection when Z ¹ is a protecting group-substituted amino group (for example, formyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, acetyl group, benzoyl group, etc.) A known method for deprotecting an amino group can be used. Particularly, in the case of a formyl group, a tert-butoxycarbonyl group, an acetyl group, or a benzoyl group, it can be represented by the formula (2c) in a suitable solvent or without a solvent. 1 to 100 mol, preferably 2 to 10 mol of hydrochloric acid, hydrobromic acid, formic acid, trifluoroacetic acid, etc. under the acidic condition of -20 ° C to 150 ° C, preferably from 0 ° C to 1 mol of the derivative. It can be deprotected by reacting at 100 ° C.

  Suitable solvents are not particularly limited as long as they do not affect the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, lower alcohols such as methanol, ethanol, propanol and isopropanol, Examples include formic acid and acetic acid, and these can be used alone or in combination.

In the case of a benzyloxycarbonyl group or a benzyl group, a derivative 1 represented by the formula (2c) in an alcohol, an ether, an ester such as ethyl acetate or butyl acetate, an organic acid such as formic acid or acetic acid, or a mixed solvent thereof. In the presence of 0.001 to 1 mol, preferably 0.01 to 0.3 mol of palladium on carbon, etc., in the presence of a reducing metal such as palladium on carbon, 0 to 120 ° C., preferably 20 to 100 ° C., and hydrogen gas is added at normal pressure to It can be obtained by applying a rolling action.
And the like.

The amine compound or hydroxyl compound represented by the compound (2a) having the leaving functional group X ¹ and the formula (2b) is known or can be produced according to a known method.

  Furthermore, the amine compound (1c) of the reaction process formula 1, that is, the following compound (3i) or the compound (3j) can also be produced by the method shown in the following reaction process formula 3.

In the above reaction scheme 3, R ^2a is the same as above, X, X ² and X ³ represent a leaving functional group, R ¹⁴ represents R ⁷ and R ¹⁵ R ¹⁶ N Represents R ¹¹ R ¹² N as described above, and p represents 2 to 4.

In the production method shown in the above reaction process formula 3, the compound represented by the formula (3b) or (3c), (3d) is reacted with the compound (3a) having a hydroxyl group, and the formula (3e) or (3f the first step of the ether compound represented by), the second step, the nitro compound obtained in the second step of condensing when the amine compound and (3 g) of the ether compound (3f) has a leaving functional group X ² A third step of obtaining an amine derivative (3j) or (3i) by reducing the nitro group of (3h) or the nitro group of the ether derivative (3e) obtained in the first step according to a conventional method. Is the method.

<First step>
(1) X, X ² , X ³ of the compound (3b), (3c) or (3d) in the first step may be any leaving functional group, for example, chlorine atom, bromine atom, iodine atom , Methylsulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group and the like.

  In a suitable solvent, 0.5 to 10 mol, preferably 0.8 to 2 mol, of the compound represented by the formula (3b, 3c) is used per 1 mol of the hydroxyl compound represented by the formula (3a). In the presence of 0.5 to 10 moles, preferably 0.8 to 3 moles of base to 1 mole of the compound to be reacted at −20 ° C. to 180 ° C., preferably 0 ° C. to 150 ° C., the formula (3e, 3f) The ether compounds shown can be obtained.

  The suitable solvent is not particularly limited as long as it does not affect the reaction. For example, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination.

  Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like, and organic bases For example, pyridine, lutidine, collidine, 4- (N, N-dimethylamino) pyridine, triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0 ] Undec-7-ene, tert-butoxypotassium, etc. can be used.

  (2) When the compound represented by the formula (3d) is used, 0.5 to 10 moles, preferably 0.8 to 2 moles of the formula (3) is used per 1 mole of the hydroxyl compound represented by the formula (3a) in an appropriate solvent. 3d) is used, and 0.5 to 10 moles, preferably 0.8 to 2 moles of a phosphorus compound such as triphenylphosphine and tributylphosphine and 1 mole of the hydroxyl compound represented by the formula (3a) and the formula (3a ) To 0.5 to 10 mol, preferably 0.8 to 2 mol, of a reagent such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc. The ether compound (3f) can also be obtained by reacting at from 100 ° C. to 100 ° C.

  The suitable solvent is not particularly limited as long as it does not affect the reaction. For example, benzene, toluene, xylene, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, N, N-dimethylformamide, N , N-dimethylacetamide and the like, and these can be used alone or in combination.

<Second step>
Subsequently, in an appropriate solvent, 0.5 to 10 mol, preferably 0.8 to 3 mol, of the amine compound represented by the formula (3g) and 1 mol of the compound represented by the formula (3f) are represented by the formula (3f). By reacting with respect to 1 mol of the compound in the presence or absence of 0.5 to 10 mol, preferably 0.8 to 3 mol of base at −20 ° C. to 180 ° C., preferably 0 ° C. to 150 ° C. Can be obtained.

  The suitable solvent is not particularly limited as long as it does not affect the reaction. For example, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination.

  Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like, and organic bases For example, pyridine, lutidine, collidine, 4- (N, N-dimethylamino) pyridine, triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0 ] Undec-7-ene, tert-butoxypotassium, etc. can be used.

<Third step>
The subsequent reduction reaction can be used under any reaction conditions as long as the nitro group is reduced to an amino group, but the nature of other functional groups of the nitro derivative (3e, 3h) is considered. Thus, it is preferable to select reaction conditions.

Examples of typical reduction methods include the following methods:
(A) In water, methanol, ethanol, alcohols such as 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, or a mixed solvent thereof, with respect to 1 mol of the nitro derivative represented by the formula (3e, 3h) 0.3 to 30 mol, preferably 0.5 to 20 mol of ammonium salt such as ammonium chloride salt, hydrazine hydrate, etc. in the presence of 0.01 to 10 mol, preferably 0.03 to 5 mol of reduced iron, tin chloride, chloride A method in which a reducing metal such as iron is allowed to act at 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.

  (B) 0.001 per mole of nitro derivative represented by the formula (3e, 3h) in alcohols, ethers, esters such as ethyl acetate and butyl acetate, organic acids such as formic acid and acetic acid, or mixed solvents thereof ~ 1 mol, preferably 0.01-0.3 mol of palladium on carbon, platinum oxide, Raney nickel, etc. in the presence of a reducing metal such as hydrogen gas at 0 to 120 ° C., preferably 20 to 100 ° C. under normal or elevated pressure. It is allowed to act under pressure, or 0.5 to 20 mol, preferably 1 to 10 mol of formic acid, ammonium formate, cyclohexene or the like is used as a hydrogen source with respect to 1 mol of the nitro derivative represented by the formula (3e, 3h) instead of hydrogen gas Method.

  The compounds (3a), (3b), (3c) and (3d) used in the reaction process formula 3 are known or can be produced according to known methods.

  Further, the amine derivative represented by the formula (1c), that is, the amine derivative represented by the following formula (4e) can also be synthesized, for example, by the method shown in the following reaction process formula 4.

In the above reaction scheme 4, m and R ^2a are the same as above, B represents an oxygen atom, a saturated or unsaturated cyclic amino group, q represents 0 to 2, R ¹⁷ represents a protecting group for a carboxyl group, for example, Alkyl group having about 1 to 6 carbon atoms, allyl group, phenyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, benzyloxymethyl group, 2-trimethylsilylethyl group, benzyl group, 4-methoxybenzyl group, 4 -Nitrobenzyl group, diphenylmethyl group, triphenylmethyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like.

  That is, the first step of deprotecting the ester group of the derivative represented by the formula (4a), the resulting carboxylic acid derivative represented by the formula (4b) is condensed with the amine compound represented by the formula (4c) by a conventional method. A second step of obtaining an amide derivative (4d) by reducing the nitro group of the obtained nitro derivative (4d) according to a conventional method, and a third step of obtaining an amine derivative (4e) It is.

<First step>
That is, in the first step, the conversion to the carboxylic acid derivative represented by the formula (4b) by deprotecting the ester group of the derivative represented by the formula (4a) varies depending on the type of R ¹⁷ , for example, tert-butyl In the case of a lower alkyl group such as a group, 1 to 100 moles, preferably 2 to 10 moles of hydrochloric acid, with respect to 1 mole of the ester group of the derivative represented by the formula (4a), in a suitable solvent or without solvent, It can be obtained by reacting at -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C under acidic conditions such as hydrobromic acid, formic acid and trifluoroacetic acid.

  Suitable solvents are not particularly limited as long as they do not affect the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, lower alcohols such as methanol, ethanol, propanol and isopropanol, Examples include formic acid and acetic acid, and these can be used alone or in combination.

When the type of R ¹⁷ is, for example, a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, 0.5 to 10 mol, preferably 1 mol of the ester group of the derivative represented by the formula (4a) in an appropriate solvent. Can also be obtained by reaction at -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C in the presence of 1 to 5 moles of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.

  A suitable solvent is not particularly limited as long as it does not affect the reaction.For example, water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, N, N-dimethylformamide, N, N -Dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and the like can be mentioned, and these can be used alone or in combination.

<Second step>
In the second step, the amine derivative represented by the formula (4c) or a salt thereof and the carboxylic acid derivative represented by the formula (4b) or a reactive derivative thereof are condensed by a conventional method to represent the compound represented by the general formula (4d). Can be obtained.

  Examples of the reactive derivative of compound (4b) include methyl ester, ethyl ester, tert-butyl ester and other ordinary esters, acid chloride, acid bromide and other acid halides, acid azide, N-hydroxybenzotriazole, and N-hydroxys. Examples thereof include active esters with succinimide, p-nitrophenol and the like, symmetric acid anhydrides, mixed acid anhydrides with alkyl carbonate, p-toluenesulfonic acid and the like.

  When reacting the compound (4b) with a free acid or reacting without isolating the active ester or acid halide, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl azide, 1-ethyl-3 It is possible to use condensing agents such as-(3-dimethylaminopropyl) carbodiimide hydrochloride and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride. Is preferred.

  When a condensing agent is used with 0.5 to 10 moles, preferably 0.8 to 2 moles of the carboxylic acid derivative represented by the formula (4b) or a reactive derivative thereof per mole of the amine derivative represented by the formula (4c) The amount used is 0.5 to 20 mol, preferably 0.8 to 3 mol, per 1 mol of the amine derivative represented by the formula (4c).

  The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, pyridine, etc., in a solvent inert to the reaction, it can be carried out at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  In the reaction, 0.5 to 20 mol, preferably 0.8 to 5 mol, of triethylamine, diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, N, N--, with respect to 1 mol of the amine derivative represented by the formula (4c). The reaction may proceed smoothly by carrying out the reaction in the presence of a base such as diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, lutidine and the like.

<Third step>
The subsequent reduction reaction can be used under any reaction condition as long as it is a reaction that reduces the nitro group to convert it to an amino group, but considering the properties of other functional groups of the nitro derivative (4d). The reaction conditions are preferably selected.
Examples of typical reduction methods include the following methods:
(A) In water, alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, or a mixed solvent thereof, 0.3 mol per mole of the nitro derivative represented by the formula (4d) -30 mol, preferably 0.5-20 mol ammonium salt such as ammonium chloride, hydrazine hydrate, etc., in the presence of 0.01-10 mol, preferably 0.03-5 mol reduced iron, tin chloride, iron chloride, etc. A method in which a metal having a reducing property of 0 to 150 ° C., preferably 20 to 120 ° C. is allowed to act.

  (B) 0.001 to 1 mole per 1 mole of the nitro derivative represented by the formula (4d) in alcohols, ethers, esters such as ethyl acetate and butyl acetate, organic acids such as formic acid and acetic acid, or mixed solvents thereof Molar, preferably 0.01-0.3 moles of palladium on carbon, platinum oxide, Raney nickel, etc. in the presence of reducing metals such as 0 to 120 ° C, preferably 20 to 100 ° C under normal or pressurized hydrogen gas action Or 0.5 to 20 mol, preferably 1 to 10 mol of formic acid, ammonium formate, cyclohexene or the like is used as a hydrogen source with respect to 1 mol of the nitro derivative represented by the formula (4d) instead of hydrogen gas.

  The compounds (4a) and (4c) used in Reaction Scheme 4 are known or can be produced according to known methods.

  The amine derivative represented by the formula (1c), that is, the amine derivative represented by the following formula (5e) can also be synthesized by the method shown in the following reaction process formula 5, for example.

In the above reaction scheme 5, m and R ^2a are the same as above, B ¹ represents a saturated or unsaturated cyclic amino group, and Z ² represents an amino-protecting group.

  That is, the first step of deprotecting a derivative having an amino-protecting group represented by the formula (5a), the resulting amine derivative represented by the formula (5b) is converted into a carboxylic acid derivative represented by the formula (5c) or The amine derivative (5e) is obtained by condensing the reactive derivative with a conventional method to obtain an amide derivative (5d), and reducing the nitro group of the obtained nitro compound (5d) according to a conventional method. It is a method comprising a third step to obtain.

<First step>
In the first step, when Z ² is a protecting group-substituted amino group (for example, a formyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, an acetyl group, a benzoyl group, etc.) is removed. For the protection, a known method for deprotecting an amino group can be used. Particularly, in the case of a formyl group, a tert-butoxycarbonyl group, an acetyl group, or a benzoyl group, the compound represented by the formula (5a ) To 1 to 100 mol, preferably 2 to 10 mol of hydrochloric acid, hydrobromic acid, formic acid, trifluoroacetic acid and the like under the acidic condition of -20 ° C to 150 ° C, preferably It can be obtained by reacting at 0 to 100 ° C.

  Suitable solvents are not particularly limited as long as they do not affect the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, lower alcohols such as methanol, ethanol, propanol and isopropanol, Examples include formic acid and acetic acid, and these can be used alone or in combination.

In the case of a benzyloxycarbonyl group or a benzyl group, a derivative 1 represented by the formula (5a) in an alcohol, an ether, an ester such as ethyl acetate or butyl acetate, an organic acid such as formic acid or acetic acid, or a mixed solvent thereof. In the presence of 0.001 to 1 mol, preferably 0.01 to 0.3 mol of palladium on carbon, etc., in the presence of a reducing metal such as palladium on carbon, 0 to 120 ° C., preferably 20 to 100 ° C., and hydrogen gas is added at normal pressure to It can be obtained by applying a rolling action.
And the like.

<Second step>
In the second step, the amine derivative represented by the formula (5b) or a salt thereof and the carboxylic acid derivative represented by the formula (5c) or a reactive derivative thereof are condensed by a conventional method to represent the compound represented by the general formula (5d). The amide compound can be obtained.

  Examples of the reactive derivative of compound (5c) include ordinary esters such as methyl ester, ethyl ester and tert-butyl ester, acid halides such as acid chloride and acid bromide, acid azide, N-hydroxybenzotriazole and N-hydroxys. Examples thereof include active esters with succinimide, p-nitrophenol and the like, symmetric acid anhydrides, mixed acid anhydrides with alkyl carbonate, p-toluenesulfonic acid and the like.

  When reacting the compound (5c) with a free acid, or when reacting without isolating the active ester or acid halide, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl azide, 1-ethyl-3- It is preferable to use a condensing agent such as (3-dimethylaminopropyl) carbodiimide hydrochloride and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride. It is.

  When a condensing agent is used using 0.5 to 10 moles, preferably 0.8 to 2 moles, of a carboxylic acid derivative represented by the formula (5c) or a reactive derivative thereof per mole of the amine derivative represented by the formula (5b) The amount used is 0.5 to 20 mol, preferably 0.8 to 3 mol, per mol of the amine derivative represented by the formula (5b).

  The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, pyridine, etc., in a solvent inert to the reaction, it can be carried out at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  In the reaction, 0.5 to 20 mol, preferably 0.8 to 5 mol, of triethylamine, diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, N, N--, with respect to 1 mol of the amine derivative represented by the formula (5b). The reaction may proceed smoothly by carrying out the reaction in the presence of a base such as diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, lutidine and the like.

<Third step>
The subsequent reduction reaction can be used under any reaction condition as long as it is a reaction that reduces the nitro group to convert it to an amino group, but considering the properties of other functional groups of the nitro derivative (5d). The reaction conditions are preferably selected.
Examples of typical reduction methods include the following methods:
(A) In water, alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, or a mixed solvent thereof, 0.3 mol per mol of the nitro derivative represented by the formula (5d) -30 mol, preferably 0.5-20 mol ammonium salt such as ammonium chloride, hydrazine hydrate, etc., in the presence of 0.01-10 mol, preferably 0.03-5 mol reduced iron, tin chloride, iron chloride, etc. A method in which a metal having reducibility of 0 to 150 ° C., preferably 20 to 120 ° C. is allowed to act.

  (B) 0.001 to 1 mol per 1 mol of the nitro derivative represented by the formula (5d) in alcohols, ethers, esters such as ethyl acetate and butyl acetate, organic acids such as formic acid and acetic acid or mixed solvents thereof Molar, preferably 0.01-0.3 moles of palladium on carbon, platinum oxide, Raney nickel, etc. in the presence of reducing metals such as 0 to 120 ° C, preferably 20 to 100 ° C under normal or pressurized hydrogen gas action Or 0.5 to 20 mol, preferably 1 to 10 mol of formic acid, ammonium formate, cyclohexene or the like is used as a hydrogen source with respect to 1 mol of the nitro derivative represented by the formula (5d) instead of hydrogen gas.

  The compounds (5a) and (5c) used in the reaction process formula 5 are known or can be produced according to known methods.

  Further, the amine derivative represented by the formula (1c), that is, the amine derivative represented by the following formula (6e) can also be synthesized, for example, by the method shown in the following reaction process formula 6.

In the above reaction scheme 6, m and R ^2a are the same as above, and R ²¹ is a protecting group for a carboxyl group, for example, an alkyl group having about 1 to 6 carbon atoms, an allyl group, a phenyl group, a methoxymethyl group, methylthiomethyl. Group, tetrahydropyranyl group, benzyloxymethyl group, 2-trimethylsilylethyl group, benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, diphenylmethyl group, triphenylmethyl group, trimethylsilyl group, tert-butyldimethylsilyl Group, tert-butyldiphenylsilyl group and the like.

  That is, the first step of deprotecting the ester group of the derivative represented by the formula (6a), the resulting carboxylic acid derivative represented by the formula (6b) is condensed with the amine compound represented by the formula (6c) by a conventional method. A second step for obtaining an amide derivative (6d) by reducing the nitro group of the obtained nitro derivative (6d) according to a conventional method, and a third step for obtaining an amine derivative (6e) It is.

<First step>
That is, in the first step, the conversion to the carboxylic acid derivative represented by the formula (6b) by deprotecting the ester group of the derivative represented by the formula (6a) varies depending on the type of R ²¹ , for example, tert-butyl In the case of a lower alkyl group such as a group, 1 to 100 moles, preferably 2 to 10 moles of hydrochloric acid, with respect to 1 mole of the ester group of the derivative represented by the formula (6a), in a suitable solvent or without solvent, It can be obtained by reacting at -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C under acidic conditions such as hydrobromic acid, formic acid and trifluoroacetic acid.

  Suitable solvents are not particularly limited as long as they do not affect the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, lower alcohols such as methanol, ethanol, propanol and isopropanol, Examples include formic acid and acetic acid, and these can be used alone or in combination.

When the type of R ²¹ is, for example, a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, 0.5 to 10 mol, preferably 1 mol of the ester group of the derivative represented by the formula (6a) in an appropriate solvent. Can also be obtained by reaction at -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C in the presence of 1 to 5 moles of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.

  A suitable solvent is not particularly limited as long as it does not affect the reaction.For example, water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, N, N-dimethylformamide, N, N -Dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and the like can be mentioned, and these can be used alone or in combination.

<Second step>
In the second step, the amine derivative represented by the formula (6c) or a salt thereof and the carboxylic acid derivative represented by the formula (6b) or a reactive derivative thereof are condensed by a conventional method to represent the compound represented by the general formula (6d). The amide compound can be obtained.

  Examples of the reactive derivative of compound (6b) include methyl ester, ethyl ester, tert-butyl ester and other ordinary esters, acid chloride, acid bromide and other acid halides, acid azide, N-hydroxybenzotriazole, N-hydroxys. Examples thereof include active esters with succinimide, p-nitrophenol and the like, symmetric acid anhydrides, mixed acid anhydrides with alkyl carbonate, p-toluenesulfonic acid and the like.

  When reacting the compound (6b) with a free acid or reacting without isolating the active ester or acid halide, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl azide, 1-ethyl-3 It is possible to use condensing agents such as-(3-dimethylaminopropyl) carbodiimide hydrochloride and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride. Is preferred.

  When a condensing agent is used with 0.5 to 10 moles, preferably 0.8 to 2 moles of the carboxylic acid derivative represented by the formula (6b) or a reactive derivative thereof per mole of the amine derivative represented by the formula (6c) The amount of use is 0.5 to 20 mol, preferably 0.8 to 3 mol, per mol of the amine derivative represented by the formula (6c).

  The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, pyridine, etc., in a solvent inert to the reaction, it can be carried out at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  In the reaction, 0.5 to 20 mol, preferably 0.8 to 5 mol, of triethylamine, diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, N, N--, with respect to 1 mol of the amine derivative represented by the formula (6c). The reaction may proceed smoothly by carrying out the reaction in the presence of a base such as diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, lutidine and the like.

<Third step>
The subsequent reduction reaction can be used under any reaction conditions as long as it is a reaction that reduces the nitro group to convert it to an amino group, but considering the properties of other functional groups of the nitro derivative (6d). The reaction conditions are preferably selected.

Examples of typical reduction methods include the following methods:
(A) In water, alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, or a mixed solvent thereof, 0.3 mol per mole of the nitro derivative represented by the formula (6d) -30 mol, preferably 0.5-20 mol ammonium salt such as ammonium chloride, hydrazine hydrate, etc., in the presence of 0.01-10 mol, preferably 0.03-5 mol reduced iron, tin chloride, iron chloride, etc. A method in which a metal having reducibility of 0 to 150 ° C., preferably 20 to 120 ° C. is allowed to act.

  (B) 0.001 to 1 mol per 1 mol of the nitro derivative represented by the formula (6d) in alcohols, ethers, esters such as ethyl acetate and butyl acetate, organic acids such as formic acid and acetic acid, or mixed solvents thereof Molar, preferably 0.01-0.3 moles of palladium on carbon, platinum oxide, Raney nickel, etc. in the presence of reducing metals such as 0 to 120 ° C, preferably 20 to 100 ° C under normal or pressurized hydrogen gas action Or 0.5 to 20 mol, preferably 1 to 10 mol of formic acid, ammonium formate, cyclohexene or the like is used as a hydrogen source with respect to 1 mol of the nitro derivative represented by the formula (6d) instead of hydrogen gas.

  The compounds (6a) and (6c) used in the reaction process formula 6 are known or can be produced according to known methods.

  Moreover, among the compounds of the present invention, those having a certain functional group can be converted to other compounds of the present invention by chemically modifying the functional group as shown in the following reaction process formulas 7-11. Can do.

In the above reaction process formula 7, R ¹ and R ^2a are the same as above, and R ²⁴ R ²⁵ N represents the above R ⁴ R ⁵ N.

  In the method shown in the above reaction process formula 7, in the first step, in the amide having a hydroxyl group represented by the formula (7a), an aldehyde derivative represented by the formula (7b) is obtained by oxidizing the hydroxyl group to an aldehyde. Thereafter, in the second step, the aldehyde derivative (7b) can be derived into an amine derivative (7d) by subjecting the aldehyde derivative (7b) to a reductive amination reaction with an amine compound represented by the formula (7c).

<First step>
That is, as a method for oxidizing the hydroxyl group of the amide compound represented by the formula (7a) to an aldehyde, an appropriate oxidant conventionally used in a suitable solvent is used as an amide compound having a hydroxyl group represented by the formula (7a). What is necessary is just to make it react at the temperature of about -80-150 degreeC, Preferably about -60-120 degreeC using 0.5-30 mol with respect to 1 mol, Preferably 0.8-20 mol.

  Examples of the oxidizing agent include manganese reagents such as activated manganese dioxide and potassium permanganate, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), chromium trioxide and other chromium reagents, sodium hypochlorite or hypochlorite. Calcium acid-2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO), dimethyl sulfoxide (DMSO) oxidation (DMSO-acetic anhydride, DMSO-trifluoroacetic anhydride, DMSO-oxalyl chloride, DMSO-dicyclohexylcarbodiimide (DCC), DMSO-1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, DMSO-sulfur trioxide pyridine complex) and the like.

  The suitable solvent is not particularly limited as long as it does not affect the reaction. For example, water, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, Examples include chlorobenzene, dimethyl sulfoxide, pyridine, triethylamine, and the like, which can be used alone or in combination.

<Second step>
In the subsequent reductive amination reaction, 0.8 to 10 mol, preferably 1 to 3 mol of the amine compound (7c) is added to 1 mol of the aldehyde compound (7b) and 1 mol of the aldehyde compound (7b) in an appropriate solvent. The reaction is carried out at a temperature of about -20 to 100 ° C., preferably about 0 to 60 ° C., to produce an imine or iminium ion, which is subjected to a reduction reaction to be derivatized into an amine derivative (7d). To do.

  The reduction reaction can be carried out by various conventional methods. For example, 0.1 to 10 moles, preferably 0.2 to 3 moles of lithium aluminum hydride, hydrogenated with respect to 1 mole of the aldehyde compound (7b). An example is a method in which a complex hydrogen compound such as sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride and the like is reacted at a temperature of about -80 to 80 ° C, preferably about -60 to 60 ° C. In addition, it can be derived into the amine derivative (7d) by other known methods such as diborane reduction, catalytic reduction using palladium carbon or Raney nickel.

  Suitable solvents vary depending on the reduction conditions, but are not particularly limited as long as they do not affect the reaction. For example, water, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, 1,2 -Dichloroethane, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, pyridine, acetic acid and the like can be mentioned, and these can be used alone or in combination.

In the above reaction process formula 8, R ¹ , R ^2a and m are the same as above, and R ²⁶ is a protecting group for a carboxyl group, for example, an alkyl group having about 1 to 6 carbon atoms, an allyl group, a phenyl group, a methoxymethyl group. , Methylthiomethyl group, tetrahydropyranyl group, benzyloxymethyl group, 2-trimethylsilylethyl group, benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, diphenylmethyl group, triphenylmethyl group, trimethylsilyl group, tert- Examples thereof include a butyldimethylsilyl group and a tert-butyldiphenylsilyl group. R ²⁷ R ²⁸ N represents the above-mentioned R ⁹ R ¹⁰ N.

  In the method shown in the above reaction step formula 8, in the first step, in the derivative represented by the formula (8a), the ester group is deprotected to convert it into the carboxylic acid derivative represented by the formula (8b). In the second step, the carboxylic acid derivative (8b) can be derived into the amide derivative (8d) by condensing with an amine compound represented by the formula (8c) by a conventional method.

<First step>
That is, in the first step, the conversion to the carboxylic acid derivative represented by the formula (8b) by deprotecting the ester group of the derivative represented by the formula (8a) varies depending on the type of R ²⁶ , but for example, tert-butyl In the case of a lower alkyl group such as a group, 1 to 100 mol, preferably 2 to 10 mol, of hydrochloric acid, in an appropriate solvent or in the absence of solvent, with respect to 1 mol of the ester group of the derivative represented by the formula (8a), It can be obtained by reacting at -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C under acidic conditions such as hydrobromic acid, formic acid and trifluoroacetic acid.

  Suitable solvents are not particularly limited as long as they do not affect the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, lower alcohols such as methanol, ethanol, propanol and isopropanol, Examples include formic acid and acetic acid, and these can be used alone or in combination.

When the type of R ²⁶ is, for example, a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, 0.5 to 10 mol, preferably 1 to 1 mol of the ester group of the derivative represented by the formula (8a) in an appropriate solvent. Can also be obtained by reaction at -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C in the presence of 1 to 5 moles of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.

  A suitable solvent is not particularly limited as long as it does not affect the reaction.For example, water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, N, N-dimethylformamide, N, N -Dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and the like can be mentioned, and these can be used alone or in combination.

<Second step>
In the second step, the amine derivative represented by the formula (8c) or a salt thereof and the carboxylic acid derivative represented by the formula (8b) or a reactive derivative thereof are condensed by a conventional method to represent the compound represented by the general formula (8d). The amide compound can be obtained.

  Examples of reactive derivatives of compound (8b) include methyl esters, ethyl esters, tert-butyl esters and other ordinary esters, acid chlorides, acid bromides and other acid halides, acid azides, N-hydroxybenzotriazole, N-hydroxys. Examples thereof include active esters with succinimide, p-nitrophenol and the like, symmetric acid anhydrides, mixed acid anhydrides with alkyl carbonate, p-toluenesulfonic acid and the like.

  When reacting the compound (8b) with a free acid or reacting without isolating the active ester or acid halide, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl azide, 1-ethyl-3 It is possible to use condensing agents such as-(3-dimethylaminopropyl) carbodiimide hydrochloride and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride. Is preferred.

  When a condensing agent is used using 0.5 to 10 moles, preferably 0.8 to 2 moles, of a carboxylic acid derivative represented by the formula (8b) or a reactive derivative thereof per mole of the amine derivative represented by the formula (8c) The amount used is 0.5 to 20 mol, preferably 0.8 to 3 mol, per mol of the amine derivative represented by the formula (8c).

  The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, pyridine, etc., in a solvent inert to the reaction, it can be carried out at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  In the reaction, 0.5 to 20 mol, preferably 0.8 to 5 mol, of triethylamine, diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, N, N--, with respect to 1 mol of the amine derivative represented by the formula (8c) The reaction may proceed smoothly by carrying out the reaction in the presence of a base such as diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, lutidine and the like.

In the above reaction scheme 9, R ¹ , R ^2a and m are the same as above, Z ⁴ represents a nitro group or a protecting group-substituted amino group, and R ²⁹ has 1 carbon atom which may have a substituent. -6 alkyl group, a C3-C7 cycloalkyl group, the phenyl group which may have a substituent, and the unsaturated heterocyclic group which may have a substituent are shown.

In the method shown in the above reaction process formula 9, in the first process, in the derivative represented by the formula (9a) (Z ⁴ is a nitro group or a protective group-substituted amino group), reduction of the nitro group or protection group of the amino group Is converted to an amine derivative represented by the formula (9b) by deprotection, and then the amine derivative (9b) is usually treated with a carboxylic acid derivative represented by the formula (9c) or a reactive derivative thereof in the second step. It can be derived into an amide derivative (9d) by condensation by the method.

<First step>
For the reduction reaction when Z ⁴ is a nitro group, any reaction condition can be used as long as it is a reaction that reduces the nitro group to convert it to an amino group. It is preferable to select the reaction conditions in consideration of the above.

  Typical reduction methods include, for example, water, methanol, ethanol, alcohols such as 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, or a mixed solvent thereof, or a nitro derivative represented by the formula (9a) In the presence of 0.3 to 30 mol, preferably 0.5 to 20 mol of ammonium salt such as ammonium chloride salt, hydrazine hydrate, etc., 0.01 to 10 mol, preferably 0.03 to 5 mol of reduced iron, A method in which a reducing metal such as tin chloride or iron chloride is allowed to act at 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C., esters such as alcohols, ethers, ethyl acetate, butyl acetate, formic acid, In an organic acid such as acetic acid or a mixed solvent thereof, 0.001 to 1 mol, preferably 0.01 to 0.3 mol of carbon-supported paradigo is used per 1 mol of the nitro derivative represented by the formula (9a). In the presence of a reducing metal such as platinum oxide and Raney nickel, hydrogen gas is allowed to act at normal pressure or under pressure at 0 ° C. to 120 ° C., preferably 20 ° C. to 100 ° C., or the formula (9a) And a method using 0.5 to 20 mol, preferably 1 to 10 mol of formic acid, ammonium formate, cyclohexene or the like as a hydrogen source with respect to 1 mol of the nitro derivative represented by formula (1).

Deprotection when Z ⁴ is a protecting group-substituted amino group (for example, formyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, acetyl group, benzoyl group, etc.) A known method for deprotecting an amino group can be used. Particularly, in the case of a formyl group, a tert-butoxycarbonyl group, an acetyl group, or a benzoyl group, it can be represented by the formula (9a) in a suitable solvent or without a solvent. 1 to 100 mol, preferably 2 to 10 mol of hydrochloric acid, hydrobromic acid, formic acid, trifluoroacetic acid, etc. under the acidic condition of -20 ° C to 150 ° C, preferably from 0 ° C to 1 mol of the derivative. It can be obtained by reacting at 100 ° C.

Suitable solvents are not particularly limited as long as they do not affect the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, lower alcohols such as methanol, ethanol, propanol and isopropanol, Examples include formic acid and acetic acid, and these may be used alone or in combination.
In the case of a benzyloxycarbonyl group or a benzyl group, a derivative 1 represented by the formula (9a) in an alcohol, an ether, an ester such as ethyl acetate or butyl acetate, an organic acid such as formic acid or acetic acid, or a mixed solvent thereof. 0.001 to 1 mol, preferably 0.01 to 0.3 mol of palladium on carbon, is present in the presence of a reducing metal such as palladium on carbon at 0 ° C to 120 ° C, preferably 20 ° C to 100 ° C. It can be obtained by applying a rolling action.
And the like.

<Second step>
In the second step, the amine derivative represented by the formula (9b) or a salt thereof and the carboxylic acid derivative represented by the formula (9c) or a reactive derivative thereof are condensed by a conventional method to represent the compound represented by the general formula (9d). Can be obtained.

  Examples of reactive derivatives of compound (9c) include normal esters such as methyl ester, ethyl ester and tert-butyl ester, acid halides such as acid chloride and acid bromide, acid azide, N-hydroxybenzotriazole, and N-hydroxys. Examples thereof include active esters with succinimide, p-nitrophenol and the like, symmetric acid anhydrides, mixed acid anhydrides with alkyl carbonate, p-toluenesulfonic acid and the like.

  When reacting the compound (9c) with a free acid, or when reacting without isolating the active ester or acid halide, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl azide, 1-ethyl-3- It is preferable to use a condensing agent such as (3-dimethylaminopropyl) carbodiimide hydrochloride and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride. It is.

  When a condensing agent is used using 0.5 to 10 mol, preferably 0.8 to 2 mol, of a carboxylic acid derivative represented by the formula (9c) or a reactive derivative thereof per 1 mol of the amine derivative represented by the formula (9b) The amount used is 0.5 to 20 mol, preferably 0.8 to 3 mol, per mol of the amine derivative represented by the formula (9b).

  The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, pyridine, etc., in a solvent inert to the reaction, it can be carried out at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  In the reaction, 0.5 to 20 moles, preferably 0.8 to 5 moles of triethylamine, diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, N, N--, with respect to 1 mole of the amine derivative represented by the formula (9b) The reaction may proceed smoothly by carrying out the reaction in the presence of a base such as diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, lutidine and the like.

In the above reaction scheme 10, R ¹ and R ^2a are the same as above, R ²⁹ represents R ⁷ , and X ⁵ represents a leaving functional group.

  In the method shown in the above reaction process formula 10, an amide derivative having a hydroxyl group represented by the formula (10a) is reacted with a compound having a leaving functional group represented by the formula (10b) and an ether derivative ( 10c).

That is, X ^{5 in} compound (10b) may be any functional group as long as it is a leaving functional group, and examples thereof include a chlorine atom, a bromine atom, an iodine atom, a methylsulfonyl group, a benzenesulfonyl group, and a p-toluenesulfonyl group.
In a suitable solvent, 0.5 to 10 mol, preferably 0.8 to 2 mol of the compound represented by formula (10b) is used per 1 mol of the hydroxy compound represented by formula (10a), and the compound represented by formula (10a) The ether compound represented by the formula (10c) is reacted with -20 ° C to 180 ° C, preferably 0 ° C to 150 ° C in the presence of 0.5 to 10 mol, preferably 0.8 to 3 mol, of base per mol. Can be obtained.

  The suitable solvent is not particularly limited as long as it does not affect the reaction. For example, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination.

  Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like, and organic bases For example, pyridine, lutidine, collidine, 4- (N, N-dimethylamino) pyridine, triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0 ] Undec-7-ene, tert-butoxypotassium, etc. can be used.

In the above reaction process formula 11, R ¹ , R ^2a , B and m, q are the same as described above, and R ³⁰ is a protective group for a carboxyl group, for example, an alkyl group having about 1 to 6 carbon atoms, an allyl group, a phenyl group. , Methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, benzyloxymethyl group, 2-trimethylsilylethyl group, benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, diphenylmethyl group, triphenylmethyl group, trimethylsilyl Group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like.

  In the method shown in the above reaction process formula 11, in the first process, in the derivative represented by the formula (11a), the ester group is deprotected to convert it into the carboxylic acid derivative represented by the formula (11b). In the second step, the carboxylic acid derivative (11b) can be derived into the amide derivative (11d) by condensing it with an amine compound represented by the formula (11c) by a conventional method.

<First step>
That is, in the first step, the conversion to the carboxylic acid derivative represented by the formula (11b) by deprotecting the ester group of the derivative represented by the formula (11a) varies depending on the type of R ³⁰ , for example, tert-butyl In the case of a lower alkyl group such as a group, 1 to 100 mol, preferably 2 to 10 mol, of hydrochloric acid, in an appropriate solvent or in the absence of solvent, with respect to 1 mol of the ester group of the derivative represented by the formula (11a), It can be obtained by reacting at -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C under acidic conditions such as hydrobromic acid, formic acid and trifluoroacetic acid.

  Suitable solvents are not particularly limited as long as they do not affect the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, lower alcohols such as methanol, ethanol, propanol and isopropanol, Examples include formic acid and acetic acid, and these can be used alone or in combination.

When the type of R ³⁰ is, for example, a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, 0.5 to 10 mol, preferably 1 to 1 mol of the ester group of the derivative represented by the formula (11a) in an appropriate solvent. Can also be obtained by reacting at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C in the presence of 1 to 5 moles of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.

  A suitable solvent is not particularly limited as long as it does not affect the reaction.For example, water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, N, N-dimethylformamide, N, N -Dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and the like can be mentioned, and these can be used alone or in combination.

<Second step>
In the second step, the amine derivative represented by the formula (11c) or a salt thereof and the carboxylic acid derivative represented by the formula (11b) or a reactive derivative thereof are condensed by a conventional method to represent the compound represented by the general formula (11d). The amide compound can be obtained.

  Examples of the reactive derivative of the compound (11b) include ordinary esters such as methyl ester, ethyl ester and tert-butyl ester, acid halides such as acid chloride and acid bromide, acid azide, N-hydroxybenzotriazole, and N-hydroxys. Examples thereof include active esters with succinimide, p-nitrophenol and the like, symmetric acid anhydrides, mixed acid anhydrides with alkyl carbonate, p-toluenesulfonic acid and the like.

  When reacting the compound (11b) with a free acid or without reacting the active ester or acid halide without isolation, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl azide, 1-ethyl-3 It is possible to use condensing agents such as-(3-dimethylaminopropyl) carbodiimide hydrochloride and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride. Is preferred.

  When a condensing agent is used with 0.5 to 10 moles, preferably 0.8 to 2 moles of the carboxylic acid derivative represented by the formula (11b) or a reactive derivative thereof per mole of the amine derivative represented by the formula (11c) The amount used is 0.5 to 20 mol, preferably 0.8 to 3 mol, per mol of the amine derivative represented by the formula (11c).

  The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, pyridine, etc., in a solvent inert to the reaction, it can be carried out at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  In the reaction, 0.5 to 20 mol, preferably 0.8 to 5 mol, of triethylamine, diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, N, N--, with respect to 1 mol of the amine derivative represented by the formula (11c) The reaction may proceed smoothly by carrying out the reaction in the presence of a base such as diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, lutidine and the like.

  The intermediate product thus obtained and the compound of the present invention can be purified by conventional separation means in synthetic chemistry such as extraction, precipitation, suspension washing, recrystallization, distillation, column chromatography and the like.

Since the compound represented by the general formula (I) or a salt thereof can inhibit hematopoietic prostaglandin D synthase, it is useful as a hematopoietic prostaglandin D synthase inhibitor.

  Accordingly, the present invention provides a pharmaceutical composition comprising an effective amount of at least one compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

  The present invention also provides use of a compound represented by the general formula (I) or a salt thereof as an inhibitor of a prostaglandin D synthase inhibitor, particularly a hematopoietic prostaglandin D synthase. is there.

  Thus, since the compound represented by the general formula (I) or a salt thereof has a prostaglandin D synthase inhibitory action, undesirable symptoms caused by prostaglandin D2 derived from the enzyme or a metabolite thereof are prevented. Useful in preventing or improving. This enzyme-inhibiting action is achieved when the compound and the pharmaceutical composition of the compound are used in mammals, particularly humans, for bronchial asthma, hay fever, allergic rhinitis, sinusitis, otitis media, allergic conjunctivitis, spring catarrh, atopic skin It is useful in the treatment, prevention, or improvement of allergic diseases such as inflammation, contact dermatitis, and food allergies.

  The compound represented by the general formula (I) or a salt thereof is used for chronic obstructive pulmonary disease, interstitial pneumonia, hypersensitivity pneumonia, eosinophilic pneumonia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, skin Disorders (such as psoriasis, eczema, erythema, itching and acne), myositis, muscular dystrophy, post-PTCA restenosis, reperfusion injury, graft rejection, but are not limited to these Useful for treatment, prevention or improvement.

  The compound represented by the general formula (I) or a salt thereof can be expected to prevent Alzheimer's disease or worsening brain damage and / or improve the prognosis of brain damage.

  Furthermore, the compound represented by the general formula (I) or a salt thereof treats, prevents or ameliorates mucus secretion disorder, reproductive disorder, blood coagulation disorder, sleep disorder, pain, visual problems, obesity and immune diseases and autoimmune diseases. It is useful to do. Furthermore, such compounds can be used in cancer therapy because they can inhibit cell malignant transformation and metastatic tumor growth.

  The compounds of general formula (I) are also used in the treatment and / or prevention of prostaglandin D2 or its metabolite-mediated proliferative disorders such as those arising from fibroblast proliferation, diabetic retinopathy and tumor angiogenesis. Is also useful.

  Since the compound represented by the general formula (I) can also suppress prostaglandin D2-induced smooth muscle contraction, it can be used for the treatment and / or prevention of infertility, dysmenorrhea, premature birth and eosinophil-related disorders. it can.

  In order to apply the compounds of the present invention and salts thereof to the treatment or prevention of the above-mentioned diseases in mammals including humans, it is a matter of course that the condition and severity of the disease to be treated and the general formula (I) Will vary depending on the compound and its route of administration. It also varies according to the age, weight, general health, sex, diet, time of administration, excretion rate, drug combination and response of individual patients. Generally, it is administered orally or parenterally. The dose is generally an effective amount for treating the above-mentioned diseases, and is a daily dose of about 0.001 to about 100 mg, preferably 0.01 to 50 mg / kg body weight of a mammal including humans. On the other hand, doses outside these ranges may be used in some cases.

  The compound of the present invention is compounded in an effective amount with a physiologically acceptable carrier, and is a solid preparation such as a tablet, capsule, granule or powder, or a liquid preparation such as a syrup or injection, an ointment, a lotion, As an external preparation such as gels and creams, orally or parenterally (external use, inhalation, subcutaneous injection, arterial / venous injection, intramuscular injection, intravesical injection, intracerebral injection, nasal drop, eye drops, supo) Can be administered.

  As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, dissolution aids , Suspending agent, isotonic agent, buffering agent, soothing agent and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary. Preferable examples of the excipient include lactose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellol sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, monostearate glycerin, for example polyvinyl Examples thereof include hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Preferable examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate. Preferable examples of the soothing agent include benzyl alcohol. Preferable examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydro vinegar, sorbic acid and the like. Preferable examples of the antioxidant include sulfite and ascorbate.

  EXAMPLES The present invention will be specifically described below with reference to examples, but these are described for the purpose of illustration and do not limit the scope of the present invention.

The ¹ H-NMR spectrum was measured using TMS (tetramethylsilane) as an internal standard, and showed a chemical shift with a δ value (ppm). Chemical shifts show absorption pattern, coupling constant (J value), and proton number in parentheses.

  The following symbols are used for the absorption pattern. s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double doublet, dt = double triplet, m = multiplet, br = broad, brs = broad singlet.

Moreover, the following symbols are used regarding the structural formula of the compound. Me = methyl, Et = ethyl, ^t Bu = tert-butyl, Ph = phenyl, Ac = acetyl, Boc = tert-butoxycarbonyl, TFA = trifluoroacetic acid.

Example 1
2-phenoxy-N- (4-hydroxymethylphenyl) -5-pyrimidinecarboxamide (1)
Example 1 (1)
2-phenoxypyrimidine-5-carboxylic acid

2-Chloropyrimidine-5-carboxylic acid ethyl ester (5.60 g, 30 mmol) was dissolved in N, N-dimethylformamide (50 ml), potassium carbonate (6.22 g, 45 mmol), phenol (3.11 g, 33 mmol) ) And stirred at 60 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure to obtain a crude ether form. The obtained ether was dissolved in tetrahydrofuran (100 ml), 1N aqueous sodium hydroxide solution (45 ml, 45 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid (45 ml, 45 mmol) under ice cooling, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was added with diethyl ether, and the precipitated solid was collected by filtration to give 2-phenoxypyrimidine-5-carboxylic acid (5.24 g, 81 %) As a white solid.
Melting point: 189-190 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 7.18-7.51 (m, 5H), 9.18 (s, 2H).

Example 1 (2)
2-phenoxy-N- (4-hydroxymethylphenyl) -5-pyrimidinecarboxamide (1)

2-Phenoxy-pyrimidine-5-carboxylic acid (1.08 g, 5.0 mmol) obtained in Example 1 (1) was dissolved in pyridine (20 ml), and 1-hydroxybenzotriazole monohydrate (842 mg, 5.5 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.15 g, 6.0 mmol), 4-aminobenzenemethanol (677 mg, 5.5 mmol) were added, and the mixture was stirred at 60 ° C. for 15 hours. did. After concentration under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4-hydroxymethyl). Phenyl) -5-pyrimidinecarboxamide (1.46 g, 91%) was obtained as a milky white solid.
Melting point: 218-220 ℃
_{^{1 H-NMR (CDCl 3)}} : δ (ppm) 4.69 (s, 2H), 7.16-7.52 (m, 7H), 7.59 (d, J = 8.6 Hz, 2H), 7.73 (brs, 1H), 9.02 ( s, 2H).

Example 2
2-phenoxy-N- (4-formylphenyl) -5-pyrimidinecarboxamide (2)

2-Phenoxy-N- (4-hydroxymethylphenyl) -5-pyrimidinecarboxamide (1.44 g, 4.5 mmol) obtained in Example 1 was dissolved in 1,2-dichloroethane (30 ml) and tetrahydrofuran (60 ml). Activated manganese dioxide (1.5 g) was added, and the mixture was stirred at room temperature for 17 hours. The insoluble material was filtered off using celite, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration to give 2-phenoxy-N- (4-formylphenyl). ) -5-pyrimidinecarboxamide (1.35 g, 94%) was obtained as a milky white solid.
Melting point: 201-202 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 7.19-7.37 (m, 3H), 7.43-7.55 (m, 2H), 7.76-8.02 (m, 5H), 9.06 (s, 2H), 9.97 (s , 1H).

Example 3
2-Phenoxy-N- (4-tert-butoxycarbonylphenyl) -5-pyrimidinecarboxamide (3)

2-Phenoxy-pyrimidine-5-carboxylic acid (10.8 g, 50 mmol) obtained in Example 1 (1) was dissolved in pyridine (150 ml), and 1-hydroxybenzotriazole monohydrate (8.0 g, 53 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (10.5 g, 55 mmol), 4-aminobenzoic acid tert-butyl ester (10.1 g, 53 mmol), and added to 60 ° C. And stirred for 16 hours. After concentration under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the precipitated solid was collected by filtration, washed with water, diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4-tert- Butoxycarbonylphenyl) -5-pyrimidinecarboxamide (9.09 g, 47%) was obtained as a milky white solid.
Melting point: 208-209 ℃ (decomposed)
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.60 (s, 9H), 7.19-7.37 (m, 3H), 7.42-7.53 (m, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.79 (brs, 1H), 8.02 (d, J = 8.6 Hz, 2H), 9.04 (s, 2H).

Example 4
4- (2-Phenoxypyrimidine-5-carboxamide) -benzoic acid (4)

2-Phenoxy-N- (4-tert-butoxycarbonylphenyl) -5-pyrimidinecarboxamide (7.83 g, 20 mmol) obtained in Example 3 was suspended in dichloromethane (40 ml) and trifluoroacetic acid (15.4 ml). , 200 mmol), and stirred at room temperature for 18 hours. After concentration under reduced pressure, water was added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 4- (2-phenoxypyrimidine-5-carboxamide) -benzoic acid (6.61 g, 99%) as a milky white solid.
Melting point: 295-297 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.22-7.35 (m, 3H), 7.49 (dd, J = 8.3, 7.3 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H), 7.96 (d, J = 8.9 Hz, 2H), 9.12 (s, 2H), 10.71 (s, 1H), 12.80 (brs, 1H).

Example 5
2-Phenoxy-N- (4- (pyrrolidin-1-yl-carbonyl) -phenyl) -5-pyrimidinecarboxamide (5)

4- (2-phenoxypyrimidine-5-carboxamide) -benzoic acid (168 mg, 0.5 mmol) obtained in Example 4 was dissolved in N, N-dimethylformamide (2.0 ml) to give 1-hydroxybenzotriazole 1 Add hydrate (84 mg, 0.55 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (115 mg, 0.6 mmol), pyrrolidine (62 μl, 0.75 mmol) and add 16 at room temperature. Stir for hours. After concentration under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the precipitated solid was collected by filtration, washed with water, diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4- (pyrrolidine 1-yl-carbonyl) -phenyl) -5-pyrimidinecarboxamide (182 mg, 94%) was obtained as a white solid.
Melting point: 225-226 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.78-2.03 (m, 4H), 3.35-3.71 (m, 4H), 7.12-7.64 (m, 9H), 9.19 (s, 2H), 9.48 (brs) , 1H).

Example 6
2-phenoxy-N- (4- (3- (dimethylamino) propylcarbamoyl) -phenyl) -5-pyrimidinecarboxamide (6)

According to Example 5, 2-phenoxy-N- (4- (3- (dimethylamino) propylcarbamoyl) -phenyl) -5-pyrimidinecarboxamide was obtained by using 3- (dimethylamino) propylamine instead of pyrrolidine. (34%) was obtained as a white solid.
Melting point: 220-223 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.69-1.78 (m, 2H), 2.29 (s, 6H), 2.47-2.52 (m, 2H), 3.50-3.57 (m, 2H), 7.18-7.49 (m, 5H), 7.71 (s, 4H), 8.72 (br, 2H), 9.11 (s, 2H).

Example 7
2-Phenoxy-N- (4- (2- (morpholin-4-yl) -ethylcarbamoyl) -phenyl) -5-pyrimidinecarboxamide (7)

According to Example 5, 2-phenoxy-N- (4- (2- (morpholin-4-yl) -ethylcarbamoyl) -phenyl) was obtained by using N- (2-aminoethyl) morpholine instead of pyrrolidine. -5-Pyrimidinecarboxamide (53%) was obtained as a white solid.
Melting point: 247-248 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.28-2.50 (m, 6H), 3.23-3.35 (m, 2H), 3.45-3.70 (m, 4H), 6.15 (brs, 1H), 7.08-7.63 (m, 9H), 8.59 (br, 1H), 9.06 (s, 2H).

Example 8
2-phenoxy-N- (4- (3- (2-oxopyrrolidin-1-yl) -propylcarbamoyl) -phenyl) -5-pyrimidinecarboxamide (8)

According to Example 5, by using 3-aminopropyl-1-pyrrolidinone instead of pyrrolidine, 2-phenoxy-N- (4- (3- (2-oxopyrrolidin-1-yl) -propylcarbamoyl)- Phenyl) -5-pyrimidinecarboxamide (75%) was obtained as a pale yellow solid.
Melting point: 222-224 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.66-1.79 (m, 2H), 1.87-1.98 (m, 2H), 2.23 (t, J = 7.6 Hz, 2H), 2.94-3.38 (m , 6H), 7.23-7.33 (m, 3H), 7.43-7.52 (m, 2H), 7.86 (s, 4H), 8.41 (t, J = 5.7 Hz, 1H), 9.15 (s, 2H), 10.73 ( s, 1H).

Example 9
2-Phenoxy-N- (4- (2- (pyridin-2-yl) ethylcarbamoyl) -phenyl) -5-pyrimidinecarboxamide (9)

According to Example 5, by using 2- (2-aminoethyl) pyridine instead of pyrrolidine, 2-phenoxy-N- (4- (2- (pyridin-2-yl) ethylcarbamoyl) -phenyl)- 5-Pyrimidinecarboxamide (72%) was obtained as a white solid.
Melting point: 150-152 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.06-3.11 (m, 2H), 3.50-3.58 (m, 2H), 7.13-7.49 (m, 7H), 7.57-7.60 (m, 1H), 7.72 (s, 4H), 8.54-8.56 (m, 1H), 8.65-8.78 (br, 2H), 9.10 (s, 2H).

Example 10
2-phenoxy-N- (benzohydrazide-4-yl) -5-pyrimidinecarboxamide (10)

According to Example 5, 2-phenoxy-N- (benzohydrazide-4-yl) -5-pyrimidinecarboxamide (60%) was obtained as a white solid by using hydrazine monohydrate instead of pyrrolidine.
Melting point: 179-181 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.00 (brs, 2H), 7.25-7.33 (m, 3H), 7.40-7.57 (m, 2H), 7.75-8.03 (m, 4H), 9.13 (s, 2H), 10.35 (br, 1H), 10.64 (brs, 1H).

Example 11
2-Phenoxy-N- (4- (pyrazolin-1-yl-carbonyl) -phenyl) -5-pyrimidinecarboxamide (11)

According to Example 5, by using pyrazoline instead of pyrrolidine, 2-phenoxy-N- (4- (pyrazolin-1-yl-carbonyl) -phenyl) -5-pyrimidinecarboxamide (39%) as a milky white solid Obtained.
Melting point: 274-276 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.95 (ddd, J = 10.2, 9.8, 1.9 Hz, 2H), 4.04 (dd, J = 10.2, 9.8 Hz, 2H), 7.02 (t, J = 1.9 Hz, 1H), 7.18-7.52 (m, 6H), 7.79-7.96 (m, 4H), 9.19 (s, 2H).

Example 12
2-Phenoxy-N- (4-tert-butoxycarbonylmethylphenyl) -5-pyrimidinecarboxamide (12)
Example 12 (1)
4-Nitrophenylacetic acid tert-butyl ester (12 raw materials)

4-Nitrophenylacetic acid (36.2 g, 200 mmol) is dissolved in dichloromethane (350 ml), and 4-dimethylaminopyridine (2.44 g, 20 mmol), tert-butanol (44.5 g, 600 mmol), 1 -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46.0 g, 240 mmol) was added, and the mixture was stirred at room temperature for 2 days. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was subjected to medium pressure silica gel flash column chromatography (ethyl acetate: chloroform: n-hexane = 1: 100: 100 to 1:30:30). To give 4-nitrophenylacetic acid tert-butyl ester (18.2 g, 38%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.45 (s, 9H), 3.64 (s, 2H), 7.44 (d, J = 8.9 Hz, 2H), 8.19 (d, J = 8.9 Hz, 2H) .

Example 12 (2)
2-Phenoxy-N- (4-tert-butoxycarbonylmethylphenyl) -5-pyrimidinecarboxamide (12)

  (a) 4-Nitrophenylacetic acid tert-butyl ester (8.30 g, 35 mmol) obtained in Example 12 (1) was dissolved in methanol (120 ml), and 10% palladium-carbon (3.0 g) was added. The mixture was stirred at room temperature under a hydrogen gas atmosphere. The insoluble material was filtered off using celite, and the filtrate was concentrated under reduced pressure to obtain a crude amine compound.

(b) 2-Phenoxy-pyrimidine-5-carboxylic acid (7.13 g, 33 mmol) was dissolved in pyridine (70 ml) to give 1-hydroxybenzotriazole monohydrate (5.58 g, 36 mmol), 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (7.59 g, 39 mmol) and a solution of the crude amine compound obtained in the reaction of (a) above in pyridine (30 ml) were added, and the solution was added at 60 ° C. for 18 hours. Stir for hours. After concentration under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the precipitated solid was collected by filtration, washed with water, diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4-tert- Butoxycarbonylmethylphenyl) -5-pyrimidinecarboxamide (7.80 g, 58%) was obtained as an opalescent solid.
Melting point: 176-178 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.44 (s, 9H), 3.52 (s, 2H), 7.18-7.36 (m, 5H), 7.43-7.60 (m, 4H), 7.69 (brs, 1H ), 9.02 (s, 2H).

Example 13
4- (2-Phenoxypyrimidine-5-carboxamide) -phenylacetic acid (13)

According to Example 4, instead of 2-phenoxy-N- (4-tert-butoxycarbonylphenyl) -5-pyrimidinecarboxamide, 2-phenoxy-N- (4-tert-butoxycarbonylmethylphenyl) -5-pyrimidinecarboxamide To give 4- (2-phenoxypyrimidine-5-carboxamide) -phenylacetic acid (96%) as a milky white solid.
Melting point: 236-237 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.59 (s, 2H), 7.15-7.54 (m, 7H), 7.67 (d, J = 8.6 Hz, 2H), 9.15 (s, 2H), 9.56 ( brs, 1H).

Example 14
2-Phenoxy-N- (4- (pyrrolidin-1-yl-carbonylmethyl) -phenyl) -5-pyrimidinecarboxamide (14)

4- (2-phenoxypyrimidine-5-carboxamide) -phenylacetic acid (168 mg, 0.5 mmol) obtained in Example 13 was dissolved in N, N-dimethylformamide (2.0 ml) to give 1-hydroxybenzotriazole 1 Add hydrate (84 mg, 0.55 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (115 mg, 0.6 mmol), pyrrolidine (62 μl, 0.75 mmol) and add 16 at room temperature. Stir for hours. After concentration under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the precipitated solid was collected by filtration, washed with water, diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4- (pyrrolidine 1-yl-carbonylmethyl) -phenyl) -5-pyrimidinecarboxamide (199 mg, 99%) was obtained as a milky white solid.
Melting point: 251-253 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.78-2.05 (m, 4H), 3.41-3.77 (m, 6H), 6.97-7.58 (m, 9H), 9.13 (s, 2H), 9.32 (brs) , 1H).

Example 15
2-Phenoxy-N- (4- (hydroxyethoxyethylcarbamoylmethyl) -phenyl) -5-pyrimidinecarboxamide (15)

According to Example 14, by using hydroxyethoxyethylamine instead of pyrrolidine, 2-phenoxy-N- (4- (hydroxyethoxyethylcarbamoylmethyl) -phenyl) -5-pyrimidinecarboxamide (73%) as an opalescent solid Obtained.
Melting point: 213-215 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.35-3.73 (m, 10H), 4.03 (t, J = 5.4 Hz, 1H), 7.15-7.50 (m, 8H), 7.69 (d, J = 8.3 Hz, 2H), 9.17 (s, 2H), 10.14 (brs, 1H).

Example 16
2-Phenoxy-N- (4- (2- (morpholin-4-yl) ethylcarbamoylmethyl) -phenyl) -5-pyrimidinecarboxamide (16)

According to Example 14, by using N- (2-aminoethyl) morpholine instead of pyrrolidine, 2-phenoxy-N- (4- (2- (morpholin-4-yl) ethylcarbamoylmethyl) -phenyl) -5-Pyrimidinecarboxamide (91%) was obtained as a milky white solid.
Melting point: 186-188 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.28-2.50 (m, 6H), 3.23-3.35 (m, 2H), 3.48-3.73 (m, 6H), 6.15 (brs, 1H), 7.08-7.63 (m, 9H), 8.59 (br, 1H), 9.08 (s, 2H).

Example 17
2-Phenoxy-N- (4- (pyridin-3-yl-methylcarbamoylmethyl) -phenyl) -5-pyrimidinecarboxamide (17)

According to Example 14, by using pyridine-3-methylamine instead of pyrrolidine, 2-phenoxy-N- (4- (pyridin-3-yl-methylcarbamoylmethyl) -phenyl) -5-pyrimidinecarboxamide ( 87%) as a milky white solid.
Melting point: 225-228 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.59 (s, 2H), 4.41 (d, J = 5.9 Hz, 2H), 6.69 (br, 1H), 7.17-7.78 (m, 11H), 8.41- 8.59 (m, 2H), 9.16 (s, 2H), 9.88 (s, 1H).

Example 18
2-phenoxy-N- (4-((N-methoxy-N-methyl) carbamoylmethyl) -phenyl) -5-pyrimidinecarboxamide (18)

According to Example 14, by using N, O-dimethylhydroxylamine hydrochloride instead of pyrrolidine, 2-phenoxy-N- (4-((N-methoxy-N-methyl) carbamoylmethyl) -phenyl)- 5-Pyrimidinecarboxamide (72%) was obtained as a pale yellow solid.
Melting point: 191-193 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.11 (s, 3H), 3.67 (s, 3H), 3.71 (s, 2H), 7.21-7.32 (m, 5H), 7.43-7.54 (m , 2H), 7.62-7.71 (m, 2H), 9.09 (s, 2H), 10.27 (s, 1H).

Example 19
2-Phenoxy-N- (4- (tert-butoxycarbonylaminomethyl) phenyl) -5-pyrimidinecarboxamide (19)
Example 19 (1)
tert-Butyl-4-aminobenzylcarbamate (19 raw materials)

4-Aminobenzylamine (2.51 g, 2.1 mmol) was dissolved in tetrahydrofuran, and di-tert-butyl dicarbonate (4.51 g, 2.1 mmol) was added dropwise under ice cooling. The mixture was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure silica gel flash column chromatography (chloroform: methanol = 50: 1-20: 1) to give tert-butyl-4-aminobenzylcarbamate (2.48 g, 54%). Obtained as a white solid.
Melting point: Amorphous solid
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.45 (s, 9H), 3.64 (brs, 2H), 4.18 (d, J = 5.7 Hz, 2H), 4.71 (br, 1H), 6.64 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H).

Example 19 (2)
2-Phenoxy-N- (4- (tert-butoxycarbonylaminomethyl) phenyl) -5-pyrimidinecarboxamide (19)

2-Phenoxy-pyrimidine-5-carboxylic acid (2.20 g, 10 mmol) dissolved in pyridine (30 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.34 g, 12 mmol) Then, tert-butyl-4-aminobenzylcarbamate (2.22 g, 10 mmol) obtained in Example 19 (1) was added, and the mixture was stirred at room temperature for 15 hours. After concentration under reduced pressure, water and saturated aqueous potassium carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4- (tert- Butoxycarbonylaminomethyl) phenyl) -5-pyrimidinecarboxamide (2.65 g, 63%) was obtained as an opalescent solid.
Melting point: 170-173 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.37 (s, 9H), 4.44 (s, 2H), 6.86 (br, 1H), 7.17-7.51 (m, 7H), 7.64 (d, J = 8.4 Hz, 2H), 9.11 (s, 2H), 10.38 (s, 1H).

Example 20
2-Phenoxy-N- (4-aminomethylphenyl) -5-pyrimidinecarboxamide (20)

2-phenoxy-N- (4- (tert-butoxycarbonylaminomethyl) phenyl) -5-pyrimidinecarboxamide (2.11 g, 5.0 mmol) obtained in Example 19 (2) was treated with 2N hydrochloric acid-ethyl acetate. It was suspended in the solution (40 ml) and stirred at 50 ° C. for 15 hours. After allowing to cool, the precipitate was collected by filtration, and the resulting solid was suspended in a saturated aqueous sodium hydrogen carbonate solution and collected by filtration. Further, it was washed with water and diethyl ether, and dried under reduced pressure to obtain 2-phenoxy-N- (4-aminomethylphenyl) -5-pyrimidinecarboxamide (1.33 g, 83%) as a pale yellow solid.
Melting point:> 300 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.87 (s, 2H), 7.23-7.50 (m, 7H), 7.73 (d, J = 8.4 Hz, 2H), 9.12 (s, 2H), 10.53 (s, 1H).

Example 21
2-Phenoxy-N- (4- (3-methoxypropylaminomethyl) -phenyl) -5-pyrimidinecarboxamide (21)

2-Phenoxy-N- (4-formylphenyl) -5-pyrimidinecarboxamide (32 mg, 0.1 mmol) obtained in Example 2 was dissolved in methanol (3 ml), and 3-methoxypropylamine (0.02 ml, 0.2 mmol) and sodium cyanoborohydride (13 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 2-Phenoxy-N- (4- (3-methoxypropylaminomethyl) was obtained by purifying the residue obtained by concentration under reduced pressure by silica gel flash column chromatography (methanol: chloroform = 1: 10). -Phenyl) -5-pyrimidinecarboxamide (25 mg, 64%) was obtained as a white solid.
Melting point: 153-154 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.94-2.06 (m, 2H), 3.04 (t, J = 7.1 Hz, 2H), 3.34 (s, 3H), 3.51 (t, J = 5.6 Hz, 2H), 4.04 (s, 2H), 7.18-7.30 (m, 3H), 7.41-7,53 (m, 4H), 7.80-7.89 (m, 2H). 9.18 (s, 2H), 10.08 (s, 1H).

Example 22
2-Phenoxy-N- (4- (3-pyridylaminomethyl) -phenyl) -5-pyrimidinecarboxamide (22)

According to Example 21, 2-phenoxy-N- (4- (3-pyridylaminomethyl) -phenyl) -5-pyrimidinecarboxamide (46%) was obtained by using 3-aminopyridine instead of 3-methoxypropylamine. Was obtained as a milky white solid.
Melting point: 205-208 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.28 (d, J = 5.9 Hz, 2H), 6.50 (t, J = 5.9 Hz, 1H), 6.85-6.94 (m, 1H), 6.99- 7.11 (m, 1H), 7.22-7.54 (m, 7H), 7.63-7.79 (m, 3H), 7.98 (d, J = 2.6 Hz, 1H), 9.10 (s, 2H), 10.42 (s, 1H) .

Example 23
2-Phenoxy-N- (4- (5-indoleaminomethyl) -phenyl) -5-pyrimidinecarboxamide (23)

According to Example 21, 2-phenoxy-N- (4- (5-indoleaminomethyl) -phenyl) -5-pyrimidinecarboxamide (37%) was obtained by using 5-aminoindole instead of 3-methoxypropylamine. ) Was obtained as a dark brown solid.
Melting point: 143-146 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.24 (s, 2H), 6.08-6.17 (m, 1H), 6.53-6.65 (m, 2H), 7.05-7.73 (m, 12H), 9.10 (s, 2H), 10.39 (s, 1H), 10.59 (s, 1H).

Example 24
2-Phenoxy-N- (4- (2- (4-sulfamoylphenyl) ethylaminomethyl) -phenyl) -5-pyrimidinecarboxamide (24)

According to Example 21, 2-phenoxy-N- (4- (2- (4-sulfamoylphenyl) was obtained by using 4- (2-aminoethyl) -benzenesulfonamide instead of 3-methoxypropylamine. ) Ethylaminomethyl) -phenyl) -5-pyrimidinecarboxamide (43%) was obtained as a milky white solid.
Melting point: 271-275 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.03-3.28 (m, 4H), 4.14 (s, 2H), 7.20-7.94 (m, 14H), 9.18 (s, 2H), 9.55 (br , 2H), 10.77 (s, 1H).

Example 25
2-Phenoxy-N- (4- (3-acetoxy-2,2-dimethylpropioamidomethyl) -5-pyrimidinecarboxamide (25)

3-Acetoxy-2,2-dimethylpropionic acid (0.16 g, 1.0 mmol) was dissolved in pyridine (5 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.2 mmol) was dissolved. ), 2-phenoxy-N- (4-aminomethylphenyl) -5-pyrimidinecarboxamide (0.32 g, 1.0 mmol) obtained in Example 20 was added, and the mixture was stirred at 70 ° C. for 15 hours. After allowing to cool, the solvent was concentrated under reduced pressure, water was added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4- (3- Acetoxy-2,2-dimethylpropioamidomethyl) -5-pyrimidinecarboxamide (0.14 g, 30%) was obtained as a white solid.
Melting point: 167-171 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.30 (s, 6H), 2.02 (s, 3H), 4.31 (s, 2H), 4.46 (br, 2H), 7.17-7.51 (m, 7H ), 7.64 (d, J = 8.4 Hz, 2H), 8.05-8.11 (br, 1H), 9.11 (s, 2H), 10.38 (s, 1H).

Example 26
2-Phenoxy-N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (26)
Example 26 (1)
4-Nitrobenzylpyrrolidine (26 ingredients)

4-Nitrobenzyl bromide (64.8 g, 300 mmol) was dissolved in tetrahydrofuran (450 ml), potassium carbonate (62.2 g, 450 mmol) and pyrrolidine (26.3 ml, 315 mmol) were added, and the mixture was stirred at room temperature for 3 hours. . The insoluble material was filtered off using celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to give 4-nitrobenzylpyrrolidine (58.5 g, 95%) as a yellow oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.70-1.87 (m, 4H), 2.45-2.58 (m, 4H), 3.71 (s, 2H), 7.51 (d, J = 8.6 Hz, 2H), 8.17 (d, J = 8.6 Hz, 2H).

Example 26 (2)
4-Aminobenzylpyrrolidine (26 raw materials)

4-Nitrobenzylpyrrolidine (10.3 g, 50 mmol) obtained in Example 26 (1) was dissolved in methanol (250 ml), and activated carbon (1.2 g) and iron chloride hexahydrate (600 mg) were dissolved. In addition, hydrazine monohydrate (19 ml) was added dropwise over 30 minutes while heating under reflux, and the mixture was further heated under reflux for 2 hours. The insoluble material was filtered off using celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel flash column chromatography (NH silica gel; ethyl acetate: chloroform = 1: 20). 4-aminobenzylpyrrolidine (7.1 g, 80%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.65-1.83 (m, 4H), 2.40-2.56 (m, 4H), 3.50 (s, 2H), 3.59 (brs, 2H), 6.64 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H).

Example 26 (3)
2-Phenoxy-N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (26)

According to Example 1 (2), 2-phenoxy-N- (4- (pyrrolidine-1) was obtained by using 4-aminobenzylpyrrolidine obtained in Example 26 (2) instead of 4-aminobenzenemethanol. -Ilmethyl) phenyl) -5-pyrimidinecarboxamide (83%) was obtained as a white solid.
Melting point: 207-209 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.70-1.85 (m, 4H), 2.43-2.57 (m, 4H), 3.60 (s, 2H), 7.18-7.39 (m, 5H), 7.41-7.58 (m, 4H), 7.75 (brs, 1H), 9.02 (s, 2H).

Example 27
2-Phenoxy-N- (4- (2-oxopyrrolidin-1-yl-methyl) -phenyl) -5-pyrimidinecarboxamide (27)
Example 27 (1)
4-Chloro-N- (4-nitrophenylmethyl) -butyrocarboxamide (27 raw materials)

4-Nitrobenzylamine hydrochloride (9.43 g, 50 mmol) was suspended in dichloromethane (100 ml), and triethylamine (17.5 ml, 125 mmol) and 4-chlorobutyroyl chloride (5.8 ml, 55 mmol) were suspended under ice cooling. In addition, the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with chloroform, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform = 1: 20 to 1: 5) to give 4 -Chloro-N- (4-nitrophenylmethyl) -butyrocarboxamide (10.33 g, 81%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.03-2.09 (m, 2H), 2.47 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 6.3 Hz, 2H), 4.55 (d, J = 6.3 Hz, 2H), 6.05 (brs, 1H), 7.44 (d, J = 8.9 Hz, 2H), 8.18 (d, J = 8.9 Hz, 2H).

Example 27 (2)
N- (4-Nitrobenzyl) -pyrrolidone (27 raw materials)

4-Chloro-N- (4-nitrophenylmethyl) -butyrocarboxamide (2.57 g, 10 mmol) obtained in Example 27 (1) was dissolved in tetrahydrofuran (60 ml), and tert-butoxy was dissolved under ice-cooling. Potassium (1.14 g, 10.2 mmol) was added, and the mixture was stirred at the same temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform = 1: 5 to 1: 1) to give N. -(4-Nitrobenzyl) -pyrrolidone (415 mg, 19%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.98-2.13 (m, 2H), 2.48 (t, J = 7.6 Hz, 2H), 3.30 (t, J = 7.1 Hz, 2H), 4.55 (s, 2H), 7.41 (d, J = 8.9 Hz, 2H), 8.20 (d, J = 8.9 Hz, 2H).

Example 27 (3)
2-Phenoxy-N- (4- (2-oxopyrrolidin-1-yl-methyl) -phenyl) -5-pyrimidinecarboxamide (27)

According to Example 12 (2), 2-phenoxy-N- (4- (2-oxopyrrolidine) was obtained by using N- (4-nitrobenzyl) -pyrrolidone instead of 4-nitrophenylacetic acid tert-butyl ester. 1-yl-methyl) -phenyl) -5-pyrimidinecarboxamide (87%) was obtained as an opalescent solid.
Melting point: 273-274 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.84-2.00 (m, 2H), 2.29 (t, J = 7.9 Hz, 2H), 3.22 (t, J = 6.9 Hz, 2H), 4.34 ( s, 2H), 7.17-7.38 (m, 5H), 7.42-7.57 (m, 2H), 7.70 (d, J = 8.2 Hz, 2H), 9.11 (s, 2H), 10.44 (s, 1H).

Example 28
2-Phenoxy-N- (4- (thiazolin-3-ylmethyl) -phenyl) -5-pyrimidinecarboxamide (28)

According to Example 21, 2-phenoxy-N- (4- (thiazolin-3-ylmethyl) -phenyl) -5-pyrimidinecarboxamide (67%) was converted to milky white by using thiazoline instead of 3-methoxypropylamine. Obtained as a solid.
Melting point: 210-213 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.92-3.16 (m, 4H), 3.56 (s, 2H), 4.05 (s, 2H), 7.17-7.76 (m, 10H), 9.03 (s, 2H ).

Example 29
2-Phenoxy-N- (4- (4- (pyrimidin-2-yl) -piperazin-1-ylmethyl) -phenyl) -5-pyrimidinecarboxamide (29)

According to Example 21, 2-phenoxy-N- (4- (4- (pyrimidin-2-yl) -piperazine-1 was obtained by using 1- (2-pyrimidinyl) piperazine instead of 3-methoxypropylamine. -Ilmethyl) -phenyl) -5-pyrimidinecarboxamide (53%) was obtained as a milky white solid.
Melting point: 205-208 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.32-2.50 (m, 4H), 3.49 (s, 2H), 3.64-3.80 (m, 4H), 6.61 (t, J = 4.6 Hz, 1H ), 7.19-7.77 (m, 9H), 8.34 (d, J = 4.6 Hz, 2H), 9.11 (s, 2H), 10.43 (s, 1H).

Example 30
2-phenoxy-N- (4- (1,2,4-triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (30)
Example 30 (1)
4-Nitrobenzyl-1,2,4-triazole (30 raw materials)

4-Nitrobenzyl bromide (21.6 g, 100 mmol) is dissolved in acetonitrile (200 ml), potassium carbonate (20.7 g, 150 mmol) and 1,2,4-triazole (7.60 g, 110 mmol) are added, and room temperature is added. For 17 hours. Insoluble material is filtered off using Celite, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 100 to 1:10). Gave 4-nitrobenzyl-1,2,4-triazole (15.1 g, 74%) as a yellow solid.
Melting point: 98-100 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 5.48 (s, 2H), 7.40 (d, J = 8.3 Hz, 2H), 8.02 (s, 1H), 8.18 (s, 1H), 8.23 (d, J = 8.3 Hz, 2H).

Example 30 (2)
2-phenoxy-N- (4- (1,2,4-triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (30)

According to Example 12 (2), by using 4-nitrobenzyl-1,2,4-triazole instead of 4-nitrophenylacetic acid tert-butyl ester, 2-phenoxy-N- (4- (1, 2,4-Triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (85%) was obtained as a pale yellow solid.
Melting point: 169-171 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 5.37 (s, 2H), 7.20-7.35 (m, 5H), 7.40-7.53 (m, 2H), 7.72 (d, J = 8.3 Hz, 2H ), 7.97 (s, 1H), 8.63 (s, 1H), 9.05 (s, 2H), 10.49 (s, 1H).

Example 31
2-phenoxy-N- (4- (1,4,5,6-tetrahydro-6-oxo-pyridazin-3-yl) phenyl) -5-pyrimidinecarboxamide (31)

According to Example 1 (2), 2-phenoxy-N— was obtained by using 6- (4-aminophenyl) -4,5-dihydropyridazin-3 (2H) -one instead of 4-aminobenzenemethanol. (4- (1,4,5,6-Tetrahydro-6-oxo-pyridazin-3-yl) phenyl) -5-pyrimidinecarboxamide (78%) was obtained as a brown solid.
Melting point: 296-298 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.45 (dd, J = 8.5, 8.5 Hz, 2H), 2.95 (dd, J = 8.5, 8.5 Hz, 2H), 7.25-7.32 (m, 3H), 7.48 (t, J = 8.3 Hz, 2H), 7.76-7.82 (m, 4H), 9.12 (s, 2H), 10.57 (s, 1H), 10.88 (s, 1H).

Example 32
2-Phenoxy-N- (4- (N-methyl-imidazol-2-yl-methyl) -phenyl) -5-pyrimidinecarboxamide (32)
Example 32 (1)
Ethyl 4-nitrobenzylimidate hydrochloride (32 raw materials)

4-Nitrobenzylnitrile (48.7 g, 300 mmol) is dissolved in chloroform (500 ml) and ethanol (21.0 ml, 360 mmol) and 4N hydrochloric acid-ethyl acetate solution (375 ml, 1500 mmol) are cooled with ice. And stirred at room temperature for 22 hours. Diisopropyl ether was added to the reaction solution, and the precipitated solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give ethyl 4-nitrobenzylimidate hydrochloride (53.8 g, 73%) as a pale yellow solid. Obtained.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.28 (t, J = 6.9 Hz, 3H), 4.25, (s, 2H), 4.44 (q, J = 6.9 Hz, 2H), 7.69 (d , J = 8.9 Hz, 2H), 8.25 (d, J = 8.9 Hz, 2H), 11.27-12.78 (br, 1H).

Example 32 (2)
1-Methyl-2- (4-nitrobenzyl) -imidazole hydrochloride (32 raw materials)

Ethyl 4-nitrobenzylimidate hydrochloride (4.89 g, 20 mmol) obtained in Example 32 (1) was suspended in 1,2-dimethoxyethane (15 ml), and N-methyl-2, 2-Dimethoxyethylamine (2.6 ml, 20 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Acetic acid (15 ml) and 4N hydrochloric acid / ethyl acetate solution (5 ml, 20 mmol) were added to the resulting reaction solution, and the mixture was stirred at 50 ° C. for 3 days. The reaction solution is allowed to cool to room temperature, diethyl ether is added, and the precipitated solid is collected by filtration, washed with diethyl ether, and dried under reduced pressure to give 1-methyl-2- (4-nitrobenzyl) -imidazole hydrochloride. (4.55 g, 90%) was obtained as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.77 (s, 3H), 4.66 (s, 2H), 7.58-7.73 (m, 4H), 8.19-8.28 (m, 2H).

Example 32 (3)
2-Phenoxy-N- (4- (N-methyl-imidazol-2-yl-methyl) -phenyl) -5-pyrimidinecarboxamide (32)

According to Example 12 (2), by using 1-methyl-2- (4-nitrobenzyl) -imidazole hydrochloride instead of 4-nitrophenylacetic acid tert-butyl ester, 2-phenoxy-N- (4 -(N-Methyl-imidazol-2-yl-methyl) -phenyl) -5-pyrimidinecarboxamide (35%) was obtained as a milky white solid.
Melting point: 199-201 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.50 (s, 3H), 3.99 (s, 2H), 6.78-6.97 (m, 4H), 7.12-7.52 (m, 7H), 9.08 (s, 2H ), 9.79 (brs, 1H).

Example 33
2-Phenoxy-N- (4- (2-hydroxy) ethylphenyl) -5-pyrimidinecarboxamide (33)

According to Example 1, by using 4-aminobenzeneethanol instead of 4-aminobenzenemethanol, 2-phenoxy-N- (4- (2-hydroxy) ethylphenyl) -5-pyrimidinecarboxamide (97%) Was obtained as a milky white solid.
Melting point: 200-202 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.87 (t, J = 7.3 Hz, 2H), 3.86 (t, J = 7.3 Hz, 2H), 7.16-7.55 (m, 9H), 7.79 (brs, 1H), 9.04 (s, 2H).

Example 34
2-Phenoxy-N- (4- (2-pivaloyloxy) ethylphenyl) -5-pyrimidinecarboxamide (34)

2-Phenoxy-N- (4- (2-hydroxy) ethylphenyl) -5-pyrimidinecarboxamide (400 mg, 1.19 mmol) obtained in Example 33 was suspended in pyridine (8 ml), and pivaloyl chloride (172 mg, 1.43 mmol) was added, and the mixture was stirred at 60 ° C. overnight. After distilling off the solvent under reduced pressure, purification by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) gave 2-phenoxy-N- (4- (2-pivaloyloxy) ethylphenyl) -5-pyrimidinecarboxamide ( 460 mg, 92%) was obtained as a pale yellow solid.
Melting point: 159-161 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.09 (s, 9H), 2.87 (t, J = 6.5 Hz, 2H), 4.21 (t, J = 6.5 Hz, 2H), 7.23-7.33 ( m, 5H), 7.44-7.52 (m, 2H), 7.65 (d, J = 8.6 Hz, 2H), 9.09 (s, 2H), 10.39 (s, 1H).

Example 35
2-Phenoxy-N- (4- (2- (2-tert-butoxycarbonylpyrrolidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide (35)
Example 35 (1)
N- (4-Nitrophenethyl) proline tert-butyl ester (35 raw materials)

4-Nitrophenethyl bromide (2.30 g, 10 mmol) was dissolved in acetonitrile (20 ml), and potassium carbonate (2.76 g, 20 mmol) and proline tert-butyl ester hydrochloride (1.04 g, 5 mmol) were added under ice-cooling. The mixture was further stirred at room temperature for 18 hours. The insoluble material was filtered off using celite, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (NH silica gel; ethyl acetate: chloroform = 1: 10) to give N- (4-Nitrophenethyl) proline tert-butyl ester (747 mg, 47%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.44 (s, 9H), 1.73-2.09 (m, 4H), 2.38-2.52 (m, 1H), 2.65-2.79 (m, 1H), 2.91-3.24 (m, 5H), 7.39 (d, J = 8.9 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H).

Example 35 (2)
2-phenoxy-N- (4- (2- (2-tert-butoxycarbonylpyrrolidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide (35)

According to Example 12 (2), 2-phenoxy-N- (4- (2) was obtained by using N- (4-nitrophenethyl) proline tert-butyl ester instead of 4-nitrophenylacetic acid tert-butyl ester. -(2-tert-Butoxycarbonylpyrrolidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide (77%) was obtained as an opalescent solid.
Melting point: 144-146 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.46 (s, 9H), 1.70-2.17 (m, 4H), 2.38-3.25 (m, 7H), 7.12-7.59 (m, 9H), 7.89 (brs , 1H), 9.03 (s, 2H).

Example 36
2-Phenoxy-N- (4- (2- (2-carboxypyrrolidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide trifluoroacetate (36)

2-phenoxy-N- (4- (2- (2-tert-butoxycarbonylpyrrolidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide (293 mg, obtained in Example 35 (2) 0.60 mmol) was dissolved in trifluoroacetic acid (3 ml) and stirred at room temperature for 20 hours. Diethyl ether was added to the resulting reaction solution, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4- (2- (2-carboxypyrrolidine-1 -Iyl) -ethyl) -phenyl) -5-pyrimidinecarboxamide trifluoroacetate (285 mg, 87%) was obtained as a pale yellow solid.
Melting point: 110-113 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.77-2.18 (m, 3H), 2.35-2.50 (m, 1H), 2.87-3.79 (m, 6H), 4.35-4.50 (m, 1H) , 7.21-7.39 (m, 5H), 7.45-7.55 (m, 2H), 7.71 (d, J = 8.6 Hz, 2H), 9.11 (s, 2H), 9.45-10.25 (br, 1H), 10.48 (s , 1H).

Example 37
2-Phenoxy-N- (4- (2- (4-tert-butoxycarbonylpiperidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide (37)
Example 37 (1)
N- (4-Nitrophenethyl) piperidine-4-carboxylic acid ethyl ester (37 raw materials)

According to Example 35 (1), N- (4-nitrophenethyl) piperidine-4-carboxylic acid ethyl ester (73%) was converted to yellow by using isonipecotic acid ethyl ester instead of proline tert-butyl ester hydrochloride. Obtained as a solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.26 (t, J = 7.2 Hz, 3H), 1.62-2.38 (m, 7H), 2.52-2.69 (m, 2H), 2.83-2.99 (m, 4H ), 4.14 (q, J = 7.2 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H).

Example 37 (2)
N- (4-Nitrophenethyl) piperidine-4-carboxylic acid (37 raw materials)

N- (4-nitrophenethyl) piperidine-4-carboxylic acid ethyl ester (6.13 g, 20 mmol) obtained in Example 37 (1) was suspended in ethanol (15 ml), and 4N aqueous sodium hydroxide solution ( 10 ml, 40 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, neutralized with 2N hydrochloric acid under ice cooling, and the precipitated solid was collected by filtration to give N- (4-nitrophenethyl) piperidine-4-carboxylic acid (3.95 g, 71%). Obtained as a yellow solid.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.38-1.63 (m, 2H), 1.72-1.85 (m, 2H), 1.93-2.27 (m, 3H), 2.47-2.65 (m, 2H) 2.78-2.99 (m, 4H), 7.52 (d, J = 8.6 Hz, 2H), 8.15 (d, J = 8.6 Hz, 2H).

Example 37 (3)
N- (4-Nitrophenethyl) piperidine-4-carboxylic acid tert-butyl ester (37 raw materials)

N- (4-nitrophenethyl) piperidine-4-carboxylic acid (2.78 g, 10 mmol) obtained in Example 37 (2) was suspended in N, N-dimethylformamide (30 ml), and 1,1 ′ -Carbonyldiimidazole (1.95 g, 12 mmol) was added, and the mixture was stirred at 40 ° C. for 1.5 hours. After the reaction solution was cooled to room temperature, tert-butanol (1.9 ml, 20 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (1.8 ml, 12 mmol) were added, and the mixture was added at 40 ° C. for 18 hours. Stir for hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 30) to give N- (4-nitro Phenethyl) piperidine-4-carboxylic acid tert-butyl ester (1.58 g, 47%) was obtained as a yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.44 (s, 9H), 1.60-2.35 (m, 7H), 2.54-2.71 (m, 2H), 2.82-3.01 (m, 4H), 7.36 (d , J = 8.9 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H).

Example 37 (4)
2-Phenoxy-N- (4- (2- (4-tert-butoxycarbonylpiperidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide (37)

According to Example 12 (2), 2-phenoxy-N— was obtained by using N- (4-nitrophenethyl) piperidine-4-carboxylic acid tert-butyl ester instead of 4-nitrophenylacetic acid tert-butyl ester. (4- (2- (4-tert-Butoxycarbonylpiperidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide (84%) was obtained as an opalescent solid.
Melting point: 159-161 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.44 (s, 9H), 1.55-2.29 (m, 7H), 2.49-2.62 (m, 2H), 2.73-3.03 (m, 4H), 7.16-7.37 (m, 5H), 7.41-7.56 (m, 4H), 7.63-7.75 (br, 1H), 9.02 (s, 2H).

Example 38
2-Phenoxy-N- (4- (2- (4-carboxypiperidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide trifluoroacetate (38)

According to Example 36, 2-phenoxy-N- (4- (2- (2-tert-butoxycarbonylpyrrolidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide instead of 2-phenoxy-N By using-(4- (2- (4-tert-butoxycarbonylpiperidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide, 2-phenoxy-N- (4- (2- (4 -Carboxypiperidin-1-yl) -ethyl) -phenyl) -5-pyrimidinecarboxamide trifluoroacetate (76%) was obtained as a pale yellow solid.
Melting point: 114-117 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.59-2.18 (m, 4H), 2.64-3.74 (m, 9H), 7.21-7.57 (m, 7H), 7.71 (d, J = 8.6 Hz , 2H), 9.11 (s, 2H), 9.37 (br, 1H), 10.46 (s, 1H).

Example 39
2-phenoxy-N- (4- (2- (4-acetoxyacetylpiperazin-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (39)
Example 39 (1)
4-Formyl-N- (4-nitrophenethyl) piperazine (39 raw materials)

4-Nitrophenethyl bromide (46.0 g, 200 mmol) is dissolved in acetonitrile (250 ml), and potassium carbonate (33.2 g, 240 mmol) and N-formylpiperazine (25.1 g, 220 mmol) are added under ice-cooling. For 3 days. The insoluble material was filtered off using celite, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 20) to give 4-formyl-N- (4-Nitrophenethyl) piperazine (24.9 g, 47%) was obtained as an opalescent solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.43-2.57 (m, 4H), 2.61-2.75 (m, 2H), 2.83-2.97 (m, 2H), 3.33-3.44 (m, 2H), 3.52 -3.65 (m, 2H), 7.37 (d, J = 8.9 Hz, 2H), 8.03 (s, 1H), 8.16 (d, J = 8.9 Hz, 2H).

Example 39 (2)
4-Acetoxyacetyl-N- (4-nitrophenethyl) piperazine (39 raw materials)

4-Formyl-N- (4-nitrophenethyl) piperazine (26.3 g, 100 mmol) obtained in Example 39 (1) was dissolved in methanol (200 ml), concentrated hydrochloric acid (20 ml) was added, and 70 Stir at 0 ° C. for 3 hours. The reaction mixture was cooled under ice-cooling, diethyl ether was added, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure. The crude amine obtained was suspended in dichloromethane, and triethylamine was cooled under ice-cooling. (35.4 g, 350 mmol) and acetoxyacetyl chloride (15.0 g, 110 ml) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 100 to 1:20) to give 4- Acetoxyacetyl-N- (4-nitrophenethyl) piperazine (31.7 g, 95%) was obtained as a milky white solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.18 (s, 3H), 2.45-2.71 (m, 6H), 2.78-2.98 (m, 2H), 3.34-3.78 (m, 4H), 4.72 (s , 2H), 7.36 (d, J = 8.9 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H).

Example 39 (3)
4-Acetoxyacetyl-N- (4-aminophenethyl) piperazine (39 raw materials)

4-acetoxyacetyl-N- (4-nitrophenethyl) piperazine (10.1 g, 30 mmol) obtained in Example 39 (2) was dissolved in ethyl acetate (130 ml), and 10% palladium-carbon (2.5 g ) Was added and stirred at room temperature for 5 hours under a hydrogen gas atmosphere. The insoluble material was filtered off using Celite, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration to give 4-acetoxyacetyl-N- (4-aminophenethyl). ) Piperazine (9.14 g, 100%) was obtained as a milky white solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.18 (s, 3H), 2.43-2.80 (m, 8H), 3.32-3.79 (m, 6H), 4.72 (s, 2H), 6.63 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H).

Example 39 (4)
2-phenoxy-N- (4- (2- (4-acetoxyacetylpiperazin-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (39)

By using acetoxymethyl-N- (4-aminophenethyl) piperazinecarboxamide instead of 4-aminobenzenemethanol according to Example 1 (2), 2-phenoxy-N- (4- (2- (4- Acetoxyacetylpiperazin-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (97%) was obtained as a white solid.
Melting point: 180-181 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.16 (s, 3H), 2.42-2.85 (m, 8H), 3.32-3.69 (m, 4H), 4.72 (s, 2H), 7.15-7.35 (m , 5H), 7.40-7.58 (m, 4H), 7.85-8.05 (br, 1H), 9.04 (s, 2H).

Example 40
2-Phenoxy-N- (4- (2- (4-hydroxyacetylpiperazin-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (40)

2-phenoxy-N- (4- (2- (4-acetoxyacetylpiperazin-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (252 mg, 0.5 mmol) obtained in Example 39 (4) It melt | dissolved in tetrahydrofuran (5 ml), 1N sodium hydroxide aqueous solution (2 ml, 2 mmol) was added under ice-cooling, and it stirred at the same temperature for 2 hours. 1N Hydrochloric acid (2 ml, 2 mmol) was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, diethyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated solid was collected by filtration to give 2-phenoxy-N- (4- (2- (4- (4- Hydroxyacetylpiperazin-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (119 mg, 86%) was obtained as a white solid.
Melting point: 186-188 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.45-2.88 (m, 8H), 3.23-3.77 (m, 5H), 4.16 (s, 2H), 7.19-7.35 (m, 5H), 7.42-7.57 (m, 4H), 7.67 (br, 1H), 9.02 (s, 2H).

Example 41
2-Phenoxy-N- (4- (2- (2-methylimidazol-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (41)
Example 41 (1)
1- (4-Nitrophenethyl) -2-methylimidazole (41 raw materials)

According to Example 39 (1), 1- (4-nitrophenethyl) -2-methylimidazole (67%) was obtained as a yellow solid by using 2-methylimidazole instead of N-formylpiperazine.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.15 (s, 3H), 3.12 (t, J = 7.0 Hz, 2H), 4.12 (t, J = 7.0 Hz, 2H), 6.71 (d, J = 1.3 Hz, 1H), 6.90 (d, J = 1.3 Hz, 1H), 7.17 (d, J = 8.9 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H).

Example 41 (2)
1- (4-Aminophenethyl) -2-methylimidazole (41 raw materials)

According to Example 39 (3), 1- (4-aminophenethyl) -2-methylimidazole was used instead of 4-acetoxyacetyl-N- (4-nitrophenethyl) piperazine to give 1- (4-amino Phenethyl) -2-methylimidazole (92%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.14 (s, 3H), 2.86 (t, J = 6.9 Hz, 2H), 3.10-4.00 (br, 2H), 3.98 (t, J = 6.9 Hz, 2H), 6.60 (d, J = 8.2 Hz, 2H), 6.72-6.94 (m, 4H).

Example 41 (3)
2-Phenoxy-N- (4- (2- (2-methylimidazol-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (41)

According to Example 1 (2), 2-phenoxy-N- (4- (2- (2- (2- (2- Methylimidazol-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (80%) was obtained as a milky white solid.
Melting point: 200-203 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.74 (s, 3H), 2.85-3.03 (m, 2H), 3.96-4.09 (m, 2H), 6.75-6.97 (m, 4H), 7.05-7.62 (m, 7H), 9.14 (s, 2H), 10.96 (s, 1H).

Example 42
2-Phenoxy-N- (4- (2- (1,2,3-triazol-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (42)
Example 42 (1)
1- (4-nitrophenethyl) -1,2,3-triazole, 2- (4-nitrophenethyl) -1,2,3-triazole (42, 43 raw materials)

According to Example 39 (1), 1- (4-nitrophenethyl) -1,2,3-triazole (29%), 2 by using 1,2,3-triazole instead of N-formylpiperazine Each of-(4-nitrophenethyl) -1,2,3-triazole (6%) was obtained as a pale yellow solid.
Melting point: 110-112 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.38 (t, J = 6.9 Hz, 2H), 4.67 (t, J = 6.9 Hz, 2H), 7.20-7.36 (m, 3H), 7.65 (s, 1H), 8.15 (d, J = 8.6 Hz, 2H)
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.40 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 7.2 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 7.58 (s, 2H), 8.12 (d, J = 8.9 Hz, 2H).

Example 42 (2)
2-Phenoxy-N- (4- (2- (1,2,3-triazol-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (42)

1- (4-Nitrophenethyl) -1H-1,2,3-triazole (10.0 g, 45.8 mmol) obtained in Example 42 (1) was dissolved in methanol (30 ml), and activated carbon (1.5 g) and iron chloride hexahydrate (1.0 g) were added and heated to 60 ° C. Hydrazine monohydrate (30 ml) was added dropwise, followed by heating to 90 ° C. and heating under reflux overnight. After cooling to room temperature, the insoluble material was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. Chloroform (100 ml), methanol (50 ml) and water (200 ml) were added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The obtained residue was dissolved in N, N-dimethylformamide (140 ml), 2-phenoxypyrimidine-5-carboxylic acid (8.30 g, 38.4 mmol), 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (8.83 g, 43.5 mmol) and 1-hydroxybenztriazole monohydrate (6.23 g, 40.7 mmol) were added, and the mixture was stirred with heating at 70 ° C. overnight. After distilling off the solvent under reduced pressure, the residue was added to water, and the resulting solid was heated and dried under reduced pressure to give 2-phenoxy-N- (4- (2- (1,2,3-triazol-1-yl ) Ethyl) phenyl) -5-pyrimidinecarboxamide (12.6 g, 79%) was obtained as a white solid.
Melting point: 217-219 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.13 (t, J = 7.0 Hz, 2H), 4.62 (t, J = 7.0 Hz, 2H), 7.09-7.32 (m, 5H), 7.44- 7.50 (m, 2H), 7.60-7.66 (m, 3H), 8.00 (s, 1H), 9.08 (s, 2H), 10.30 (s, 1H).

Example 43
2-Phenoxy-N- (4- (2- (1,2,3-triazol-2-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (43)
Example 43 (1)
2- (4-Aminophenethyl) -1,2,3-triazole (43 raw materials)

According to Example 39 (3), 2- (4-nitrophenethyl) -1,2,3 obtained in Example 42 (1) instead of 4-acetoxyacetyl-N- (4-nitrophenethyl) piperazine -Triazole was used to give 2- (4-aminophenethyl) -1,2,3-triazole (66%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.15 (t, J = 7.6 Hz, 2H), 3.59 (br, 2H), 4.60 (t, J = 7.6 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 7.58 (s, 2H).

Example 43 (2)
2-Phenoxy-N- (4- (2- (1,2,3-triazol-2-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (43)

According to Example 1 (2), 2-phenoxy-N- (4- (2- (2- (1,2,3-Triazol-2-yl) ethyl) phenyl) -5-pyrimidinecarboxamide (68%) was obtained as an opalescent solid.
Melting point: 207-208 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.27 (t, J = 6.8 Hz, 2H), 4.67 (t, J = 6.8 Hz, 2H), 7.02-7.83 (m, 12H), 9.00 (s, 2H).

Example 44
2-Phenoxy-N- (4- (2- (1,2,4-triazol-1-yl) -ethyl) phenyl) -5-pyrimidinecarboxamide (44)
Example 44 (1)
1- (4-Nitrophenethyl) -1,2,4-triazole, 1- (4-nitrophenethyl) -1,3,4-triazole (44, 45 raw materials)

According to Example 39 (1), 1- (4-nitrophenethyl) -1,2,4-triazole (24%), 1 by using 1,2,4-triazole instead of N-formylpiperazine -(4-Nitrophenethyl) -1,3,4-triazole (2%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.32 (t, J = 6.9 Hz, 2H), 4.45 (t, J = 6.9 Hz, 2H), 7.21 (d, J = 8.9 Hz, 2H), 7.80 (s, 1H), 7.98 (s, 1H), 8.14 (d, J = 8.9 Hz, 2H)
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.22 (t, J = 6.9 Hz, 2H), 4.34 (t, J = 6.9 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 8.02 (s, 2H), 8.19 (d, J = 8.6 Hz, 2H).

Example 44 (2)
2-Phenoxy-N- (4- (2- (1,2,4-triazol-1-yl) -ethyl) phenyl) -5-pyrimidinecarboxamide (44)

According to Example 12 (2), instead of 4-nitrophenylacetic acid tert-butyl ester, 1- (4-nitrophenethyl) -1,2,4-triazole obtained in Example 44 (1) is used. This gave 2-phenoxy-N- (4- (2- (1,2,4-triazol-1-yl) -ethyl) phenyl) -5-pyrimidinecarboxamide (54%) as a milky white solid.
Melting point: 212-214 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.16 (t, J = 6.6 Hz, 2H), 4.38 (t, J = 6.6 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 7.15 -7.36 (m, 3H), 7.39-7.55 (m, 4H), 7.70 (s, 1H), 7.94 (s, 1H), 8.38 (s, 1H), 9.02 (s, 2H).

Example 45
2-Phenoxy-N- (4- (2- (1,2,4-triazol-4-yl) -ethyl) phenyl) -5-pyrimidinecarboxamide (45)

According to Example 12 (2), instead of 4-nitrophenylacetic acid tert-butyl ester, 1- (4-nitrophenethyl) -1,3,4-triazole obtained in Example 44 (1) is used. This gave 2-phenoxy-N- (4- (2- (1,2,4-triazol-4-yl) -ethyl) phenyl) -5-pyrimidinecarboxamide (51%) as a milky white solid.
Melting point: 227-229 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.06 (t, J = 6.3 Hz, 2H), 4.29 (t, J = 6.3 Hz, 2H), 6.98-7.53 (m, 7H), 7.65-7.78 ( m, 2H), 8.00 (s, 2H), 9.17 (s, 2H), 10.06 (s, 1H).

Example 46
2-Phenoxy-N- (4- (2- (tert-butoxycarbonylamino) ethyl) phenyl) -5-pyrimidinecarboxamide (46)
Example 46 (1)
tert-Butyl-4-aminophenethyl carbamate (46 raw materials)

According to Example 19 (1), tert-butyl-4-aminophenethylcarbamate (53%) was obtained by using 4- (2-aminoethyl) aniline instead of 4-aminobenzylamine.
Melting point: Amorphous solid
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.37 (s, 9H), 2.64-2.70 (m, 2H), 3.09-3.17 (m, 2H), 3.64 (br, 2H), 4.73 (br , 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H).

Example 46 (2)
2-Phenoxy-N- (4- (2- (tert-butoxycarbonylamino) ethyl) phenyl) -5-pyrimidinecarboxamide (46)

According to Example 19 (2), 2-phenoxy-N- (4- (2- (tert-butoxy) was obtained by using tert-butyl-4-aminophenethylcarbamate instead of tert-butyl-4-aminobenzylcarbamate. Carbonylamino) ethyl) phenyl) -5-pyrimidinecarboxamide (82%) was obtained as a white solid.
Melting point: 182-183 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.37 (s, 9H), 2.64-2.70 (m, 2H), 3.09-3.17 (m, 2H), 6.84-6.88 (m, 1H), 7.17 -7.51 (m, 7H), 7.64 (d, J = 8.1 Hz, 2H), 9.10 (s, 2H), 10.37 (s, 1H).

Example 47
2-Phenoxy-N- (4- (2-aminoethyl) phenyl) -5-pyrimidinecarboxamide (47)

According to Example 20, instead of 2-phenoxy-N- (4- (tert-butoxycarbonylaminomethyl) phenyl) -5-pyrimidinecarboxamide, 2-phenoxy-N- ( By using 4- (2- (tert-butoxycarbonylamino) ethyl) phenyl) -5-pyrimidinecarboxamide, 2-phenoxy-N- (4- (2-aminoethyl) phenyl) -5-pyrimidinecarboxamide (91% ) Was obtained as a white solid.
Melting point: 224-231 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.64-2.70 (m, 2H), 3.09-3.17 (m, 2H), 4.09-4.12 (m, 2H), 7.17-7.51 (m, 7H) , 7.64 (d, J = 8.1 Hz, 2H), 9.11 (s, 2H), 10.38 (s, 1H).

Example 48
2-Phenoxy-N- (4- (2- (cyclopropanecarboxamido) ethyl) phenyl) -5-pyrimidinecarboxamide (48)

Cyclopropylcarboxylic acid (50 mg, 0.58 mmol) was dissolved in pyridine (3 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.12 g, 0.6 mmol) was obtained in Example 47. The obtained 2-phenoxy-N- (4- (2-aminoethyl) phenyl) -5-pyrimidinecarboxamide (0.17 g, 0.5 mmol) was added and stirred at 70 ° C. for 16 hours. After concentration under reduced pressure, water and saturated aqueous potassium carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4- (2- (Cyclopropanecarboxamide) ethyl) phenyl) -5-pyrimidinecarboxamide (82 mg, 41%) was obtained.
Melting point: 188-191 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 0.40-0.65 (m, 4H), 1.15-1.21 (m, 1H), 2.64-2.70 (m, 2H), 3.09-3.17 (m, 2H) 6.84-6.88 (m, 1H), 7.17-7.51 (m, 7H), 7.64 (d, J = 8.1 Hz, 2H), 9.10 (s, 2H), 10.37 (s, 1H).

Example 49
2-Phenoxy-N- (4- (2- (3-ethoxypropanamido) ethyl) phenyl) -5-pyrimidinecarboxamide (49)

According to Example 48, 2-phenoxy-N- (4- (2- (3-ethoxypropanamido) ethyl) phenyl) -5- was obtained by using 3-ethoxypropionic acid instead of cyclopropylcarboxylic acid. Pyrimidinecarboxamide (48%) was obtained as a white solid.
Melting point: 181-187 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.07 (t, J = 7.0 Hz, 3H), 2.26 (t, J = 6.5 Hz, 2H), 2.60-2.72 (m, 2H), 3.05- 3.30 (m, 2H), 3.37 (q, J = 7.0 Hz, 2H), 3.53 (t, J = 6.5 Hz, 2H), 7.16-7.50 (m, 7H), 7.63 (d, J = 8.4 Hz , 2H), 7.81-7.96 (br, 1H), 9.09 (s, 2H), 10.36 (s, 1H).

Example 50
2-phenoxy-N- (4- (2- (thiophene-2-carboxamido) ethyl) phenyl) -5-pyrimidinecarboxamide (50)

According to Example 48, 2-phenoxy-N- (4- (2- (thiophene-2-carboxamido) ethyl) phenyl) -5- was obtained by using thiophene-2-carboxylic acid instead of cyclopropylcarboxylic acid. Pyrimidinecarboxamide (58%) was obtained.
Melting point: 213-215 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.63-2.71 (m, 2H), 3.07-3.18 (m, 2H), 6.84-6.88 (m, 1H), 7.15-7.52 (m, 10H) , 7.64 (d, J = 8.4 Hz, 2H), 9.10 (s, 2H), 10.38 (s, 1H).

Example 51
2-Phenoxy-N- (4- (3- (piperidin-1-yl) -propyl) phenyl) -5-pyrimidinecarboxamide (51)
Example 51 (1)
tert-Butyl 4- (3-hydroxypropyl) phenylcarbamate (51 raw materials)

Dissolve the known compound 1-hydroxy-3- (4-nitrophenyl) -2-propene (11.5 g, 64.2 mmol) in ethyl acetate (120 ml), add 10% palladium-carbon (0.6 g), The mixture was stirred for one day at room temperature under a gas atmosphere. Insoluble material was filtered off using Celite, and the filtrate was concentrated under reduced pressure to obtain a crude amine compound. The obtained amine compound was dissolved in 1,4-dioxane (120 ml) and water (60 ml) and cooled in an ice bath. 1N Aqueous sodium hydroxide solution (66 ml) was added dropwise, di-tert-butyl dicarbonate (15.4 g, 70.6 mmol) was added, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium-pressure silica gel flash column chromatography (methanol: chloroform = 2: 98) to give tert-butyl 4- ( 3-Hydroxypropyl) phenyl carbamate (11.0 g, 68%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.51 (s, 9H), 1.81-1.91 (m, 2H), 2.65 (t, J = 7.8 Hz, 2H), 3.62-3.72 (m, 3H), 6.43 (br, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H).

Example 51 (2)
tert-Butyl 4- (3-iodopropyl) phenylcarbamate (51 raw materials)

Tert-butyl 4- (3-hydroxypropyl) phenylcarbamate (11.0 g, 44.1 mmol) obtained in Example 51 (1) was dissolved in dichloromethane (50 ml), and N, N-diisopropylethylamine ( 13.8 ml, 79.4 mmol) and methanesulfonyl chloride (5.12 ml, 66.2 mmol) were sequentially added, and the mixture was warmed to room temperature and stirred for 5 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and concentrated under reduced pressure to obtain a crude mesyl form. The obtained mesyl form was dissolved in acetone (200 ml), sodium iodide (19.8 g, 132.3 mmol) was added, and the mixture was stirred for 20 minutes under reflux with heating, and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium-pressure silica gel flash column chromatography (methanol: chloroform = 2: 98) to give tert-butyl 4- ( 3-Iodopropyl) phenyl carbamate (11.1 g, 70%) was obtained as a yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.51 (s, 9H), 2.04-2.14 (m, 2H), 2.67 (t, J = 7.0 Hz, 2H), 3.15 (t, J = 7.0 Hz, 2H), 6.42 (br, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H).

Example 51 (3)
tert-Butyl 4- (3-piperidin-1-yl-propyl) phenylcarbamate (51 raw materials)

Tert-butyl 4- (3-iodopropyl) phenylcarbamate (1.0 g, 2.77 mmol) obtained in Example 51 (2) was dissolved in acetonitrile (6 ml), potassium carbonate (0.57 g, 4.15 mmol), Piperidine (0.33 ml, 3.32 mmol) was added, and the mixture was heated with stirring at 80 ° C. for 6 hours. After allowing to cool to room temperature, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure and purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 2: 98) to give tert-butyl 4- ( 3-Piperidin-1-yl-propyl) phenyl carbamate (836 mg, 95%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.24-1.49 (m, 2H), 1.51 (s, 9H), 1.63-1.69 (m, 4H), 1.80-1.91 (m, 2H), 2.39 (t , J = 7.6 Hz, 2H), 2.46 (br, 4H), 2.58 (t, J = 7.6 Hz, 2H), 6.42 (br, 1H), 7.10 (d, J = 8.3 Hz, 2H), 7.26 (d , J = 8.3 Hz, 2H).

Example 51 (4)
2-Phenoxy-N- (4- (3- (piperidin-1-yl) -propyl) phenyl) -5-pyrimidinecarboxamide (51)

  (a) Dissolving tert-butyl 4- (3- (piperidin-1-yl) -propyl) phenylcarbamate (800 mg, 2.51 mmol) obtained in Example 51 (3) in methanol (15 ml), 4N Hydrochloric acid-ethyl acetate solution (6.3 ml, 25.1 mmol) was added, and the mixture was heated to reflux for 1 hr. After allowing to cool to room temperature, the solvent was removed under reduced pressure to obtain a crude amine compound.

(b) 2-Phenoxypyrimidine-5-carboxylic acid (543 mg, 2.51 mmol) was dissolved in pyridine (15 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (530 mg, 2.76 mmol), 1-hydroxybenzotriazole monohydrate (415 mg, 2.76 mmol) and the crude amine obtained in the above (a) were added and stirred at 75 ° C. for 3 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the system, the mixture was extracted with a chloroform / methanol (7: 1) solution, washed with saturated brine, and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 2: 98) to give 2-phenoxy-N—. (4- (3- (Piperidin-1-yl) -propyl) phenyl) -5-pyrimidinecarboxamide (464 mg, 44%) was obtained as a white solid.
Melting point: 175 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.42-1.44 (br, 2H), 1.74-1.77 (br, 3H), 1.77-1.85 (m, 2H), 2.31 (t, J = 5.2 Hz, 2H ), 2.36 (br, 5H), 2.61 (t, J = 5.2 Hz, 2H), 7.18-7.50 (m, 9H), 7.81 (br, 1H), 9.02 (s, 1H).

Example 52
2-phenoxy-N- (4- (3- (morpholin-4-yl) -propyl) phenyl) -5-pyrimidinecarboxamide (52)
Example 52 (1)
tert-Butyl 4- (3- (morpholin-4-yl) -propyl) phenylcarbamate (52 raw materials)

According to Example 51 (3), using morpholine instead of piperidine, tert-butyl 4- (3- (morpholin-4-yl) -propyl) phenylcarbamate (860 mg, 97%) as an oil Obtained.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.51 (s, 9H), 1.72-1.83 (m, 2H), 2.34 (t, J = 7.6 Hz, 2H), 2.40-2.44 (m, 4H), 2.59 (t, J = 7.6 Hz, 2H), 3.70-3.73 (m, 4H), 6.43 (br, 1H), 7.10 (d, J = 8.6Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H ).

Example 52 (2)
2-Phenoxy-N- (4- (3- (morpholin-4-yl) -propyl) phenyl) -5-pyrimidinecarboxamide (52)

According to Example 51 (4), tert-butyl 4- (3- (3- (piperidin-1-yl) -propyl) phenylcarbamate obtained in Example 52 (1) instead of tert-butyl 4- (3- (piperidin-1-yl) -propyl) phenylcarbamate By using (morpholin-4-yl) -propyl) phenyl carbamate, 2-phenoxy-N- (4- (3- (morpholin-4-yl) -propyl) phenyl) -5-pyrimidinecarboxamide (28%) Was obtained as a white solid.
Melting point: 190-191 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.74-1.85 (m, 2H), 2.35 (t, J = 5.1 Hz, 2H), 2.42 (br, 4H), 2.64 (t, J = 5.1 Hz, 2H), 3.72 (br, 4H), 7.19-7.51 (m, 9H), 7.72 (s, 1H), 9.02 (s, 2H).

Example 53
2-Phenoxy-N- (4- (4- (4-hydroxypiperidin-1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (53)
Example 53 (1)
4- (4-Iodobutyl) -nitrobenzene (53 raw materials)

4- (4-Hydroxybutyl) -nitrobenzene (10.2 g, 52 mmol) was dissolved in 1,2-dichloroethane (60 ml) and thionyl chloride (15.2 ml, 208 mmol), N, N-dimethylformamide (2 drops) ) Was added, and the mixture was stirred at 75 ° C. for 3 hours. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and then dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure to obtain a crude chloro compound (11.0 g, 99%). The obtained crude chloro compound was dissolved in 2-butanone (200 ml), sodium iodide (38.5 g, 257 mmol) was added, and the mixture was heated to reflux for 8 hours. The insoluble material was filtered off using celite, and the filtrate was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, n-hexane was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated solid was collected by filtration to give 4- (4-iodobutyl) -nitrobenzene (12.2 g, 77 %) As a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.71-1.98 (m, 4H), 2.79 (t, J = 6.9 Hz, 2H), 3.21 (d, J = 6.6 Hz, 2H), 7.34 (d, J = 8.9 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H).

Example 53 (2)
4- (4-Aminophenyl) butyl-4-hydroxypiperidine (53 raw materials)

4- (4-Iodobutyl) -nitrobenzene (1.53 g, 5.0 mmol) obtained in Example 53 (1) was dissolved in acetonitrile (20 ml) and water (5 ml), and potassium carbonate (3.46 g, 25 mmol) was dissolved. ), 4-hydroxypiperidine (759 mg, 7.5 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure to obtain a crude nitro compound. The obtained crude nitro compound was dissolved in methanol (20 ml), 10% palladium-carbon (500 mg) was added, and the mixture was stirred at room temperature for 1.5 hours in a hydrogen gas atmosphere. The insoluble material was filtered off using celite, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration to give 4- (4-aminophenyl) butyl-4- Hydroxypiperidine (1.02 g, 82%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.39-1.68 (m, 7H), 1.81-1.96 (m, 2H), 2.01-2.18 (m, 2H), 2.25-2.39 (m, 2H), 2.44 -2.60 (m, 2H), 2.67-2.85 (m, 2H), 3.43-3.76 (m, 3H), 6.61 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H).

Example 53 (3)
2-Phenoxy-N- (4- (4- (4-hydroxypiperidin-1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (53)

According to Example 1 (2), 2- (4-aminophenyl) butyl-4-hydroxypiperidine was used in place of 4-aminobenzenemethanol to give 2-phenoxy-N- (4- (4- (4 -Hydroxypiperidin-1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (63%) was obtained as a milky white solid.
Melting point: 167-168 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.41-1.75 (m, 7H), 1.80-1.94 (m, 2H), 2.02-2.17 (m, 2H), 2.24-2.37 (m, 2H), 2.53 -2.82 (m, 4H), 3.59-3.74 (m, 1H), 7.13-7.34 (m, 5H), 7.40-7.54 (m, 4H), 7.80 (brs, 1H), 9.02 (s, 2H).

Example 54
2-Phenoxy-N- (4- (4- (pyrrolidin-1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (54)
Example 54 (1)
4- (4-Aminophenyl) butyl-4-pyrrolidine (54 raw materials)

According to Example 53 (2), 4- (4-aminophenyl) butyl-4-pyrrolidine (94%) was obtained as an amorphous substance by using pyrrolidine instead of 4-hydroxypiperidine.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.47-1.85 (m, 8H), 2.35-2.63 (m, 8H), 3.53 (s, 2H), 6.62 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H).

Example 54 (2)
2-Phenoxy-N- (4- (4- (pyrrolidin-1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (54)

By using 4- (4-aminophenyl) butyl-4-pyrrolidine instead of 4-aminobenzenemethanol according to Example 1 (2), 2-phenoxy-N- (4- (4- (pyrrolidine- 1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (94%) was obtained as a milky white solid.
Melting point: 175-177 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.49-1.83 (m, 8H), 2.38-2.53 (m, 6H), 2.62, (t, J = 7.3 Hz, 2H), 7.14-7.33 (m, 5H), 7.40-7.54 (m, 4H), 7.77 (brs, 1H), 9.01 (s, 2H).

Example 55
2-Phenoxy-N- (4- (4- (2-methylimidazol-1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (55)
Example 55 (1)
4- (4-Nitrophenyl) butyl-2-methyl-imidazole (55 raw materials)

4- (4-Iodobutyl) -nitrobenzene (1.53 g, 5.0 mmol) obtained in Example 53 (1) was dissolved in acetonitrile (20 ml) and water (5 ml), and potassium carbonate (3.46 g, 25 mmol) was dissolved. ), 2-methylimidazole (616 mg, 7.5 mmol) was added, and the mixture was stirred at room temperature for 12 hours and at 80 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 50 to 1:20) to give 4- (4-Nitrophenyl) butyl-2-methyl-imidazole (770 mg, 59%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.48-1.86 (m, 4H), 2.36 (s, 3H), 2.74 (t, J = 7.6 Hz, 2H), 3.86 (t, J = 6.9 Hz, 2H), 6.78 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 1.3 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 8.15 (d, J = 8.3 Hz, 2H) .

Example 55 (2)
2-Phenoxy-N- (4- (4- (2-methylimidazol-1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (55)

According to Example 12 (2), by using 4- (4-nitrophenyl) butyl-2-methyl-imidazole obtained in Example 55 (1) instead of 4-nitrophenylacetic acid tert-butyl ester 2-phenoxy-N- (4- (4- (2-methylimidazol-1-yl) -butyl) phenyl) -5-pyrimidinecarboxamide (70%) was obtained as a milky white solid.
Melting point: 154-155 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.53-1.84 (m, 4H), 2.29 (s, 3H), 2.62 (t, J = 7.3 Hz, 2H), 3.81 (t, J = 7.1 Hz, 2H), 6.77 (d, J = 1.3 Hz, 1H), 6.86 (d, J = 1.3 Hz, 1H), 7.07-7.36 (m, 5H), 7.39-7.58 (m, 4H), 8.88 (br, 1H ), 9.06 (s, 2H).

Example 56
2-phenoxy-N- (4-nitrophenyl) -5-pyrimidinecarboxamide (56)

2-Phenoxy-pyrimidine-5-carboxylic acid (1.12 g, 5.2 mmol) dissolved in pyridine (10 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.16 g, 6.1 mmol) 4-nitroaniline (0.69 g, 5.0 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After concentration under reduced pressure, water and saturated aqueous potassium carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4-nitrophenyl). -5-pyrimidinecarboxamide (1.29 g, 77%) was obtained as a milky white solid.
Melting point: 249-253 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.23-7.51 (m, 5H), 8.00 (d, J = 8.6 Hz, 2H), 8.28 (d, J = 8.6 Hz, 2H), 9.13 ( s, 2H), 10.96 (s, 1H).

Example 57
2-Phenoxy-N- (4-aminophenyl) -5-pyrimidinecarboxamide (57)

2-Phenoxy-N- (4-nitrophenyl) -5-pyrimidinecarboxamide (1.0 g, 3.0 mmol) obtained in Example 56 was dissolved in methanol (15 ml), and 5% palladium-carbon (0.22 g) was obtained. And stirred for 16 hours at room temperature in a hydrogen gas atmosphere. Insoluble matter was filtered, and the filtrate was concentrated and dried under reduced pressure to give 2-phenoxy-N- (4-aminophenyl) -5-pyrimidinecarboxamide (0.54 g, 59%) as a pale green solid.
Melting point: Amorphous solid
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.00 (br, 2H), 7.24-7.72 (m, 9H), 9.10 (s, 2H), 10.18 (s, 1H).

Example 58
2-Phenoxy-N- (4- (furan-2-carboxamido) phenyl) -5-pyrimidinecarboxamide (58)

2-Phenoxy-N- (4-aminophenyl) -5-pyrimidinecarboxamide (0.11 g, 0.36 mmol), furan-2-carboxylic acid (0.05 g, 0.39 mmol) obtained in Example 57 was added to pyridine (3 ml 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.08 g, 0.44 mmol) was added, and the mixture was stirred at 70 ° C. for 16 hours. After cooling and concentration under reduced pressure, water and saturated aqueous potassium carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4- (Furan-2-carboxamide) phenyl) -5-pyrimidinecarboxamide (0.12 g, 84%) was obtained as a milky white solid.
Melting point: 271-275 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 6.68-6.70 (m, 1H), 7.24-7.72 (m, 10H), 7.90-7.93 (m, 1H), 9.10 (s, 2H), 10.18 (s, 1H), 10.42 (s, 1H).

Example 59
2-Phenoxy-N- (4- (4-hydroxymethylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (59)
Example 59 (1)
4-Hydroxymethyl-N- (4-nitrophenyl) piperidine (59 raw materials)

4-Fluoronitrobenzene (1.2 g, 8.50 mmol) is dissolved in N, N-dimethylacetamide (20 ml), and potassium carbonate (3.5 g, 25.3 mmol) and 4-hydroxymethylpiperidine (978 mg, 8.49 mmol) are added. And stirred at 130 ° C. overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was added to water, and the precipitated solid was collected by filtration. The obtained solid was heated and dried under reduced pressure to give 4-hydroxymethyl-N- (4-nitrophenyl) piperidine (1.80 g, 90%) as a yellow solid.
Melting point: 168-170 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.08-1.22 (m, 2H), 1.63-1.75 (m, 3H), 2.90-3.07 (m, 2H), 3.23-3.51 (m, 2H) , 4.01-4.06 (m, 2H), 4.47-4.51 (m, 1H), 6.97 (d, J = 9.7 Hz, 2H), 8.01 (d, J = 9.7 Hz, 2H).

Example 59 (2)
2-Phenoxy-N- (4- (4-hydroxymethylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (59)

4-hydroxymethyl-N- (4-nitrophenyl) piperidine (700 mg, 2.96 mmol) obtained in Example 59 (1) was suspended in methanol (14 ml), activated carbon (235 mg), iron chloride Hexahydrate (70 mg) was added and heated to 60 ° C. After adding hydrazine monohydrate (2.1 ml), the mixture was heated to 90 ° C. and refluxed overnight. After cooling to room temperature, insolubles were filtered off using Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (chloroform: acetone = 1: 1) to obtain a crude amine compound.

The obtained crude amine compound was dissolved in N, N-dimethylformamide (14 ml), 2-phenoxypyrimidine-5-carboxylic acid (524 mg, 2.42 mmol), 1-ethyl-3- (3-dimethylamino) Propyl) carbodiimide hydrochloride (463 mg, 2.42 mmol) and 1-hydroxybenztriazole monohydrate (327 mg, 2.14 mmol) were added, and the mixture was stirred with heating at 70 ° C. overnight. After cooling to room temperature and concentrating under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (chloroform: acetone = 1: 1) to give 2-phenoxy-N- (4- (4 -Hydroxymethylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (588 mg, 43%) was obtained as a pale yellow solid.
Melting point: 218-220 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.14-1.29 (m, 2H), 1.44-1.50 (m, 1H), 1.71-1.75 (m, 2H), 2.50-2.63 (m, 2H) , 3.25-3.31 (m, 2H), 3.63-3.67 (m, 2H), 4.44-4.48 (m, 1H), 6.93 (d, J = 9.2 Hz, 2H), 7.21-7.31 (m, 3H), 7.42 -7.55 (m, 4H), 9.07 (s, 2H), 10.20 (s, 1H).

Example 60
2-Phenoxy-N- (4- (4-methoxymethylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (60)
Example 60 (1)
4-Methoxymethyl-N- (4-nitrophenyl) piperidine (60 raw materials)

4-Hydroxymethyl-N- (4-nitrophenyl) piperidine (650 mg, 2.60 mmol) obtained in Example 59 (1) was dissolved in tetrahydrofuran (13 ml), and 60% sodium hydride (99 mg, 2.48 mmol) and methyl iodide (507 mg, 3.57 mmol) were added and stirred overnight at room temperature. After stopping the reaction with aqueous hydrochloric acid, the mixture was concentrated under reduced pressure to distill off the solvent, followed by extraction with chloroform (10 ml) and water (3 ml). The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 4-methoxymethyl-N- (4-nitrophenyl) piperidine (585 mg, 85%). Obtained as a yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.22-1.39 (m, 2H), 1.81-1.98 (m, 3H), 2.91-3.10 (m, 2H), 3.34 (d, J = 6.7 Hz, 2H ), 3.41 (s, 3H), 3.92-4.02 (m, 2H), 6.79 (d, J = 9.7 Hz, 2H), 8.08 (d, J = 9.7 Hz, 2H).

Example 60 (2)
2-Phenoxy-N- (4- (4-methoxymethylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (60)

According to Example 59 (2), using 4- (methoxymethyl) -1- (4-nitrophenyl) piperidine instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine, 2-phenoxy- N- (4- (4-methoxymethylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (70%) was obtained as a brown solid.
Melting point: 216-218 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.25-1.40 (m, 2H), 1.61-1.80 (m, 3H), 2.53-2.69 (m, 2H), 3.16-3.27 (m, 2H) , 3.25 (s, 3H), 3.58-3.77 (m, 2H), 6.93 (d, J = 9.2 Hz, 2H), 7.22-7.33 (m, 3H), 7.44-7.57 (m, 4H), 9.08 (s , 2H), 10.22 (s, 1H).

Example 61
2-Phenoxy-N- (4- (4-ethoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (61)
Example 61 (1)
1- (4-Nitrophenyl) piperidine-4-carboxylic acid ethyl ester (61 raw materials)

According to Example 59 (1), 1- (4-nitrophenyl) piperidine-4-carboxylic acid ethyl ester (95%) as a yellow solid was obtained by using isonipecotic acid ethyl ester instead of 4-hydroxymethylpiperidine. Obtained.
Melting point: 87-89 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.27 (t, J = 7.2 Hz, 3H), 1.80-1.90 (m, 2H), 2.00-2.08 (m, 2H), 2.54-2.62 (m, 1H ), 3.01-3.14 (m, 2H), 3.84-3.92 (m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 6.83 (d, J = 7.2 Hz, 2H), 8.11 (d, J = 7.2 Hz, 2H).

Example 61 (2)
2-Phenoxy-N- (4- (4-ethoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (61)

By using 1- (4-nitrophenyl) piperidine-4-carboxylic acid ethyl ester instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine according to Example 59 (2), 2-phenoxy- N- (4- (4-Ethoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (85%) was obtained as a pale yellow solid.
Melting point: 197-199 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.19 (t, J = 7.3 Hz, 3H), 1.58-1.76 (m, 2H), 1.82-1.99 (m, 2H), 2.45-2.50 (m , 1H), 2.68-2.83 (m, 2H), 3.55-3.68 (m, 2H), 4.07 (q, J = 7.3 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 7.24-7.33 ( m, 3H), 7.42-7.54 (m, 2H), 7.56 (d, J = 9.2 Hz, 2H), 9.09 (s, 2H), 10.22 (s, 1H).

Example 62
2-Phenoxy-N- (4- (4-tert-butoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (62)
Example 62 (1)
1- (4-Nitrophenyl) piperidine-4-carboxylic acid (62 raw materials)

1- (4-Nitrophenyl) piperidine-4-carboxylic acid ethyl ester (2.78 g, 10 mmol) obtained in Example 61 (1) was dissolved in ethanol (10 ml), and 4N aqueous sodium hydroxide solution ( 5 ml, 20 mmol) was added and the mixture was heated to reflux for 1 hour. After cooling to room temperature, water (30 ml), 2N hydrochloric acid (10 ml) were added, and the precipitated solid was collected by filtration to give 1- (4-nitrophenyl) piperidine-4-carboxylic acid (2.47 g, 97% ) Was obtained as a yellow solid.
Melting point: 184-186 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.49-1.68 (m, 2H), 1.84-2.00 (m, 2H), 2.50-2.66 (m, 1H), 3.01-3.19 (m, 2H) 3.90-4.05 (m, 2H), 7.02 (d, J = 9.4 Hz, 2H), 8.03 (d, J = 9.4 Hz, 2H), 12.28 (br, 1H).

Example 62 (2)
1- (4-Nitrophenyl) piperidine-4-carboxylic acid tert-butyl ester (62 raw materials)

1- (4-Nitrophenyl) piperidine-4-carboxylic acid (20.0 g, 79.9 mmol) obtained in Example 62 (1) was suspended in tetrahydrofuran (160 ml), and tert-butanol (23.7 g, 320 mmol), 4- (N, N-dimethylamino) pyridine (1.95 g, 16.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18.4 g, 96.0 mmol) was added at room temperature. For 6 hours. The reaction solution was added to 5% aqueous sodium hydrogen carbonate solution and stirred. The precipitated solid was collected by filtration, washed with water, and then dried by heating under reduced pressure to give 1- (4-nitrophenyl) piperidine-4-carboxylic acid. The acid tert-butyl ester (21.8 g, 90%) was obtained as a yellow solid.
Melting point: 135-137 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.46 (s, 9H), 1.71-1.86 (m, 2H), 1.97-2.03 (m, 2H), 2.43-2.53 (m, 1H), 3.03 -3.13 (m, 2H), 3.83-3.91 (m, 2H), 6.82 (d, J = 9.7 Hz, 2H), 8.11 (d, J = 9.7 Hz, 2H).

Example 62 (3)
2-Phenoxy-N- (4- (4-tert-butoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (62)

1- (4-Nitrophenyl) piperidine-4-carboxylic acid tert-acid obtained in Example 62 (2) instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine according to Example 59 (2) By using -butyl ester, 2-phenoxy-N- (4- (4-tert-butoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (90%) was obtained as a pale yellow solid.
Melting point: 191-193 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.41 (s, 9H), 1.56-1.68 (m, 2H), 1.85-1.89 (m, 2H), 2.33-2.41 (m, 1H), 2.69 -2.77 (m, 2H), 3.56-3.61 (m, 2H), 6.95 (d, J = 8.6 Hz, 2H), 7.24-7.33 (m, 3H), 7.45-7.51 (m, 2H), 7.56 (d , J = 8.6 Hz, 2H), 9.09 (s, 2H), 10.24 (brs, 1H).

Example 63
2-Phenoxy-N- (4- (4-carboxylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (63)

2-Phenoxy-N- (4- (4-tert-butoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (2.0 g, 4.22 mmol) obtained in Example 62 (3) was converted to trifluoroacetic acid. (20 ml) and stirred overnight at room temperature. After evaporating the solvent under reduced pressure, the residue was dissolved in tetrahydrofuran (20 ml), neutralized by the slow addition of triethylamine, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = Purification by 4: 1) gave 2-phenoxy-N- (4- (4-carboxylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (1.23 g, 70%) as a pale yellow solid.
Melting point: 226-232 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.58-1.72 (m, 2H), 1.88-1.93 (m, 2H), 2.33-2.43 (m, 1H), 2.69-2.78 (m, 2H) , 3.57-3.62 (m, 2H), 6.95 (d, J = 8.9 Hz, 2H), 7.24-7.33 (m, 3H), 7.44-7.51 (m, 2H), 7.56 (d, J = 8.9 Hz, 2H ), 9.09 (s, 2H), 10.24 (s, 1H), 12.20 (s, 1H).

Example 64
2-Phenoxy-N- (4- (4- (1-pyrrolidinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (64)
Example 64 (1)
((1- (4-Nitrophenyl) piperidin-4-yl) -carbonyl) pyrrolidine (64 raw materials)

1- (4-Nitrophenyl) piperidine-4-carboxylic acid (10.1 g, 40.0 mmol) obtained in Example 62 (1) was dissolved in N, N-dimethylformamide (25 ml) and pyrrolidine ( 4.3 g, 60.5 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (9.3 g, 48.5 mmol), 1-hydroxybenztriazole monohydrate (6.5 g, 42.4 mmol), The mixture was stirred at 70 ° C. overnight. After cooling to room temperature, the precipitated solid was added to water and collected by filtration, and dried by heating under reduced pressure to give ((1- (4-nitrophenyl) piperidin-4-yl) -carbonyl) pyrrolidine (10.8 g, 87% ) Was obtained as a yellow solid.
Melting point: 173-175 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.48-1.62 (m, 2H), 1.71-1.92 (m, 6H), 2.71-2.82 (m, 1H), 3.01-3.11 (m, 2H) , 3.23-3.30 (m, 2H), 3.47-3.52 (m, 2H), 4.03-4.08 (m, 2H), 7.00 (d, J = 9.6 Hz, 2H), 8.02 (d, J = 9.6 Hz, 2H ).

Example 64 (2)
2-Phenoxy-N- (4- (4- (1-pyrrolidinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (64)

According to Example 59 (2), instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine, it was obtained in Example 64 (1) ((1- (4-nitrophenyl) piperidine-4- Yl) -carbonyl) pyrrolidine to give 2-phenoxy-N- (4- (4- (1-pyrrolidinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (55%) Obtained as a brown solid.
Melting point: 262-264 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.58-1.93 (m, 8H), 2.51-2.62 (m, 1H), 2.64-2.74 (m, 2H), 3.25-3.30 (m, 2H) , 3.47-3.52 (m, 2H), 3.67-3.72 (m, 2H), 6.94 (d, J = 9.2 Hz, 2H), 7.22-7.33 (m, 3H), 7.44-7.51 (m, 2H), 7.56 (d, J = 9.2 Hz, 2H), 9.09 (s, 2H), 10.22 (s, 1H).

Example 65
2-Phenoxy-N- (4- (4- (1-pyrazolinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (65)
Example 65 (1)
((1- (4-Nitrophenyl) piperidin-4-yl) -carbonyl) pyrazoline (65 raw materials)

According to Example 64 (1), ((1- (4-nitrophenyl) piperidin-4-yl) -carbonyl) pyrazoline (70%) was obtained as a yellow solid by using pyrazoline instead of pyrrolidine. .
Melting point:
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.82-2.03 (m, 4H), 2.84-3.47 (m, 5H), 3.78-4.06 (m, 4H), 6.82 (d, J = 9.7 Hz, 2H ), 6.97 (s, 1H), 8.11 (d, J = 9.7 Hz, 2H).

Example 65 (2)
2-Phenoxy-N- (4- (4- (1-pyrazolinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (65)

By using ((1- (4-nitrophenyl) piperidin-4-yl) -carbonyl) pyrazoline instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine according to Example 59 (2) 2-Phenoxy-N- (4- (4- (1-pyrazolinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (65%) was obtained as a pale white solid.
Melting point: 228-230 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.68-1.81 (m, 4H), 2.66-2.75 (m, 2H), 2.84-2.92 (m, 2H), 3.05-3.20 (m, 1H) , 3.57-3.72 (m, 4H), 6.94 (d, J = 8.9 Hz, 2H), 7.19-7.32 (m, 4H), 7.45-7.58 (m, 4H), 9.09 (s, 2H), 10.22 (s , 1H).

Example 66
2-Phenoxy-N- (4- (4- (4-morpholinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (66)
Example 66 (1)
((4- (4-Nitrophenyl) piperidin-4-yl) -carbonyl) morpholine (66 raw materials)

According to Example 64 (1), ((4- (4-nitrophenyl) piperidin-4-yl) -carbonyl) morpholine (65%) was obtained as a yellow solid by using morpholine instead of pyrrolidine.
Melting point: 157-159 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.80-2.08 (m, 4H), 2.70-2.81 (m, 1H), 2.93-3.10 (m, 2H), 3.56-3.70 (m, 8H), 3.98 (dt, J = 13.23, 3.51 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H).

Example 66 (2)
2-Phenoxy-N- (4- (4- (4-morpholinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (66)

According to Example 59 (2), using ((4- (4-nitrophenyl) piperidin-4-yl) -carbonyl) morpholine gave 2-phenoxy-N- (4- (4- (4-mol Folinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (65%) was obtained as a pale yellow solid.
Melting point: 250-252 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.57-1.78 (m, 4H), 2.61-2.84 (m, 3H), 3.36-3.75 (m, 10H), 6.94 (d, J = 9.2 Hz , 2H), 7.21-7.35 (m, 3H), 7.43-7.64 (m, 4H), 9.09 (s, 2H), 10.23 (s, 1H).

Example 67
2-phenoxy-N- (4- (4- (N-methoxy-N-methyl) -carboxamidepiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (67)
Example 67 (1)
1- (4-Nitrophenyl) piperidine-4- (N-methoxy-N-methyl) carboxamide (67 raw materials)

According to Example 64 (1), 1- (4-nitrophenyl) piperidine-4- (N-methoxy-N-methyl) carboxamide (by using N, O-dimethylhydroxylamine hydrochloride instead of pyrrolidine) 70%) was obtained as a yellow solid.
Melting point: 115-117 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.85-1.93 (m, 4H), 2.93-3.12 (m, 3H), 3.21 (s, 3H), 3.74 (s, 3H), 3.95-4.02 (m , 2H), 6.82 (d, J = 9.7 Hz, 2H), 8.12 (d, J = 9.7 Hz, 2H).

Example 67 (2)
2-phenoxy-N- (4- (4- (N-methoxy-N-methyl) -carboxamidepiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (67)

According to Example 59 (2), 1- (4-nitrophenyl) piperidine-4- (N-methoxy-N-methyl) carboxamide is used instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine This gave 2-phenoxy-N- (4- (4- (N-methoxy-N-methyl) -carboxamidopiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (75%) as a pale yellow solid. .
Melting point: 167-169 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.61-1.75 (m, 4H), 2.67-2.78 (m, 3H), 3.10 (s, 3H), 3.67-3.69 (m, 2H), 3.69 (s, 3H), 6.94 (d, J = 9.1 Hz, 2H), 7.23-7.31 (m, 3H), 7.44-7.56 (m, 4H), 9.08 (s, 2H), 10.22 (s, 1H).

Example 68
2-Phenoxy-N- (4- (morpholin-4-yl) phenyl) -5-pyrimidinecarboxamide (68)

By using 4-morpholinoaniline instead of 4-aminobenzenemethanol according to Example 1 (2), 2-phenoxy-N- (4- (morpholin-4-yl) phenyl) -5-pyrimidinecarboxamide ( 75%) was obtained as a brown solid.
Melting point: 249-251 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.06-3.10 (m, 4H), 3.72-3.76 (m, 4H), 6.95 (d, J = 9.2 Hz, 2H), 7.22-7.33 (m , 3H), 7.44-7.51 (m, 2H), 7.58 (d, J = 9.3 Hz, 2H), 9.09 (s, 2H), 10.25 (s, 1H).

Example 69
2-phenoxy-N- (4- (2,3-dihydro-5-methyl-3-oxopyrazol-1-yl) phenyl) -5-pyrimidinecarboxamide (69)
Example 69 (1)
2,3-Dihydro-5-methyl-3-oxopyrazol-1-yl-4-nitrobenzene (69 raw materials)

4-Fluoronitrobenzene (4.23 g, 30 mmol) is dissolved in N, N-dimethylformamide (20 ml), potassium carbonate (6.21 g, 45 mmol), 3-hydroxy-5-methylpyrazole (3.53 g, 36 mmol) ) Was added and stirred at 70 ° C. for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform = 1: 10 to 1: 2) to obtain 2 , 3-Dihydro-5-methyl-3-oxopyrazol-1-yl-4-nitrobenzene (3.99 g, 61%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.30 (s, 3H), 5.74 (s, 1H), 6.96-7.20 (m, 2H), 8.04-8.15 (m, 2H), 10.18 (br, 1H ).

Example 69 (2)
2,3-Dihydro-5-methyl-3-oxopyrazol-1-yl-4-aminobenzene (69 raw materials)

2,3-Dihydro-5-methyl-3-oxopyrazol-1-yl-4-nitrobenzene (658 mg, 3.0 mmol) obtained in Example 69 (1) was dissolved in ethyl acetate (20 ml). 10% Palladium-carbon (300 mg) was added, and the mixture was stirred at room temperature for 3 hr in a hydrogen gas atmosphere. The insoluble material was filtered off using Celite, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration to give 2,3-dihydro-5-methyl-3- Oxopyrazol-1-yl-4-aminobenzene (469 mg, 83%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.22 (s, 3H), 3.70 (br, 2H), 5.72 (s, 1H), 6.58-6.69 (m, 2H), 6.87-7.00 (m, 2H ), 10.86 (br, 1H).

Example 69 (3)
2-phenoxy-N- (4- (2,3-dihydro-5-methyl-3-oxopyrazol-1-yl) phenyl) -5-pyrimidinecarboxamide (69)

According to Example 1 (2), 2-phenoxy-N was obtained by using 2,3-dihydro-5-methyl-3-oxopyrazol-1-yl-4-aminobenzene instead of 4-aminobenzenemethanol. -(4- (2,3-Dihydro-5-methyl-3-oxopyrazol-1-yl) phenyl) -5-pyrimidinecarboxamide (94%) was obtained as an opalescent solid.
Melting point: 201-203 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.27 (s, 3H), 5.56 (s, 1H), 7.01-7.82 (m, 9H), 9.16 (s, 2H), 9.75 (br, 1H), 10.64 (br, 1H).

Example 70
2-Phenoxy-N- (4- (4,5-dihydropyrazol-1-yl-) phenyl) -5-pyrimidinecarboxamide (70)
Example 70 (1)
4,5-Dihydropyrazol-1-yl-4-nitrobenzene (70 raw materials)

According to Example 69 (1), 4,5-dihydropyrazol-1-yl-4-nitrobenzene (19%) was obtained by using 4,5-dihydropyrazole instead of 3-hydroxy-5-methylpyrazole. Obtained as a brown amorphous.
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.00-3.13 (m, 2H), 3.80 (dd, J = 10.6, 9.5 Hz, 2H), 6.93-7.05 (m, 3H), 8.17 (d, J = 9.3 Hz, 2H).

Example 70 (2)
4,5-dihydropyrazol-1-yl-4-aminobenzene (70 raw materials)

4,5-Dihydropyrazol-1-yl-4-nitrobenzene (191 mg, 1.0 mmol) obtained in Example 70 (1) was dissolved in methanol (10 ml), and activated carbon (30 mg), iron chloride was dissolved. Hexahydrate (15 mg) and hydrazine monohydrate (0.39 ml) were added, and the mixture was heated to reflux for 2 hours. Insoluble material was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform = 1: 10 to 1: 5). Gave 4,5-dihydropyrazol-1-yl-4-aminobenzene (126 mg, 78%) as a brown amorphous.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.79-2.94 (m, 2H), 3.10-3.70 (m, 4H), 6.63-6.84 (m, 3H), 6.88-6.97 (m, 2H).

Example 70 (3)
2-Phenoxy-N- (4- (4,5-dihydropyrazol-1-yl-) phenyl) -5-pyrimidinecarboxamide (70)

By using 4,5-dihydropyrazol-1-yl-4-aminobenzene instead of 4-aminobenzenemethanol according to Example 1 (2), 2-phenoxy-N- (4- (4,5 -Dihydropyrazol-1-yl-) phenyl) -5-pyrimidinecarboxamide (70%) was obtained as an opalescent solid.
Melting point: 231-234 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.87-3.02 (m, 2H), 3.66 (dd, J = 10.6, 10.2 Hz, 2H), 6.86 (t, J = 1.9 Hz, 1H), 7.03 ( d, J = 8.9 Hz, 2H), 7.17-7.34 (m, 3H), 7.39-7.72 (m, 5H), 9.01 (s, 2H).

Example 71
2-Phenoxy-N- (4- (pyrazol-1-yl-) phenyl) -5-pyrimidinecarboxamide (71)
Example 71 (1)
1- (4-Nitrophenyl) -1H-pyrazole (71 raw materials)

4-Fluoronitrobenzene (1.57 g, 11.1 mmol) is dissolved in dimethyl sulfoxide (20 ml). Pyrazole (755 mg, 11.1 mmol) and potassium tert-butoxide (1.49 g, 13.3 mmol) are added at 65 ° C. The mixture was heated and stirred for 2 hours. After cooling to room temperature, the reaction solution was added dropwise to water and stirred. The precipitated solid was collected by filtration and dried by heating under reduced pressure to give 1- (4-nitrophenyl) -1H-pyrazole (1.78 g, 85%) Was obtained as a yellow solid.

Example 71 (2)
2-Phenoxy-N- (4- (pyrazol-1-yl-) phenyl) -5-pyrimidinecarboxamide (71)

According to Example 59 (2), by using 1- (4-nitrophenyl) -1H-pyrazole instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine, 2-phenoxy-N- ( 4- (Pyrazol-1-yl-) phenyl) -5-pyrimidinecarboxamide (8%) was obtained as a white solid.
Melting point: 235-237 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 6.54 (dd, J = 2.7, 1.6 Hz, 1H), 7.23-7.35 (m, 3H), 7.43-7.55 (m, 2H), 7.73 (d , J = 1.6 Hz, 1H), 7.85 (s, 4H), 8.46 (d, J = 2.7 Hz, 1H), 9.13 (s, 2H), 10.56 (s, 1H).

Example 72
2-phenoxy-N- (4-hydroxyphenyl) -5-pyrimidinecarboxamide (72)

2-Phenoxypyrimidine-5-carboxylic acid (6.49 g, 30 mmol) was dissolved in pyridine (50 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.33 g, 33 mmol), 4-aminophenol (3.27 g, 30 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After concentration under reduced pressure, water was added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4-hydroxyphenyl) -5-pyrimidinecarboxamide. (7.63 g, 83%) was obtained as a pale purple solid.
Melting point: 215-218 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 6.74 (d, J = 8.9 Hz, 2H), 7.22-7.50 (m, 7H), 9.07 (s, 2H), 9.31 (s, 1H), 10.20 (s, 1H).

Example 73
2-Phenoxy-N- (4-isobutyloxyphenyl) -5-pyrimidinecarboxamide (73)

2-Phenoxy-N- (4-hydroxyphenyl) -5-pyrimidinecarboxamide (0.31 g, 1.0 mmol) obtained in Example 72 and isobutyl bromide (0.15 g, 1.1 mmol) were combined with N, N-dimethylformamide ( 5 ml), potassium carbonate (0.55 g, 4.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Insoluble matter was filtered, the filtrate was concentrated under reduced pressure, water was added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4-iso Butyloxyphenyl) -5-pyrimidinecarboxamide (0.16 g, 45%) was obtained as a pale yellow solid.
Melting point:> 300 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 0.97 (d, J = 7.0 Hz, 6H), 1.96-2.10 (m, 1H), 3.72 (d, J = 6.5 Hz, 2H), 6.93 ( d, J = 8.9 Hz, 2H), 7.22-7.50 (m, 5H), 7.60 (d, J = 8.9 Hz, 2H), 9.08 (s, 2H), 10.30 (s, 1H).

Example 74
2-Phenoxy-N- (4-allyloxyphenyl) -5-pyrimidinecarboxamide (74)

According to Example 73, 2-phenoxy-N- (4-allyloxyphenyl) -5-pyrimidinecarboxamide (65%) was obtained as a milky white solid by using allyl bromide instead of isobutyl bromide.
Melting point: 189-190 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.52-4.56 (m, 2H), 5.21-5.43 (m, 2H), 5.95-6.11 (m, 1H), 6.95 (d, J = 9.2 Hz , 2H), 7.22-7.50 (m, 5H), 7.61 (d, J = 9.2 Hz, 2H), 9.08 (s, 2H), 10.30 (s, 1H).

Example 75
2-Phenoxy-N- (4- (3-hydroxypropyloxy) phenyl) -5-pyrimidinecarboxamide (75)

According to Example 73, 2-phenoxy-N- (4- (3-hydroxypropyloxy) phenyl) -5-pyrimidinecarboxamide (65%) was prepared by using 3-bromopropanol instead of isobutyl bromide. Obtained as a yellow solid.
Melting point: 177-182 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.34-2.40 (m, 2H), 3.20-3.40 (m, 2H), 3.91 (t, J = 5.7 Hz, 2H), 6.87 (d, J = 9.2 Hz, 2H), 7.18-7.32 (m, 3H), 7.43-7.52 (m, 4H), 8.05 (s, 1H), 9.02 (s, 2H).

Example 76
2-Phenoxy-N- (4- (2- (2-methylimidazol-1-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (76)
Example 76 (1)
1- (2-Bromoethoxy) -4-nitrobenzene (76 raw materials)

4-Nitrophenol (8.05 g, 57.9 mmol) is dissolved in toluene (160 ml) and 2-bromoethanol (7.23 g, 57.9 mmol) and triphenylphosphine (18.2 g, 69.4 mmol) are added. Lower toluene solution of diethylazodicarboxylate (31.7 ml) was slowly added dropwise. The temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to distill off the solvent, and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 1- (2-bromoethoxy) -4-nitrobenzene (10.5 g , 74%) as a white solid.
Melting point: 67-69 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.67 (t, J = 6.0 Hz, 2H), 4.37 (t, J = 6.0 Hz, 2H), 6.97 (d, J = 7.3 Hz, 2H), 8.23 (d, J = 7.3 Hz, 2H).

Example 76 (2)
1- (2- (4-Nitrophenoxy) ethyl) -2-methyl-1H-imidazole (76 raw materials)

1- (2-Bromoethoxy) -4-nitrobenzene (1.57 g, 6.82 mmol) obtained in Example 76 (1) was dissolved in N, N-dimethylformamide (30 ml), and potassium carbonate (1.77 g, 12.8 mmol) and 2-methylimidazole (1.05 g, 12.8 mmol) were added, and the mixture was stirred with heating at 70 ° C. for 2 hours. After cooling to room temperature, insolubles were removed by celite filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (NH silica gel, chloroform: ethyl acetate = 1: 1). -(2- (4-Nitrophenoxy) ethyl) -2-methyl-1H-imidazole (1.18 g, 75%) was obtained as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.43 (s, 3H), 4.31 (br, 4H), 6.78-7.03 (m, 4H), 8.13-8.28 (m, 2H).

Example 76 (3)
2-Phenoxy-N- (4- (2- (2-methylimidazol-1-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (76)

Use 1- (2- (4-nitrophenoxy) ethyl) -2-methyl-1H-imidazole instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine according to Example 59 (2). Gave 2-phenoxy-N- (4- (2- (2-methylimidazol-1-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (75%) as a white solid.
Melting point: 222-224 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.31 (s, 3H), 4.21-2.24 (m, 4H), 6.71 (brs, 1H), 6.86-6.93 (m, 2H), 7.10 (brs) , 1H), 7.23-7.31 (m, 3H), 7.44-7.47 (m, 2H), 7.60-7.63 (m, 2H), 9.08 (s, 2H), 10.19 (s, 1H).

Example 77
2-phenoxy-N- (4- (2- (1,2,3-triazol-1-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (77)
Example 77 (1)
1- (2- (4-Nitrophenoxy) ethyl) -1H-1,2,3-triazole (77 raw materials)
1- (2- (4-Nitrophenoxy) ethyl) -2H-1,2,3-triazole (78 raw materials)

1- (2-Bromoethoxy) -4-nitrobenzene (2.5 g, 10.2 mmol) obtained in Example 76 (1) was dissolved in acetone (30 ml), and potassium carbonate (3.43 g, 24.8 mmol), 1 , 2,3-triazole (1.41 g, 20.4 mmol) was added, and the mixture was stirred with heating at 70 ° C. overnight. After cooling to room temperature, insolubles were removed by celite filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 1- (2 -(4-Nitrophenoxy) ethyl) -1H-1,2,3-triazole (1.60 g, 55%) and 1- (2- (4-nitrophenoxy) ethyl) -2H-1,2,3-triazole (870 mg, 30%) were obtained as pale yellow solids, respectively.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.55 (t, J = 5.0 Hz, 2H), 4.83 (t, J = 5.0 Hz, 2H), 7.12 (d, J = 9.2 Hz, 2H) , 7.73 (s, 1H), 8.16 (s, 1H), 8.18 (d, J = 9.2 Hz, 2H)
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.63 (t, J = 5.0 Hz, 2H), 4.84 (t, J = 5.0 Hz, 2H), 7.10 (d, J = 9.2 Hz, 2H) , 7.79 (s, 2H), 8.16 (d, J = 9.2 Hz, 2H).

Example 77 (2)
2-phenoxy-N- (4- (2- (1,2,3-triazol-1-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (77)

According to Example 59 (2), 1- (2- (4-nitrophenoxy) ethyl)-obtained in Example 77 (1) instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine By using 1H-1,2,3-triazole, 2-phenoxy-N- (4- (2- (1,2,3-triazol-1-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide ( 70%) was obtained as a pale yellow solid.
Melting point: 183-185 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.38 (br, 2H), 4.77 (br, 2H), 6.91 (br, 2H), 7.22-7.30 (m, 3H), 7.43-7.48 (m , 2H), 7.58-7.61 (m, 2H), 7.73 (d, J = 6.2 Hz, 1H), 8.18 (d, J = 6.2 Hz, 1H), 9.07 (s, 2H), 10.25-10.33 (br, 1H).

Example 78
2-phenoxy-N- (4- (2- (1,2,3-triazol-2-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (78)

According to Example 59 (2), 1- (2- (4-nitrophenoxy) ethyl)-obtained in Example 77 (1) instead of 4-hydroxymethyl-N- (4-nitrophenyl) piperidine By using 2H-1,2,3-triazole, 2-phenoxy-N- (4- (2- (1,2,3-triazol-2-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide ( 63%) was obtained as a pale yellow solid.
Melting point: 196-198 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.47 (t, J = 5.1 Hz, 2H), 4.80 (t, J = 5.2 Hz, 2H), 6.91 (d, J = 9.2 Hz, 2H) , 7.22-7.33 (m, 3H), 7.44-7.51 (m, 2H), 7.61 (d, J = 8.9 Hz, 2H), 7.81 (s, 2H), 9.09 (s, 2H), 10.31 (br, 1H ).

Example 79
2-Phenoxy-N- (4- (3- (4-hydroxypiperidin-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (79)
Example 79 (1)
4-Nitrophenoxypropyl bromide (79 raw materials)

4-Nitrophenol (13.9 g, 100 mmol) is dissolved in acetonitrile (200 ml) and 1,3-dibromopropane (202 g, 1 mol) and potassium carbonate (20.7 g, 150 mmol) are added for 2 hours. Heated to reflux. After allowing the reaction solution to cool to room temperature, insolubles were filtered off using Celite, and the filtrate was evaporated under reduced pressure. Toluene (100 ml) was added to the resulting residue, and the solvent was evaporated under reduced pressure again. did. N-Hexane was added to the obtained residue, and the precipitated solid was collected by filtration to obtain 4-nitrophenoxypropyl bromide (92%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.29-2.45 (m, 2H), 3.61 (t, J = 6.3 Hz, 2H), 4.22 (t, J = 5.9 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 8.21 (d, J = 9.2 Hz, 2H).

Example 79 (2)
3- (4-Nitrophenoxy) -propyl-4-hydroxypiperidine (79 raw materials)

4-Nitrophenoxypropyl bromide (780 mg, 3.0 mmol) obtained in Example 79 (1) was dissolved in acetonitrile (10 ml), potassium carbonate (829 mg, 6.0 mmol), 4-hydroxypiperidine (455 mg). , 4.5 mmol), and stirred at room temperature for 14 hours. The insoluble material was filtered off using celite, and the filtrate was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration to give 3- (4-nitrophenoxy) -propyl-4-hydroxy. Piperidine (89%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.53-2.32 (m, 9H), 2.51 (t, J = 6.9 Hz, 2H), 2.73-2.90 (m, 2H), 3.68-3.85 (m, 1H ), 4.12 (t, J = 6.3 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 8.19 (d, J = 9.2 Hz, 2H).

Example 79 (3)
2-Phenoxy-N- (4- (3- (4-hydroxypiperidin-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (79)

In accordance with Example 12 (2), 2- (3-nitrophenoxy) -propyl-4-hydroxypiperidine was used instead of 4-nitrophenylacetic acid tert-butyl ester to give 2-phenoxy-N- (4- (3- (4-Hydroxypiperidin-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (76%) was obtained as an opalescent solid.
Melting point: 183-185 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.37-2.32 (m, 9H), 2.52 (d, J = 7.3 Hz, 2H), 2.74-2.88 (m, 2H), 3.69-3.81 (m, 1H ), 4.01 (t, J = 6.6 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 7.16-7.51 (m, 7H), 7.64 (brs, 1H), 9.01 (s, 2H).

Example 80
2-Phenoxy-N- (4- (3- (pyrrolidin-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (80)
Example 80 (1)
3- (4-Nitrophenoxy) propylpyrrolidine (80 raw materials)

By using pyrrolidine instead of 4-hydroxypiperidine according to Example 79 (2), 3- (4-nitrophenoxy) propylpyrrolidine (89%) was obtained as a pale yellow solid.

Example 80 (2)
2-Phenoxy-N- (4- (3- (pyrrolidin-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (80)

According to Example 12 (2), 2-phenoxy-N- (4- (3- (pyrrolidine) was obtained by using 3- (4-nitrophenoxy) propylpyrrolidine instead of 4-nitrophenylacetic acid tert-butyl ester. 1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (60%) was obtained as a pale yellow solid.
Melting point: 168-170 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.77-1.85 (m, 4H), 1.98-2.05 (m, 2H), 2.55-2.66 (m, 6H), 4.04, (t, J = 6.3 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 7.19-7.34 (m, 3H), 7.43-7.58 (m, 4H), 7.61 (br, 1H), 9.02 (s, 2H).

Example 81
2-Phenoxy-N- (4 (3- (1H-pyrrol-1-yl) propyloxy) phenyl) -5-pyrimidinecarboxamide (81)

Purify by medium pressure silica gel flash column chromatography (chloroform: methanol = 50: 0 to 50: 1) using 1- (3-bromopropyl) pyrrole instead of isobutyl bromide according to Example 73. , 2-phenoxy-N- (4 (3- (1H-pyrrol-1-yl) propyloxy) phenyl) -5-pyrimidinecarboxamide (10%) was obtained as a milky white solid.
Melting point: Amorphous solid
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.34-2.40 (m, 2H), 3.93 (t, J = 5.7 Hz, 2H), 4.42 (t, J = 6.7 Hz, 2H), 6.75-6.97 ( m, 4H), 7.05-7.62 (m, 9H), 9.14 (s, 2H), 10.96 (s, 1H).

Example 82
2-phenoxy-N- (4- (3- (1,2,4-triazol-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (82)
Example 82 (1)
3- (4-Nitrophenoxy) propyl-1,2,4-triazole (82 raw materials)

According to Example 79 (2), 3- (4-nitrophenoxy) propyl-1,2,4-triazole (38%) was obtained by using 1,2,4-triazole instead of 4-hydroxypiperidine. Obtained as a pale yellow solid.

Example 82 (2)
2-phenoxy-N- (4- (3- (1,2,4-triazol-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (82)

According to Example 12 (2), 2-phenoxy-N- () was obtained by using 3- (4-nitrophenoxy) propyl-1,2,4-triazole instead of 4-nitrophenylacetic acid tert-butyl ester. 4- (3- (1,2,4-triazol-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide (37%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.34-2.40 (m, 2H), 3.93 (t, J = 5.7 Hz, 2H), 4.42 (t, J = 6.7 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 7.18-7.32 (m, 3H), 7.43-7.52 (m, 4H), 7.84 (brs, 1H), 7.96 (s, 1H), 8.05 (s, 1H), 9.02 (s , 2H).

Example 83
2-Phenoxy-N- (4-((pyridin-3-yl) methoxy) phenyl) -5-pyrimidinecarboxamide (83)

According to Example 73, 2-phenoxy-N- (4 (((pyridin-3-yl) methoxy) phenyl) -5-pyrimidinecarboxamide (by using 3-chloromethylpyridine hydrochloride instead of isobutyl bromide) 55%) was obtained as a light brown solid.
Melting point: 188.5-189.5 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 5.14 (s, 2H), 7.04 (d, J = 8.9 Hz, 2H), 7.22-7.50 (m, 6H), 7.64 (d, J = 8.9 Hz, 2H), 7.84-7.88 (m, 1H), 8.54 (dd, J = 1.6 Hz, 4.9 Hz, 1H), 8.66 (d, J = 1.6 Hz, 1H), 9.08 (s, 2H), 10.32 ( s, 1H).

Example 84
2-Phenoxy-N- (4-((5- (4-morpholinylcarbonyl) -pyridin-2-yl) methoxy) phenyl) -5-pyrimidinecarboxamide (84)
Example 84 (1)
(6-Methylpyridin-3-yl) (morpholino) methanone (84 raw materials)

6-Methylnicotinic acid methyl ester (3.0 g, 20 mmol) was dissolved in tetrahydrofuran (9 ml), 4N aqueous sodium hydroxide solution was added under ice cooling, and the mixture was stirred at room temperature for 3 hr. The solvent was concentrated under reduced pressure, and the resulting residue was dissolved in water and neutralized with 2N hydrochloric acid. The precipitated solid was collected by filtration and dried under reduced pressure to obtain a crude carboxylic acid. Crude carboxylic acid (0.69 g, 5.0 mmol) was dissolved in pyridine (10 ml), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.15 g, 6.0 mmol), morpholine (0.44 g, 5.0 mmol) was dissolved. mmol) was added, and the mixture was stirred at 60 ° C. for 16 hours. After concentration under reduced pressure, water was added and the precipitate was collected by filtration, further washed with water and dried under reduced pressure to give (6-methylpyridin-3-yl) (morpholino) methanone (0.78 g, 76%) Got.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.60 (s, 3H), 3.51-3.75 (m, 8H), 7.23 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 2.4, 8.1 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H).

Example 84 (2)
(6- (Bromomethyl) pyridin-3-yl) (morpholino) methanone (84 raw materials)

(6-Methylpyridin-3-yl) (morpholino) methanone (0.78 g, 3.8 mmol) obtained in Example 84 (1) was dissolved in chloroform (10 ml), and N-bromosuccinimide (1.0 g, 5.7 mmol) and azobisisobutyronitrile (0.09 g, 0.6 mmol) were added, and the mixture was stirred with heating under reflux for 15 hours. After cooling, insoluble matters were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel flash column chromatography (n-hexane: chloroform: diethyl ether = 1: 1: 1 to 1: 10: 1) to give (6- (bromomethyl) pyridine- 3-yl) (morpholino) methanone (0.09 g, 8%) was obtained.
Melting point: Amorphous solid
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.51-3.75 (m, 8H), 4.86 (s, 2H), 7.22 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 2.4, 8.1 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H).

Example 84 (3)
2-Phenoxy-N- (4-((5- (4-morpholinylcarbonyl) -pyridin-2-yl) methoxy) phenyl) -5-pyrimidinecarboxamide (84)

According to Example 73, by using (6- (bromomethyl) pyridin-3-yl) (morpholino) methanone instead of isobutyl bromide, 2-phenoxy-N- (4-((5- (4-mol Folinylcarbonyl) -pyridin-2-yl) methoxy) phenyl) -5-pyrimidinecarboxamide (61%) was obtained as a brown solid.
Melting point: 148-157 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.35-3.60 (m, 8H), 5.16 (s, 2H), 7.03 (d, J = 9.0 Hz, 2H), 7.20-7.51 (m, 6H ), 7.63-7.70 (m, 3H), 8.56 (d, J = 2.2 Hz, 1H), 9.08 (s, 2H), 10.32 (s, 1H).

Example 85
2-Phenoxy-N- (4- (tert-butoxycarbonylmethyloxy) phenyl) -5-pyrimidinecarboxamide (85)

According to Example 73, 2-phenoxy-N- (4 (tert-butoxycarbonylmethyloxy) phenyl) -5-pyrimidinecarboxamide (70%) was obtained by using bromoacetic acid tert-butyl ester instead of isobutyl bromide. Was obtained as a light brown solid.
Melting point: 154-157 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.08 (s, 9H), 4.51 (s, 2H), 6.95 (d, J = 9.2 Hz, 2H), 7.22-7.50 (m, 5H), 7.61 (d, J = 9.2 Hz, 2H), 9.08 (s, 2H), 10.30 (s, 1H).

Example 86
2- (4- (2-Phenoxypyrimidine-5-carboxamide) phenoxy) acetic acid (86)

2-Phenoxy-N- (4 (tert-butoxycarbonylmethyloxy) phenyl) -5-pyrimidinecarboxamide (0.3 g, 0.71 mmol) obtained in Example 85 was dissolved in tetrahydrofuran (5 ml), and trifluoroacetic acid was dissolved. (1 ml) was added and stirred at room temperature for 3 hours. After concentration under reduced pressure, water was added and neutralized with an aqueous potassium carbonate solution. The precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2- (4- (2-phenoxypyrimidine-5-carboxamido) phenoxy) acetic acid (0.26 g, 92%) in white Obtained as a solid.
Melting point: 221-228 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.43 (s, 2H), 6.96 (d, J = 9.2 Hz, 2H), 7.22-7.50 (m, 5H), 7.63 (d, J = 9.2 Hz, 2H), 9.06 (s, 2H), 10.35 (s, 1H), 11.94 (br, 1H).

Example 87
2-Phenoxy-N- (4- (2-morpholino-2-oxoethoxy) phenyl) -5-pyrimidinecarboxamide (87)

2- (4- (2-phenoxypyrimidine-5-carboxamido) phenoxy) acetic acid (0.25 g, 0.68 mmol) obtained in Example 86 was dissolved in N, N-dimethylformamide (3 ml), and 1-hydroxy Add benzotriazole monohydrate (0.13 g, 0.82 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.16 g, 0.82 mmol), morpholine (0.06 g, 0.69 mmol), 60 Stir at 16 ° C. for 16 hours. After concentration under reduced pressure, the obtained residue was purified by medium pressure silica gel flash column chromatography (chloroform: methanol = 50: 1-20: 1) to give 2-phenoxy-N- (4- (2 -Morpholino-2-oxoethoxy) phenyl) -5-pyrimidinecarboxamide (0.20 g, 68%) was obtained as a pale yellow solid.
Melting point: 201-203 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.35-3.60 (m, 8H), 4.81 (s, 2H), 6.94 (d, J = 9.2 Hz, 2H), 7.20-7.51 (m, 5H ), 7.61 (d, J = 9.2 Hz, 2H), 9.09 (s, 2H), 10.31 (s, 1H).

Example 88
2-Phenoxy-N- (4- (2- (morpholin-4-yl) -ethylthio) phenyl) -5-pyrimidinecarboxamide (88)
Example 88 (1)
N- (2- (4-Nitrophenylthio) ethyl) morpholine (88 raw materials)

4-Nitrothiophenol (1.55 g, 10 mmol), N- (2-chloroethyl) morpholine hydrochloride (1.86 g, 10 mmol) was dissolved in N, N-dimethylformamide (20 ml) and potassium carbonate (4.15 g , 30 mmol) and stirred at room temperature for 15 hours. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel flash column chromatography (chloroform: methanol = 50: 0 to 50: 1) to give N- (2- (4-nitrophenylthio) ethyl) morpholine (0.58 g, 22%) as a yellow solid.
Melting point: Amorphous solid
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.50-2.54 (m, 4H), 2.70 (t, J = 5.7 Hz, 2H), 3.17 (t, J = 5.7 Hz, 2H), 3.71-3.75 ( m, 4H), 7.35 (d, J = 9.2 Hz, 2H), 8.13 (d, J = 9.2 Hz, 2H).

Example 88 (2)
2-Phenoxy-N- (4- (2- (morpholin-4-yl) -ethylthio) phenyl) -5-pyrimidinecarboxamide (88)

N- (2- (4-nitrophenylthio) ethyl) morpholine (0.57 g, 2.1 mmol) obtained in Example 88 (1) was dissolved in methanol (10 ml), and 5% palladium-carbon (0.12 g ) Was added and stirred at room temperature under a hydrogen gas atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude amine compound. 2-Phenoxypyrimidine-5-carboxylic acid (0.45 g, 2.1 mmol) was dissolved in pyridine (10 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g, 2.3 mmol) was added and stirred at room temperature for 16 hours. After concentration under reduced pressure, the obtained residue was purified by medium pressure silica gel flash column chromatography (chloroform: methanol = 100: 1 to 20: 1) to give 2-phenoxy-N- (4- (2 -(Morpholin-4-yl) -ethylthio) phenyl) -5-pyrimidinecarboxamide (0.09 g, 9%) was obtained as a yellow solid.
Melting point: Amorphous solid
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.45-2.50 (m, 4H), 2.64 (t, J = 5.7 Hz, 2H), 3.13 (t, J = 5.7 Hz, 2H), 3.65-3.71 ( m, 4H), 7.21-7.65 (m, 9H), 8.04 (brs, 1H), 9.03 (s, 2H).

Example 89
2-Phenoxy-N- (3-tert-butoxycarbonylphenyl) -5-pyrimidinecarboxamide (89)

According to Example 3, by using 3-aminobenzoic acid tert-butyl ester instead of 4-aminobenzoic acid tert-butyl ester, 2-phenoxy-N- (3-tert-butoxycarbonylphenyl) -5- Pyrimidinecarboxamide (84%) was obtained as a milky white solid.
Melting point: 83-87 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.59 (s, 9H), 7.17-7.38 (m, 3H), 7.41-7.53 (m, 3H), 7.76-7.87 (m, 1H), 7.90-8.08 (m, 3H), 9.06 (s, 2H).

Example 90
3- (2-Phenoxypyrimidine-5-carboxamide) -benzoic acid (90)

According to Example 4, 2-phenoxy-N- (3-tert-butoxycarbonylphenyl) -5-pyrimidinecarboxamide was used instead of 2-phenoxy-N- (4-tert-butoxycarbonylphenyl) -5-pyrimidinecarboxamide. By use, 3- (2-phenoxypyrimidine-5-carboxamide) -benzoic acid (94%) was obtained as a milky white solid.
Melting point: 264-267 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 7.15-7.53 (m, 6H), 7.74-7.88 (m, 1H), 8.13-8.39 (m, 2H), 9.22 (s, 2H), 10.27 (brs , 1H).

Example 91
2-Phenoxy-N- (3- (morpholin-4-yl-carbonyl) -phenyl) -5-pyrimidinecarboxamide (91)

3- (2-Phenoxypyrimidine-5-carboxamide) -benzoic acid (168 mg, 0.5 mmol) obtained in Example 90 was dissolved in N, N-dimethylformamide (2.0 ml) to give 1-hydroxybenzotriazole 1 Add hydrate (84 mg, 0.55 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (115 mg, 0.6 mmol), morpholine (66 μl, 0.75 mmol) and add 16 at room temperature. Stir for hours. After concentration under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (3- (morpholine -4-yl-carbonyl) -phenyl) -5-pyrimidinecarboxamide (200 mg, 99%) was obtained as a milky white solid.
Melting point: 242-243 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.32-3.94 (m, 8H), 6.99-7.12 (m, 1H), 7.16-7.53 (m, 7H), 7.78-7.86 (m, 1H), 9.09 (s, 2H), 9.25 (brs. 1H).

Example 92
2-Phenoxy-N- (3- (4-pyridylmethylcarbamoyl) -phenyl) -5-pyrimidinecarboxamide (92)

According to Example 91, 2-phenoxy-N- (3- (4-pyridylmethylcarbamoyl) -phenyl) -5-pyrimidinecarboxamide (97%) was milky white by using 4-pyridylmethylamine instead of morpholine. Obtained as a solid.
Melting point: 225-227 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 4.61 (d, J = 5.9 Hz, 2H), 7.17-7.34 (m, 5H), 7.49-7.52 (m, 3H), 7.69 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 8.24 (s, 1H), 8.47-8.70 (m, 3H), 9.21 (s, 2H), 10.42 (s, 1H).

Example 93
2-Phenoxy-N- (4-tert-butoxycarbonylmethoxy-3- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (93)
Example 93 (1)
2-Formyl-4-nitrophenoxyacetic acid tert-butyl ester (93 raw materials)

2-Hydroxy-5-nitrobenzaldehyde (2.34 g, 20 mmol) is dissolved in acetonitrile (50 ml), potassium carbonate (4.15 g, 30 mmol), bromoacetic acid tert-butyl ester (3.2 ml, 22 mmol), 18-Crown-6-ether (158 mg, 0.6 mmol) was added, and the mixture was stirred at 80 ° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue obtained by adding diethyl ether and diisopropyl ether to the residue was collected by filtration to give 2-formyl-4-nitrophenoxyacetic acid tert -Butyl ester (4.17 g, 74%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.50 (s, 9H), 4.78 (s, 2H), 6.96 (d, J = 8.9 Hz, 1H), 8.42 (dd, J = 8.9, 2.9 Hz, 1H), 8.74 (d, J = 2.9 Hz, 1H), 10.54 (s, 1H).

Example 93 (2)
4-Nitro-2- (pyrrolidin-1-yl) methylphenoxyacetic acid tert-butyl ester (93 raw materials)

2-Formyl-4-nitrophenoxyacetic acid tert-butyl ester (1.41 g, 5.0 mmol) obtained in Example 93 (1) was dissolved in methanol (10 ml) and tetrahydrofuran (5 ml), and pyrrolidine (0.50 ml , 6.0 mmol) and sodium cyanoborohydride (314 mg, 5.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by concentration under reduced pressure was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 50 to 1:20) to give 4-nitro-2. -(Pyrrolidin-1-yl) methylphenoxyacetic acid tert-butyl ester (940 mg, 56%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.48 (s, 9H), 1.73-1.98 (m, 4H), 2.53-2.72 (m, 4H), 3.77 (s, 2H), 4.64 (s, 2H ), 6.75 (d, J = 8.9 Hz, 1H), 8.11 (dd, J = 8.9, 2.6 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H).

Example 93 (3)
2-Phenoxy-N- (4-tert-butoxycarbonylmethoxy-3- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (93)

In accordance with Example 12 (2), by using 4-nitro-2- (pyrrolidin-1-yl) methylphenoxyacetic acid tert-butyl ester instead of 4-nitrophenylacetic acid tert-butyl ester, 2-phenoxy- N- (4-tert-butoxycarbonylmethoxy-3- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (82%) was obtained as a yellow solid.
Melting point: 64-67 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.48 (s, 9H), 1.75-1.87 (m, 4H), 2.55-2.69 (m, 4H), 3.74 (s, 2H), 4.54 (s, 2H ), 6.73 (d, J = 8.9 Hz, 1H), 7.18-7.53 (m, 6H), 7.57-7.74 (m, 2H), 9.01 (s, 2H).

Example 94
2-Phenoxy-N- (4-carboxymethoxy-3- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide trifluoroacetate (94)

2-Phenoxy-N- (4-tert-butoxycarbonylmethoxy-3- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (50 mg, 0.10 mmol) obtained in Example 93 (3) Dissolved in fluoroacetic acid (1 ml) and stirred at room temperature for 20 hours. The reaction solution was diluted with diethyl ether, and the precipitated solid was collected by filtration to give 2-phenoxy-N- (4-carboxymethoxy-3- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide trifluoro Acetic acid salt (44 mg, 78%) was obtained as a light brown solid.
Melting point: 81-85 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.90-2.17 (m, 4H), 2.89-3.13 (m, 2H), 3.37-3.62 (m, 2H), 4.22 (s, 2H), 4.75 (s , 2H), 6.85 (d, J = 9.3 Hz, 1H), 7.12-7.50 (m, 5H), 7.68-7.90 (m, 2H), 9.13 (s, 2H), 9.80 (s, 1H), 10.64 ( s, 1H).

Example 95
2-Phenoxy-N- (3-chloro-4- (1-pyrrolidinylcarbonyl) -phenyl-1-yl) -5-pyrimidinecarboxamide (95)
Example 95 (1)
(4-Amino-2-chlorophenyl) -1-carbonylpyrrolidine (95 raw materials)

4-Amino-2-chlorobenzoic acid (5.15 g, 30 mmol) was suspended in acetonitrile (50 ml) and N, N-dimethylformamide (30 ml), and 1-hydroxybenzotriazole monohydrate (4.82 g, 31.5 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.33 g, 33 mmol) and pyrrolidine (3.8 ml, 45 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, diethyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated solid was collected by filtration to give (4-amino-2-chlorophenyl) -1-carbonylpyrrolidine ( 4.52 g, 67%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.80-2.03 (m, 4H), 3.18-3.32 (m, 2H), 3.55-3.94 (m, 4H), 6.56 (dd, J = 8.3, 2, 3 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H).

Example 95 (2)
2-Phenoxy-N- (3-chloro-4- (1-pyrrolidinylcarbonyl) -phenyl-1-yl) -5-pyrimidinecarboxamide (95)

According to Example 3, by using (4-amino-2-chlorophenyl) -1-carbonylpyrrolidine instead of 4-aminobenzoic acid tert-butyl ester, 2-phenoxy-N- (3-chloro-4- (1-Pyrrolidinylcarbonyl) -phenyl-1-yl) -5-pyrimidinecarboxamide (61%) was obtained as a milky white solid.
Melting point: 201-202 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.83-2.06 (m, 4H), 3.13-3.32 (m, 2H), 3.58-3.77 (m, 2H), 7.02 (d, J = 8.3 Hz, 1H ), 7.18-7.54 (m, 7H), 9.26 (s, 2H), 10.01 (s, 1H).

Example 96
2-Phenoxy-N- (3-difluoromethoxy-4- (1-pyrrolidinylcarbonyl) phenyl-1-yl) -5-pyrimidinecarboxamide (96)
Example 96 (1)
(2-Hydroxy-4-nitrophenyl) -1-carbonylpyrrolidine (96 raw materials)

According to Example 95 (1), by using 2-hydroxy-4-nitrobenzoic acid instead of 4-amino-2-chlorobenzoic acid, (2-hydroxy-4-nitrophenyl) -1-carbonylpyrrolidine (16%) was obtained as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.72-1.94 (m, 4H), 3.10-3.23 (m, 2H), 3.38-3.55 (m, 2H), 7.43 (d, J = 8.9 Hz , 1H), 7.65-7.77 (m, 2H), 10.89 (s, 1H).

Example 96 (2)
(2-Difluoromethoxy-4-nitrophenyl) -1-carbonylpyrrolidine (96 raw materials)

(2-Hydroxy-4-nitrophenyl) -1-carbonylpyrrolidine (354 mg, 1.5 mmol) obtained in Example 96 (1) was suspended in dioxane (5 ml), and 50% aqueous sodium hydroxide solution (1.0 ml) and benzyltriethylammonium chloride (17 mg, 0.08 mmol) were added, and the mixture was stirred at room temperature for 6 hours in a chlorodifluoromethane gas atmosphere. The reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, and the precipitated solid was collected by filtration to give (2-difluoromethoxy-4-nitrophenyl) -1-carbonyl. Pyrrolidine (336 mg, 78%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.87-2.08 (m, 4H), 3.16-3.28 (m, 2H), 3.50-3.74 (m, 2H), 6.46 (t, J = 72.9 Hz, 1H ), 7.56 (d, J = 8.3 Hz, 1H), 8.07-8.21 (m, 2H).

Example 96 (3)
2-Phenoxy-N- (3-difluoromethoxy-4- (1-pyrrolidinylcarbonyl) phenyl-1-yl) -5-pyrimidinecarboxamide (96)

According to Example 12 (2), 2-phenoxy-N- (3 was obtained by using (2-difluoromethoxy-4-nitrophenyl) -1-carbonylpyrrolidine instead of 4-nitrophenylacetic acid tert-butyl ester. -Difluoromethoxy-4- (1-pyrrolidinylcarbonyl) phenyl-1-yl) -5-pyrimidinecarboxamide (41%) was obtained as a milky white solid.
Melting point: 219-222 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.77-2.05 (m, 4H), 3.17-3.32 (m, 2H), 3.54-3.73 (m, 2H), 6.44 (t, J = 73.2 Hz, 1H ), 6.99-7.57 (m, 8H), 9.21 (s, 2H), 10.03 (s, 1H).

Example 97
2-Phenoxy-N- (2- (2- (morpholin-4-yl) -ethoxy) -4- (1-pyrrolidinylcarbonyl) phenyl-1-yl) -5-pyrimidinecarboxamide hydrochloride (97)
Example 97 (1)
(2- (2- (morpholin-4-yl) -ethoxy) -4-nitrophenyl) -1-carbonylpyrrolidine (97 raw materials)

(2-Hydroxy-4-nitrophenyl) -1-carbonylpyrrolidine (354 mg, 1.5 mmol) obtained in Example 96 (1) was dissolved in N, N-dimethylformamide (4 ml), and potassium carbonate ( 622 mg, 4.5 mmol) and 2-chloroethylmorpholine hydrochloride (419 mg, 2.25 mmol) were added, and the mixture was stirred at 70 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure to give (2- (2- (morpholin-4-yl) -ethoxy) -4-nitrophenyl) -1-carbonylpyrrolidine (514 mg, 98%) Was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.84-2.02 (m, 4H), 2.50-2.64 (m, 4H), 2.75-2.87 (m, 2H), 3.12-3.34 (br, 2H), 3.15 -3.30 (m, 6H), 4.18-4.31 (m, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.80 (J = 2.0 Hz, 1H), 7.89 (dd, J = 8.3, 2.0 Hz, 1H).

Example 97 (2)
2-Phenoxy-N- (2- (2- (morpholin-4-yl) -ethoxy) -4- (1-pyrrolidinylcarbonyl) phenyl-1-yl) -5-pyrimidinecarboxamide hydrochloride (97)

According to Example 12 (2), (2- (2- (morpholin-4-yl) -ethoxy) -4-nitrophenyl) -1-carbonylpyrrolidine is used instead of 4-nitrophenylacetic acid tert-butyl ester 2-phenoxy-N- (2- (2- (morpholin-4-yl) -ethoxy) -4- (1-pyrrolidinylcarbonyl) phenyl-1-yl) -5-pyrimidinecarboxamide was obtained. After dissolving in ethyl acetate (10 ml), 4N hydrochloric acid-ethyl acetate solution (2 ml) was added and stirred at room temperature for 1 hour. Diethyl ether was added, and the precipitated solid was collected by filtration to give 2-phenoxy-N- (2- (2- (morpholin-4-yl) -ethoxy) -4- (1-pyrrolidinylcarbonyl as a pale yellow solid). ) Phenyl-1-yl) -5-pyrimidinecarboxamide hydrochloride (336 mg, 61%) was obtained as a pale yellow solid.
Melting point: 145-150 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.72-1.93 (m, 4H), 3.07-4.67 (m, 16H), 7.20-7.34 (m, 4H), 7.41-7.55 (m, 3H) , 7.70 (d, J = 1.7 Hz, 1H), 9.18 (s, 2H), 10.84 (s, 1H), 11.57 (s, 1H).

Example 98
2-phenoxy-N- (2- (pyrrolidin-1-yl) pyrimidin-5-yl) pyrimidine-5-carboxamide (98)
Example 98 (1)
5-Nitro-2- (pyrrolidin-1-yl) pyrimidine (98 ingredients)

2-Chloro-5-nitropyrimidine (0.8 g, 5.0 mmol) known in the literature (Heterocycles, 1984, Vol. 22, p. 79) is dissolved in N, N-dimethylformamide (5 ml) and pyrrolidine (0.54 g , 7.5 mmol) and potassium carbonate (1.38 g, 10 mmol) were added, and the mixture was stirred at 130 ° C. for 16 hours. After standing to cool, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by medium pressure silica gel flash column chromatography (chloroform: methanol = 50: 1 to 10: 1) to give 5-nitro-2- (pyrrolidin-1-yl) pyrimidine (0.51 g , 53%).
Melting point: Amorphous solid
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.90-1.95 (m, 4H), 3.40-3.45 (m, 4H), 9.59 (s, 2H).

Example 98 (2)
2-phenoxy-N- (2- (pyrrolidin-1-yl) pyrimidin-5-yl) pyrimidine-5-carboxamide (98)

5-Nitro-2- (pyrrolidin-1-yl) pyrimidine (0.29 g, 1.5 mmol) is dissolved in methanol (5 ml), 10% palladium-carbon (0.06 g) is added, and the mixture is brought to room temperature under a hydrogen gas atmosphere. And stirred. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude amine compound. The obtained crude amine compound and 2-phenoxypyrimidine-5-carboxylic acid (0.32 g, 1.5 mmol) were dissolved in pyridine (5 ml), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was dissolved. (0.32 g, 1.7 mmol) was added, and the mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, water and aqueous potassium carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (2- (pyrrolidine-1 -Yl) pyrimidin-5-yl) pyrimidine-5-carboxamide (0.15 g, 28%) was obtained as a brown solid.
Melting point: 186-191 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.90-1.95 (m, 4H), 3.40-3.45 (m, 4H), 7.22-7.45 (m, 5H), 8.58 (s, 2H), 9.09 (s, 2H), 10.31 (s, 1H).

Example 99
2-Phenoxy-N- (6- (3-methoxypropylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (99)
Example 99 (1)
2- (3-Methoxypropylamino) -5-nitropyridine (99 raw materials)

2-Chloro-5-nitropyridine (7.93 g, 50 mmol) is dissolved in N, N-dimethylacetamide (100 ml), potassium carbonate (10.4 g, 75 mmol), 3-methoxypropylamine (6.1 ml, 60 mmol). mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, water was added, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, diisopropyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated solid was collected by filtration to give 2- (3-methoxypropylamino) -5-nitropyridine ( 7.96 g, 75%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.87-2.01 (m, 2H), 3.37 (s, 3H), 3.46-3.62 (m, 4H), 5.90 (brs, 1H), 6.35 (d, J = 9.6 Hz, 1H), 8.17 (dd, J = 9.6, 2.6 Hz, 1H), 9.01 (d, J = 2.6 Hz, 1H).

Example 99 (2)
5-Amino-2- (3-methoxypropylamino) pyridine (99 raw materials)

2- (3-methoxypropylamino) -5-nitropyridine (2.11 g, 10 mmol) obtained in Example 99 (1) was dissolved in ethyl acetate (50 ml) and 10% palladium-carbon (500 mg ) Was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen gas atmosphere. The insoluble material was filtered off using celite, and the filtrate was concentrated under reduced pressure to give 5-amino-2- (3-methoxypropylamino) pyridine (1.79 g, 99%) as a red-brown oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.82-1.93 (m, 2H), 3.02-3.40 (m, 7H), 3.50 (t, J = 6.1 Hz, 2H), 4.35 (brs, 1H), 6.32 (d, J = 8.6 Hz, 1H), 6.96 (dd, J = 8.6, 2.7 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H).

Example 99 (3)
2-Phenoxy-N- (6- (3-methoxypropylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (99)

According to Example 1 (2), 2-phenoxy-N- (6- (3-methoxypropyl) was obtained by using 5-amino-2- (3-methoxypropylamino) pyridine instead of 4-aminobenzenemethanol. Amino) -pyridin-3-yl) -5-pyrimidinecarboxamide (56%) was obtained as a milky white solid.
Melting point: 141-142 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.83-1.95 (m, 2H), 3.30-3.45 (m, 5H), 3.50 (t, J = 5.9 Hz, 2H), 4.89 (t, J = 5.3 Hz, 1H), 6.40 (d, J = 8.9 Hz, 1H), 7.17-7.35 (m, 3H), 7.42-7.53 (m, 2H), 7.78 (dd, J = 8.9, 2.3 Hz, 1H), 7.93 (brs, 1H), 8.10 (d, J = 2.3 Hz, 1H), 9.02 (s, 2H).

Example 100
2-Phenoxy-N- (6- (2-dimethylaminoethyl-N-methylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (100)
Example 100 (1)
2- (2-Dimethylaminoethyl-N-methylamino) -5-nitropyridine (100 raw materials)

According to Example 99 (1), 2- (2-dimethylaminoethyl-N-methylamino) -5-nitropyridine was obtained by using N, N, N′-trimethylethylenediamine instead of 3-methoxypropylamine. (73%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.29 (s, 6H), 2.52 (t, J = 6.9 Hz, 2H), 3.19 (s, 3H), 3.79 (t, J = 6.9 Hz, 2H) 6.46 (d, J = 9.4 Hz, 1H), 8.19 (dd, J = 9.4, 2.6 Hz, 1H), 9.05 (d, J = 2.6 Hz, 1H).

Example 100 (2)
2-Phenoxy-N- (6- (2-dimethylaminoethyl-N-methylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (100)

According to Example 12 (2), 2-phenoxy-N was obtained by using 2- (2-dimethylaminoethyl-N-methylamino) -5-nitropyridine instead of 4-nitrophenylacetic acid tert-butyl ester. -(6- (2-Dimethylaminoethyl-N-methylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (50%) was obtained as a red purple solid.
Melting point: 131-132 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.27 (s, 6H), 2.48 (t, J = 7.3 Hz, 2H), 3.05 (s, 3H), 3.65 (t, J = 7.3 Hz, 2H) , 6.49 (d, J = 9.3 Hz, 1H), 7.15-7.37 (m, 3H), 7.40-7.53 (m, 2H), 7.79 (dd, J = 9.0, 2.4 Hz, 1H), 8.01 (s, 1H ), 8.16 (d, J = 2.4 Hz, 1H), 9.02 (s, 2H).

Example 101
2-Phenoxy-N- (6- (2- (morpholin-4-yl) -ethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (101)
Example 101 (1)
2- (2- (morpholin-4-yl) -ethylamino) -5-nitropyridine (101 raw materials)

According to Example 99 (1), 2- (2- (morpholin-4-yl) -ethylamino) -5-nitropyridine (quant.) Was obtained by using 2-morpholinoethylamine instead of 3-methoxypropylamine. ) Was obtained as a reddish brown oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.43-2.70 (m, 6H), 3.40-3.57 (m, 2H), 3.71-3.80 (m, 4H), 5.97 (brs, 1H), 6.39 (d , J = 9.0 Hz, 1H), 8.18 (dd, J = 9.0, 2.7 Hz, 1H), 9.02 (d, J = 2.7 Hz, 1H).

Example 101 (2)
2-Phenoxy-N- (6- (2- (morpholin-4-yl) -ethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (101)

According to Example 12 (2), 2- (2- (morpholin-4-yl) -ethylamino) -5-nitropyridine was used instead of 4-nitrophenylacetic acid tert-butyl ester to give 2-phenoxy -N- (6- (2- (morpholin-4-yl) -ethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (70%) was obtained as an off-white solid.
Melting point: 179-182 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.38-2.67 (m, 6H), 3.31-3.42 (m, 2H), 3.65-3.80 (m, 4H), 5.14 (t, J = 4.6 Hz, 1H ), 6.44 (d, J = 8.9 Hz, 1H), 7.17-7.35 (m, 3H), 7.40-7.53 (m, 2H), 7.64 (s, 1H), 7.72-7.86 (m, 1H), 8.05- 8.18 (m, 1H), 9.02 (s, 2H).

Example 102
2-phenoxy-N- (6- (3- (2-oxopyrrolidin-1-yl) -propylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (102)
Example 102 (1)
2- (3- (2-oxopyrrolidin-1-yl) -propylamino) -5-nitropyridine (102 raw materials)

According to Example 99 (1), 2- (3- (2-oxopyrrolidin-1-yl) -propylamino) -5-nitro was obtained by using 3-aminopropylpyrrolidone instead of 3-methoxypropylamine. Pyridine (84%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.75-1.85 (m, 2H), 2.02-2.13 (m, 2H), 2.45 (t, J = 8.1 Hz, 2H), 3.37-3.54 (m, 6H ), 6.41 (d, J = 9.3 Hz, 1H), 6.64 (brs, 1H), 8.10 (dd, J = 9.3, 2.7 Hz, 1H), 9.00 (d, J = 2.7 Hz, 1H).

Example 102 (1)
2-phenoxy-N- (6- (3- (2-oxopyrrolidin-1-yl) -propylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (102)

According to Example 12 (2), by using 2- (3- (2-oxopyrrolidin-1-yl) -propylamino) -5-nitropyridine instead of 4-nitrophenylacetic acid tert-butyl ester, 2-phenoxy-N- (6- (3- (2-oxopyrrolidin-1-yl) -propylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (70%) was obtained as a pale yellow solid.
Melting point: 189-192 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.75-1.85 (m, 2H), 2.02-2.13 (m, 2H), 2.45 (t, J = 8.1 Hz, 2H), 3.37-3.54 (m, 6H ), 4.89 (br, 1H), 6.42 (d, J = 8.9 Hz, 1H), 7.18-7.50 (m, 5H), 7.71 (s, 1H), 7.79 (d, J = 9.2 Hz, 1H), 8.12 (brs, 1H), 9.02 (s, 2H).

Example 103
2-Phenoxy-N- (6- (2- (pyridin-2-yl) -ethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (103)
Example 103 (1)
2- (2- (Pyridin-2-yl) -ethylamino) -5-nitropyridine (103 raw materials)

According to Example 99 (1), 2- (2- (pyridin-2-yl) -ethylamino) -5-nitropyridine (90) was obtained by using pyridine-2-ethylamine instead of 3-methoxypropylamine. %) As a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.12 (t, J = 6.2 Hz, 2H), 3.77-3.98 (br, 2H), 6.37 (d, J = 9.3 Hz, 1H), 6.30-6.50 ( br, 1H), 7.13-7.22 (m, 2H), 7.59-7.67 (m, 1H), 8.06-8.20 (br, 1H), 8.51-8.63 (m, 1H), 9.01 (d, J = 2.4 Hz, 1H).

Example 103 (2)
2-Phenoxy-N- (6- (2- (pyridin-2-yl) -ethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (103)

According to Example 12 (2), 2- (2- (pyridin-2-yl) -ethylamino) -5-nitropyridine was used instead of 4-nitrophenylacetic acid tert-butyl ester to give 2-phenoxy -N- (6- (2- (Pyridin-2-yl) -ethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (70%) was obtained as a pale yellow solid.
Melting point: 150-152 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.12 (t, J = 6.2 Hz, 2H), 3.77-3.98 (br, 2H), 4.49 (s, 1H), 6.37 (d, J = 9.3 Hz, 1H), 6.30-6.50 (br, 1H), 7.15-7.35 (m, 6H), 7.40-7.50 (m, 2H), 7.79 (d, J = 9.2 Hz, 1H), 8.12 (s, 1H), 8.51 -8.63 (m, 1H), 9.02 (s, 2H).

Example 104
2-Phenoxy-N- (6- (3- (imidazol-1-yl) -propylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (104)
Example 104 (1)
2- (3- (imidazol-1-yl) -propylamino) -5-nitropyridine (104 raw materials)

According to Example 99 (1), 2- (3- (imidazol-1-yl) -propylamino) was obtained by using 3- (imidazol-1-yl) -propylamine instead of 3-methoxypropylamine. -5-Nitropyridine (89%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.11-2.23 (m, 2H), 3.40-3.55 (m, 2H), 4.09 (t, J = 6.8 Hz, 2H), 5.97 (brs, 1H), 6.37 (d, J = 9.3 Hz, 1H), 6.96 (d, J = 1.1 Hz, 1H), 7.09 (d, J = 1.1 Hz, 1H), 7.48 (s, 1H), 8.15 (dd, J = 9.3 , 2.7 Hz, 1H), 9.02 (d, J = 2.7 Hz, 1H).

Example 104 (2)
2-Phenoxy-N- (6- (3- (imidazol-1-yl) -propylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (104)

According to Example 12 (2), 2- (3- (imidazol-1-yl) -propylamino) -5-nitropyridine was used instead of 4-nitrophenylacetic acid tert-butyl ester to give 2-phenoxy -N- (6- (3- (3- (imidazol-1-yl) -propylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (70%) was obtained as a pale yellow solid.
Melting point: 215-219 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.05-2.15 (m, 2H), 3.31-3.40 (m, 2H), 4.05-4.15 (m, 2H), 4.45-4.65 (br, 1H), 6.38 (d, J = 8.6 Hz, 1H), 6.95 (s, 1H), 7.07 (s, 1H), 7.20-7.50 (m, 6H), 7.64-7.86 (m, 2H), 8.16 (s, 1H), 9.04 (s, 2H).

Example 105
2-Phenoxy-N- (6- (2-ethoxycarbonylethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (105)
Example 105 (1)
2- (2-Ethoxycarbonylethylamino) -5-nitropyridine (105 raw materials)

According to Example 99 (1), 2- (2-ethoxycarbonylethylamino) -5-nitropyridine (91%) was diluted lightly by using β-alanine ethyl ester hydrochloride instead of 3-methoxypropylamine. Obtained as a yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.27 (t, J = 7.3 Hz, 3H), 2.66 (t, J = 6.2 Hz, 2H), 3.71-3.84 (m, 2H), 4.18 (q, J = 7.3 Hz, 2H), 5.79 (brs, 1H), 6.38 (d, J = 9.2 Hz, 1H), 8.16 (dd, J = 9.2, 2.6 Hz, 1H), 9.02 (d, J = 2.6 Hz, 1H).

Example 105 (2)
2-Phenoxy-N- (6- (2-ethoxycarbonylethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (105)

According to Example 12 (2), 2-phenoxy-N- (6- (6- (2-ethoxycarbonylethylamino) -5-nitropyridine) was used instead of 4-nitrophenylacetic acid tert-butyl ester. (2-Ethoxycarbonylethylamino) -pyridin-3-yl) -5-pyrimidinecarboxamide (62%) was obtained as a red purple solid.
Melting point: 169-170 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.26 (t, J = 7.3 Hz, 3H), 2.63 (t, J = 6.3 Hz, 2H), 3.63 (dt, J = 6.3, 6.3 Hz, 2H) , 4.16 (q, J = 7.3 Hz, 2H), 4.92 (t, J = 6.3 Hz, 1H), 6.41 (d, J = 8.9 Hz, 1H), 7.17-7.35 (m, 3H), 7.40-7.53 ( m, 2H), 7.70-7.88 (m, 2H), 8.13 (d, J = 2.3 Hz, 1H), 9.02 (s, 2H).

Example 106
2-Phenoxy-N- (6- (2-methoxyethoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (106)
Example 106 (1)
2- (2-Methoxyethoxy) -5-nitropyridine (106 raw materials)

Dissolve 2-methoxyethanol (913 mg, 12 mmol) in N, N-dimethylformamide (15 ml), add 55% sodium hydride (480 mg, 11 mmol) under ice-cooling, and stir at room temperature for 30 minutes did. To the reaction solution was added a solution of 2-chloro-5-nitropyridine (1.59 g, 10 mmol) in N, N-dimethylformamide (5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform = 1: 100) to give 2- (2-methoxy). Ethoxy) -5-nitropyridine (1.22 g, 62%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.44 (s, 3H), 3.72-3.84 (m, 2H), 4.55-4.64 (m, 2H), 6.89 (d, J = 9.3 Hz, 1H), 8.36 (dd, J = 9.3, 2.7 Hz, 1H), 9.06 (d, J = 2.7 Hz, 1H).

Example 106 (2)
2-Phenoxy-N- (6- (2-methoxyethoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (106)

According to Example 12 (2), 2-phenoxy-N- (6- (2) was obtained by using 2- (2-methoxyethoxy) -5-nitropyridine instead of 4-nitrophenylacetic acid tert-butyl ester. -Methoxyethoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (83%) was obtained as a milky white solid.
Melting point: 154-155 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.44 (s, 3H), 3.70-3.80 (m, 2H), 4.38-4.52 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 7.15-7.34 (m, 3H), 7.38-7.52 (m, 2H), 7.80-8.02 (m, 2H) 8.23 (brs, 1H), 9.03 (s, 2H).

Example 107
2-Phenoxy-N- (6- (2- (N-benzyl-N-methylamino) -ethoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (107)
Example 107 (1)
2- (2- (N-Benzyl-N-methylamino) -ethoxy) -5-nitropyridine (107 raw materials)

According to Example 106 (1), 2- (2- (N-benzyl-N-methylamino) -ethoxy) -5 was obtained by using N-benzyl-N-methylaminoethanol instead of 2-methoxyethanol. -Nitropyridine (67%) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.35 (s, 3H), 2.83 (t, J = 5.9 Hz, 2H), 3.61 (s, 2H), 4.56 (t, J = 5.9 Hz, 2H) , 6.82 (d, J = 9.0 Hz, 1H), 7.20-7.40 (m, 5H), 8.34 (dd, J = 9.0, 2.7 Hz, 1H), 9.03 (d, J = 2.7 Hz, 1H).

Example 107 (2)
2-Phenoxy-N- (6- (2- (N-benzyl-N-methylamino) -ethoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (107)

According to Example 12 (2), by using 2- (2- (N-benzyl-N-methylamino) -ethoxy) -5-nitropyridine instead of 4-nitrophenylacetic acid tert-butyl ester, 2 -Phenoxy-N- (6- (2- (N-benzyl-N-methylamino) -ethoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (85%) was obtained as a white solid.
Melting point: 138-139 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.38 (s, 3H), 2.82 (t, J = 5.9 Hz, 2H), 3.61 (s, 2H), 4.44 (t, J = 5.9 Hz, 2H) , 6.79 (d, J = 9.1 Hz, 1H), 7.17-7.57 (m, 10H), 7.82 (brs, 1H), 7.93 (dd, J = 9.1, 2.7 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 9.03 (s, 2H).

Example 108
2-Phenoxy-N- (6- (pyridin-2-yl-methoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (108)
Example 108 (1)
2- (Pyridin-2-yl-methoxy) -5-nitropyridine (108 raw materials)

According to Example 106 (1), 2- (pyridin-2-yl-methoxy) -5-nitropyridine (77%) was converted to a pale yellow solid by using pyridine-2-methanol instead of 2-methoxyethanol. Got as.
¹ H-NMR (CDCl ₃ ): δ (ppm) 5.61 (s, 2H), 6.97 (d, J = 9.0 Hz, 1H), 7.22-7.30 (m, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.68-7.77 (m, 1H), 8.39 (dd, J = 9.0, 2.9 Hz, 1H), 8.58-8.67 (m, 1H), 9.08 (d, J = 2.9 Hz, 1H).

Example 108 (2)
2-Phenoxy-N- (6- (pyridin-2-yl-methoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (108)

According to Example 12 (2), 2-phenoxy-N- (6) was obtained by using 2- (pyridin-2-yl-methoxy) -5-nitropyridine instead of 4-nitrophenylacetic acid tert-butyl ester. -(Pyridin-2-yl-methoxy) -pyridin-3-yl) -5-pyrimidinecarboxamide (62%) was obtained as a flesh-colored solid.
Melting point: 182-183 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 5.49 (s, 2H), 6.88 (d, J = 8.8 Hz, 1H), 7.13-7.34 (m, 4H), 7.37-7.52 (m, 3H), 7.62-7.73 (m, 1H), 7.94-8.07 (m, 1H), 8.15-8.37 (m, 2H), 8.50-8.62 (m, 1H), 9.05 (s, 2H).

Example 109
2-Phenoxy-N- (6-hydroxymethylpyridin-3-yl) -5-pyrimidinecarboxamide (109)
Example 109 (1)
5-Aminopyridine-2-methanol dihydrochloride (109 raw materials)

Literature (J. Med. Chem., 43, 5017 (2000)) A known 5-tert-butoxycarbamoylpyridine-2-methanol (5.61 g, 25 mmol) was mixed with methanol (25 ml) and tetrahydrofuran (50 ml). After dissolution, 4N hydrochloric acid-ethyl acetate solution (50 ml, 200 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hr. Diethyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated solid was collected by filtration to give 5-aminopyridine-2-methanol dihydrochloride (4.90 g, 100%) as a pale yellow solid. Obtained.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.66 (s, 2H), 5.20-6.80 (br, 5H), 7.62 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.6 , 2.6 Hz, 1H), 7.94 (d, J = 2.6 Hz, 1H).

Example 109 (2)
2-Phenoxy-N- (6-hydroxymethylpyridin-3-yl) -5-pyrimidinecarboxamide (109)

According to Example 1 (2), 2-phenoxy-N- (6-hydroxymethylpyridin-3-yl) was obtained by using 5-aminopyridine-2-methanol dihydrochloride instead of 4-aminobenzenemethanol. -5-pyrimidinecarboxamide (41%) was obtained as a pale yellow solid.
Melting point: 186-188 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 4.77 (s, 2H), 7.19-7.52 (m, 6H), 7.90 (brs, 1H), 8.18 (dd, J = 8.6, 2.6 Hz, 1H), 8.66 (d, J = 2.6 Hz, 1H), 9.06 (s, 2H).

Example 110
2-Phenoxy-N- (6-formylpyridin-3-yl) -5-pyrimidinecarboxamide (110)

According to Example 2, 2-phenoxy-N- (6-hydroxymethylpyridin-3-yl) obtained in Example 109 instead of 2-phenoxy-N- (4-hydroxymethylphenyl) -5-pyrimidinecarboxamide ) -5-pyrimidinecarboxamide was used to give 2-phenoxy-N- (6-formylpyridin-3-yl) -5-pyrimidinecarboxamide (83%) as a white solid.
Melting point: 196-198 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 7.17-7.37 (m, 3H), 7.43-7.55 (m, 2H), 8.04 (d, J = 8.6 Hz, 1H), 8.15 (s, 1H), 8.45 (dd, J = 8.6, 2.5 Hz, 1H), 8.90 (d, J = 2.5 Hz, 1H), 9.09 (s, 2H), 10.04 (s, 1H).

Example 111
2- (4-Fluorophenoxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (111)
Example 111 (1)
2- (4-Fluorophenoxy) pyrimidine-5-carboxylic acid

In accordance with Example 1 (1), 2- (4-fluorophenoxy) pyrimidine-5-carboxylic acid (73%) was obtained as an opalescent solid by using 4-fluorophenol instead of phenol.
¹ H-NMR (CDCl ₃ ): δ (ppm) 7.06-7.24 (m, 4H), 9.17 (s, 2H).

Example 111 (2)
2- (4-Fluorophenoxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (111)

According to Example 26 (3), 2- (4-fluorophenoxy) pyrimidine-5-carboxylic acid was used instead of 2-phenoxypyrimidine-5-carboxylic acid to give 2- (4-fluorophenoxy) -N -(4- (Pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (50%) was obtained as a flesh-colored solid.
Melting point: 205-206 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.78-1.97 (m, 4H), 2.57-2.84 (m, 4H), 3.72 (s, 2H), 7.07-7.26 (m, 4H), 7.39 (d , J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 9.17 (s, 2H), 9.78 (brs, 1H).

Example 112
2- (2-Chlorophenoxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (112)
Example 112 (1)
2- (2-Chlorophenoxy) pyrimidine-5-carboxylic acid

According to Example 1 (1), 2- (2-chlorophenoxy) pyrimidine-5-carboxylic acid (67%) was obtained as a white solid by using 2-chlorophenol instead of phenol.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.20-7.50 (m, 4H), 9.06 (s, 2H), 13.36 (br, 1H).

Example 112 (2)
2- (2-Chlorophenoxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (112)

According to Example 26 (3), 2- (2-chlorophenoxy) pyrimidine-5-carboxylic acid was used instead of 2-phenoxypyrimidine-5-carboxylic acid to give 2- (2-chlorophenoxy) -N -(4- (Pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (50%) was obtained as a flesh-colored solid.
Melting point: 78-80 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.67-1.75 (m, 4H), 2.35-2.45 (m, 4H), 3.53 (s, 2H), 7.20-7.50 (m, 6H), 7.66 (d, J = 8.4 Hz, 2H), 9.09 (s, 2H), 10.39 (s, 1H).

Example 113
2- (3-Methylphenoxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (113)
Example 113 (1)
2- (3-Methylphenoxy) pyrimidine-5-carboxylic acid

According to Example 1 (1), 2- (3-methylphenoxy) pyrimidine-5-carboxylic acid (65%) was obtained as an opalescent solid by using 3-methylphenol instead of phenol.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.33 (s, 3H), 7.01-7.37 (m, 4H), 9.04 (s, 2H), 13.56 (br, 1H).

Example 113 (2)
2- (3-Methylphenoxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (113)

According to Example 26 (3), 2- (3-methylphenoxy) pyrimidine-5-carboxylic acid was used in place of 2-phenoxypyrimidine-5-carboxylic acid to give 2- (3-methylphenoxy) -N -(4- (Pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (60%) was obtained as a milky white solid.
Melting point: 147-151 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.67-1.85 (m, 4H), 2.33 (s, 3H), 2.40-2.47 (m, 4H), 3.53 (s, 2H), 7.01-7.37 (m, 6H), 7.66 (d, J = 8.4 Hz, 2H), 9.09 (s, 2H), 10.39 (s, 1H).

Example 114
2- (2-Pyridyloxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (114)
Example 114 (1)
2- (2-Pyridyloxy) pyrimidine-5-carboxylic acid

According to Example 1 (1), 2- (2-pyridyloxy) pyrimidine-5-carboxylic acid (27%) was obtained as a brown solid by using 2-hydroxypyridine instead of phenol.
¹ H-NMR (CDCl ₃ ): δ (ppm) 6.24-6.36 (m, 1H), 6.66 (d, J = 9.6 Hz, 1H), 7.35-7.47 (m, 1H), 7.64-7.78 (m, 1H ), 9.40 (s, 2H).

Example 114 (2)
2- (2-Pyridyloxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (114)

According to Example 26 (3), 2- (2-pyridyloxy) pyrimidine-5-carboxylic acid was used instead of 2-phenoxypyrimidine-5-carboxylic acid to give 2- (2-pyridyloxy) -N -(4- (Pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (26%) was obtained as a pale yellow solid.
Melting point: 201-203 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.73-1.89 (m, 4H), 2.43-2.60 (m, 4H), 3.61 (s, 2H), 6.33-6.42 (m, 1H), 6.66 (d , J = 9.2 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.40-7.53 (m, 1H), 7.67-7.83 (m, 3H), 9.53 (s, 2H), 9.65 (brs, 1H).

Example 115
2- (3-Pyridyloxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (115)
Example 115 (1)
2- (3-Pyridyloxy) pyrimidine-5-carboxylic acid

According to Example 1 (1), 2- (3-pyridyloxy) pyrimidine-5-carboxylic acid (82%) was obtained as a brown solid by using 3-hydroxypyridine instead of phenol.
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.49-7.58 (m, 1H), 7.74-7.83 (m, 1H), 8.50-8.59 (m, 2H), 9.08 (s, 2H), 13.65 (br, 1H).

Example 115 (2)
2- (3-Pyridyloxy) -N- (4- (pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (115)

In accordance with Example 26 (3), 2- (3-pyridyloxy) pyrimidine-5-carboxylic acid was used instead of 2-phenoxypyrimidine-5-carboxylic acid to give 2- (3-pyridyloxy) -N -(4- (Pyrrolidin-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (50%) was obtained as a pale yellow solid.
Melting point: 184-185 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.74-1.87 (m, 4H), 2.42-2.57 (m, 4H), 3.61 (s, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.37-7.46 (m, 1H), 7.49-7.66 (m, 3H), 7.95 (brs, 1H), 8.52-8.60 (m, 2H), 9.04 (s, 2H).

Example 116
2- (3-Pyridyloxy) -N- (4- (2-methylimidazol-1-yl) phenyl) -5-pyrimidinecarboxamide (116)
Example 116 (1)
1- (4-Nitrophenyl-1-yl) -2-methylimidazole (116 raw materials)

According to Example 69 (1), 1- (4-nitrophenyl-1-yl) -2-methylimidazole (65%) was obtained by using 2-methylimidazole instead of 3-hydroxy-5-methylpyrazole. Was obtained as a yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.44 (s, 3H), 7.07 (d, J = 1.5 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.43-7.55 (m, 2H), 8.32-8.47 (m, 2H).

Example 116 (2)
1- (4-Aminophenyl-1-yl) -2-methylimidazole (116 raw materials)

According to Example 69 (2), by using 1- (4-nitrophenyl-1-yl) -2-methylimidazole instead of 3-hydroxy-5-methylpyrazol-1-yl-4-nitrobenzene, 1- (4-Aminophenyl-1-yl) -2-methylimidazole (90%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.31 (s, 3H), 3.83 (br, 2H), 6.69-6.76 (m, 2H), 6.91-7.08 (m, 4H).

Example 116 (3)
2- (3-Pyridyloxy) -N- (4- (2-methylimidazol-1-yl) phenyl) -5-pyrimidinecarboxamide (116)

2- (3-pyridyloxy) -pyrimidine-5-carboxylic acid (217 mg, 1.0 mmol) was suspended in pyridine (8 ml) and 1-hydroxybenzotriazole monohydrate (168 mg, 1.1 mmol), 1 -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (230 mg, 1.2 mmol), 1- (4-aminophenyl-1-yl) -2-methylimidazole (191 mg, 1.1 mmol) were added, The mixture was stirred at 60 ° C. for 18 hours. After concentration under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the precipitated solid was collected by filtration and washed with water and diethyl ether. The obtained solid was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 30 to 1:15) to give 2- (3-pyridyloxy) -N- (4- (2-methyl Imidazole-1-yl) phenyl) -5-pyrimidinecarboxamide (207 mg, 56%) was obtained as a milky white solid.
Melting point: 219-221 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.35 (s, 3H), 6.95-7.07 (m, 2H), 7.28 (d, J = 8.9 Hz, 2H), 7.38-7.51 (m, 1H), 7.55-7.68 (m, 1H), 7.90 (d, J = 8.9 Hz, 2H), 8.49-8.64 (m, 2H), 9.22 (s, 2H), 10.28 (s, 1H).

Example 117
2- (3-Pyridyloxy) -N- (4- (1,2,4-triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (117)
Example 117 (1)
4-Aminobenzyl-1,2,4-triazole (117 raw materials)

According to Example 26 (2), 4-aminobenzyl-1,2,4-triazole (71%) was obtained by using 4-nitrobenzyl-1,2,4-triazole instead of 4-nitrobenzylpyrrolidine. Was obtained as a pale yellow solid.
Melting point: 127-128 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.75 (br, 2H), 5.21 (s, 2H), 6.67 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H) , 7.94 (s, 1H), 7.97 (s, 1H).

Example 117 (2)
2- (3-Pyridyloxy) -N- (4- (1,2,4-triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (117)

According to Example 116 (3), using 4-aminobenzyl-1,2,4-triazole instead of 1- (4-aminophenyl-1-yl) -2-methylimidazole gave 2- (3 -Pyridyloxy) -N- (4- (1,2,4-triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide (66%) was obtained as a pale yellow solid.
Melting point: 212-213 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 5.35 (s, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.39-7.47 (m, 1H), 7.55-7.70 (m, 3H), 7.98 (s, 1H), 8.02-8.12 (br, 1H), 8.07 (s, 1H), 8.52-8.59 (m, 2H), 9.05 (s, 2H).

Example 118
2- (3-Pyridyloxy) -N- (4- (4-hydroxypiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (118)
Example 118 (1)
4-Hydroxypiperidin-1-yl-4-nitrobenzene (118 raw materials)

According to Example 69 (1), 4-hydroxypiperidin-1-yl-4-nitrobenzene (91%) was obtained as a yellow solid by using 4-hydroxypiperidine instead of 3-hydroxy-5-methylpyrazole. It was.
Melting point: 117-118 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.52-1.74 (m, 2H), 1.96-2.14 (m, 2H), 3.14-3.35 (m, 2H), 3.71-4.18 (m, 3H), 6.82 (d, J = 9.6 Hz, 2H), 8.11 (d, J = 9.6 Hz, 2H).

Example 118 (2)
4-Hydroxypiperidin-1-yl-4-aminobenzene (118 raw materials)

According to Example 69 (2) by using 4-hydroxypiperidin-1-yl-4-nitrobenzene instead of 2,3-dihydro-5-methyl-3-oxopyrazol-1-yl-4-nitrobenzene 4-hydroxypiperidin-1-yl-4-aminobenzene (82%) was obtained as a pale yellow solid.
Melting point: 173-177 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.65-1.77 (m, 2H), 1.94-2.11 (m, 2H), 2.71-2.85 (m, 2H), 3.23-3.92 (m, 5H), 6.64 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H).

Example 118 (3)
2- (3-Pyridyloxy) -N- (4- (4-hydroxypiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (118)

According to Example 116 (3), by using 4-hydroxypiperidin-1-yl-4-aminobenzene instead of 1- (4-aminophenyl-1-yl) -2-methylimidazole, 3-Pyridyloxy) -N- (4- (4-hydroxypiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide (83%) was obtained as a pale yellow solid.
Melting point: 203-205 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.38-1.57 (m, 2H), 1.73-1.89 (m, 2H), 2.72-2.90 (m, 2H), 3.39-3.70 (m, 3H) , 4.66 (d, J = 4.0 Hz, 1H), 6.94 (d, J = 9.2 Hz, 2H), 7.46-7.61 (m, 3H), 7.75-7.84 (m, 1H), 8.44-8.62 (m, 2H ), 9.11 (s, 2H), 10.24 (s, 1H).

Example 119
2- (3-Pyridyloxy) -N- (4- (4-hydroxyacetylpiperazin) -1-ylphenyl) -5-pyrimidinecarboxamide (119)
Example 119 (1)
4-Acetoxyacetyl-N- (4-nitrophenyl) piperazine (119 raw materials)

N- (4-Nitrophenyl) piperazine (6.22 g, 30 mmol) was suspended in dichloromethane, and triethylamine (6.3 ml, 45 mmol) and acetoxyacetyl chloride (4.92 g, 36 ml) were added under ice-cooling at room temperature. Stir for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water and diethyl ether to give 4-acetoxyacetyl-N- (4-nitrophenyl) piperazine (8.14 g, 88% ) Was obtained as a yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.20 (s, 3H), 3.35-3.97 (m, 8H), 4.77 (s, 2H), 6.84 (d, J = 9.2 Hz, 2H), 8.16 ( d, J = 9.2 Hz, 2H).

Example 119 (2)
4-Hydroxyacetyl-N- (4-nitrophenyl) piperazine (119 raw materials)

4-acetoxyacetyl-N- (4-nitrophenyl) piperazine (3.07 g, 10 mmol) obtained in Example 119 (1) was suspended in tetrahydrofuran (30 ml) and methanol (15 ml), and cooled with ice. 4N Aqueous sodium hydroxide solution (5 ml, 20 mmol) was added, and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration to give 4-hydroxyacetyl-N- (4-nitrophenyl) piperazine (2.23 g, 84%) as a yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.30-3.97 (m, 8H), 4.23 (s, 2H), 6.85 (d, J = 9.2 Hz, 2H), 8.16 (d, J = 9.2 Hz, 2H).

Example 119 (3)
4-Hydroxyacetyl-N- (4-aminophenyl) piperazine (119 raw materials)

According to Example 39 (3), 4-hydroxyacetyl-N- (4-nitrophenyl) piperazine was used instead of 4-acetoxyacetyl-N- (4-nitrophenethyl) piperazine. N- (4-aminophenyl) piperazine (95%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.88-3.08 (m, 4H), 3.22-3.95 (m, 6H), 4.20 (s, 2H), 6.66 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H).

Example 119 (4)
2- (3-Pyridyloxy) -N- (4- (4-hydroxyacetylpiperazin) -1-ylphenyl) -5-pyrimidinecarboxamide (119)

According to Example 116 (3), by using 4-hydroxyacetyl-N- (4-aminophenyl) piperazine instead of 1- (4-aminophenyl-1-yl) -2-methylimidazole, (3-Pyridyloxy) -N- (4- (4-hydroxyacetylpiperazin) -1-ylphenyl) -5-pyrimidinecarboxamide (47%) was obtained as a pale yellow solid.
Melting point: 195-198 ° C
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.07-3.28 (m, 4H), 3.39-3.90 (m, 5H), 4.22 (d, J = 4.6 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 7.35-7.72 (m, 4H), 8.48-8.63 (m, 2H), 9.18 (s, 2H), 9.81 (brs, 1H).

Example 120
2- (3-Pyridyloxy) -N- (4- (2- (morpholin-4-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (120)
Example 120 (1)
N- (2- (4-Nitrophenoxy) ethyl) morpholine (120 raw materials)

4-Nitrophenol (13.93 g, 0.1 mol) and N- (2-chloroethyl) morpholine hydrochloride (18.77 g, 0.1 mol) were dissolved in N, N-dimethylformamide (250 ml), and potassium carbonate (28.23 g, 0.2 mol) was added and stirred at 80 ° C. for 16 hours. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to give N- (2- (4-nitrophenoxy) ethyl) morpholine (23.16 g, 92%) as a pale yellow solid. Got as.
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.57-2.60 (m, 4H), 2.84 (t, J = 5.7 Hz, 2H), 3.72-3.75 (m, 4H), 4.20 (t, J = 5.7 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 8.20 (d, J = 9.2 Hz, 2H).

Example 120 (2)
2- (3-Pyridyloxy) -N- (4- (2- (morpholin-4-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (120)

  (a) 2- (4-Nitrophenoxy) -ethylmorpholine (580 mg, 2.3 mmol) obtained in Example 120 (1) was dissolved in methanol (5 ml) and 10% palladium-carbon (230 mg) And stirred at room temperature for 2 hours under a hydrogen gas atmosphere. The insoluble material was filtered off using celite, and the filtrate was concentrated under reduced pressure to obtain a crude amine compound.

(b) 2- (3-pyridyloxy) -pyrimidine-5-carboxylic acid (434 mg, 2.0 mmol) was suspended in pyridine (15 ml) and 1-hydroxybenzotriazole monohydrate (337 mg, 2.2 mmol) ), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (460 mg, 2.4 mmol), and a solution of the crude amine compound obtained in the above reaction (a) in pyridine (5 ml). Stir at 15 ° C. for 15 hours. After concentration under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the precipitated solid was collected by filtration and washed with water and diethyl ether. The obtained solid was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 50 to 1:10) to give 2- (3-pyridyloxy) -N- (4- (2- ( Morpholin-4-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide (503 mg, 60%) was obtained as a milky white solid.
Melting point: 171-173 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.49-2.67 (m, 4H), 2.81 (t, J = 5.6 Hz, 2H), 3.68-3.80 (m, 4H), 4.12 (t, J = 5.6 Hz, 2H), 6.86-7.00 (m, 2H), 7.38-7.65 (m, 4H), 7.04 (brs, 1H), 8.50-8.61 (m, 2H), 9.04 (s, 2H).

Example 121
2-Phenoxy-N- (indol-5-yl) -5-pyrimidinecarboxamide (121)

According to Example 1 (2), 2-phenoxy-N- (indol-5-yl) -5-pyrimidinecarboxamide (72%) was obtained by using indole-5-amine instead of 4-aminobenzenemethanol. Obtained as a brown solid.
Melting point: 220-222 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 6.37-6.49 (m, 1H), 7.20-7.57 (m, 8H), 7.97 (s, 1H), 9.13 (s, 2H), 10.29 (s , 1H), 11.08 (s, 1H).

Example 122
2-phenoxy-N- (2- (dimethylaminoethylcarbamoyl) -1H-indol-5-yl) -5-pyrimidinecarboxamide (122)

According to Example 1 (2), 2-phenoxy-N- (2- (2-dimethylaminoethylamino) -5-aminoindole-2-carboxamide was used instead of 4-aminobenzenemethanol. (Dimethylaminoethylcarbamoyl) -1H-indol-5-yl) -5-pyrimidinecarboxamide (74%) was obtained as a red purple solid.
Melting point: 257-260 ° C
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.19 (s, 6H), 2.42 (t, J = 6.6 Hz, 2H), 3.30-3.46 (m, 2H), 7.09 (s, 1H), 7.21-7.55 (m, 7H), 8.07 (s, 1H), 8.37 (t, J = 5.6 Hz, 1H), 9.13 (s, 2H), 10.24 (s, 1H), 11.57 (s, 1H).

Example 123
2-Phenoxy-N- (2- (1-pyrrolidinylcarbonyl) -1H-indol-5-yl) -5-pyrimidinecarboxamide (123)

Indole-2-carboxylic acid (0.75 g, 3.6 mmol) was dissolved in N, N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (0.67 g, 4.4 mmol), 1-ethyl-3 -(3-Dimethylaminopropyl) carbodiimide hydrochloride (0.84 g, 4.4 mmol) and pyrrolidine (0.31 g, 4.4 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give crude (5-nitro-1H- Indol-2-yl) (pyrrolidin-1-yl) methanone was obtained. This was dissolved in methanol (10 ml), 5% palladium-carbon (0.16 g) was added, and the mixture was stirred at room temperature for 16 hours in a hydrogen gas atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude amine compound. This and 2-phenoxypyrimidine-5-carboxylic acid (0.22 g, 0.9 mmol) were dissolved in pyridine (5 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.19 g, 1 mmol) was added and stirred at room temperature for 15 hours. After concentration under reduced pressure, water and an aqueous potassium carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and chloroform, and dried under reduced pressure to give 2-phenoxy-N- (2- (1-pyrrolidini (Lucarbonyl) -1H-indol-5-yl) -5-pyrimidinecarboxamide (0.13 g, 8%) was obtained as a brown solid.
Melting point: 265-268 ℃
¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.85-1.99 (m, 4H), 3.50-3.61 (m, 2H), 3.75-3.87 (m, 2H), 6.96 (d, J = 1.1 Hz , 1H), 7.23-7.50 (m, 7H), 8.07 (s, 1H), 9.11 (s, 2H), 10.33 (s, 1H), 11.52 (s, 1H).

Example 124
2-phenoxy-N- (2- (carboxamido) -benzofuran-5-yl) -5-pyrimidinecarboxamide (124)
Example 124 (1)
5-Nitrobenzofuran-2-carboxamide (124 raw materials)

1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (81 mg, 0.42 mmol) in a solution of 5-nitrobenzofuran-2-carboxylic acid (80 mg, 0.39 mmol), a known compound, in pyridine (4 ml) ), 1-hydroxybenzotriazole monohydrate (65 mg, 0.42 mmol) and 28% aqueous ammonia (0.02 ml, 3.86 mmol) were added, and the mixture was stirred at 75 ° C. for 4 hours. After cooling to room temperature and stirring, the solvent was distilled off under reduced pressure, and 5-nitrobenzofuran-2-carboxamide (74 mg, 93%) was obtained by purification using column chromatography (chloroform: methanol = 98: 2). Obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ): δ (ppm) 7.01 (br, 1H), 7.20 (br, 1H), 7.65-7.69 (m, 2H), 8.33-8.36 (m, 1H), 8.65 (s, 1H ).

Example 124 (2)
2-phenoxy-N- (2- (carboxamido) -benzofuran-5-yl) -5-pyrimidinecarboxamide (124)

According to Example 12 (2), 2-phenoxy-N- (2- (carboxamide) -benzofuran-5- was obtained by using 5-nitrobenzofuran-2-carboxamide instead of 4-nitroacetic acid tert-butyl ester. Yl) -5-pyrimidinecarboxamide (68%) was obtained as a pale yellow solid.
Melting point: 241-244 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 7.24-7.31 (m, 3H), 7.45-7.49 (m, 3H), 7.67 (m, 2H), 8.20 (s, 1H), 9.12 (s, 2H ), 10.55 (s, 1H).

Example 125
2-phenoxy-N- (2- (4-morpholinylcarbonyl) -benzofuran-5-yl) -5-pyrimidinecarboxamide (125)
Example 125 (1)
(5-Nitrobenzofuran-2-yl) -carbonyl) morpholine (125 raw materials)

(5-Nitrobenzofuran-2yl) -carbonyl) morpholine (71%) was obtained as a yellow solid by using morpholine instead of 28% aqueous ammonia according to Example 124 (1).
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.81-3.87 (br, 8H), 7.45 (s, 1H), 7.64 (d, J = 6.6 Hz, 1H), 8.34 (d, J = 6.6 Hz, 1H), 8.62 (s, 1H).

Example 125 (2)
2-phenoxy-N- (2- (4-morpholinylcarbonyl) -benzofuran-5-yl) -5-pyrimidinecarboxamide (125)

According to Example 12 (2), by using (5-nitrobenzofuran-2-yl) -carbonyl) morpholine instead of 4-nitroacetic acid tert-butyl ester, 2-phenoxy-N- (2- (4- (4- Morpholinylcarbonyl) -benzofuran-5-yl) -5-pyrimidinecarboxamide (68%) was obtained as a pale yellow solid.
Melting point: 199-206 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 3.67-3.74 (br, 8H), 7.24-7.31 (m, 3H), 7.45-7.49 (m, 3H), 7.67 (br, 2H), 8.20 (s , 1H), 9.12 (s, 2H), 10.54 (s, 1H).

Example 126
2-Phenoxy-N- (4- (2-ethoxycarbonyl) -1H-pyrrole) -5-pyrimidinecarboxamide (126)

4-Nitropyrrole-2-carboxylic acid ethyl ester (1.85 g, 10 mmol) is dissolved in methanol (30 ml), 10% palladium-carbon (0.38 g) is added, and hydrogen gas atmosphere is used at room temperature for 5 hours. Stir. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude amine compound. 2-Phenoxypyrimidine-5-carboxylic acid (2.1 g, 9.7 mmol) was dissolved in pyridine (30 ml), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.0 g, 11 mmol) was added and stirred at room temperature for 2 days. After concentration under reduced pressure, water and aqueous potassium carbonate solution were added, and the precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-phenoxy-N- (4- (2-ethoxy Carbonyl) -1H-pyrrole) -5-pyrimidinecarboxamide (2.3 g, 67%) was obtained as a brown solid.
Melting point: 224-228 ℃
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.36 (t, J = 7.0 Hz, 3H), 4.33 (q, J = 7.0 Hz, 2H), 6.82 (brs, 1H), 7.13-7.50 (m, 5H), 7.59 (s, 1H), 7.78 (br, 1H), 9.01 (s, 2H).

Experimental Example 1: Hematopoietic prostaglandin D synthase inhibitory action
This was carried out in accordance with the method of Urade, Y. et al. (J. Biol. Chem. 262, 3820-3825 (1987)). That is, reaction solution (49 μL); 100 mM Tris-HCl (pH 8.0), 1 mM reduced glutathione, 0.1 mg / mL γ-globulin, human hematopoietic prostaglandin D synthase (appropriate amount) and compound (final concentration: 0.01) ˜100 μM) was preincubated at 25 ° C. for 5 minutes. In addition, a final concentration 1% DMSO solution was added to the solvent control group (Control group). Subsequently, the reaction was started by adding 1 μL of [ ¹⁴ C] prostaglandin H2 (final concentration: 10 μM). One minute after the start of the reaction, the reaction was stopped by adding 250 μL of a reaction stop solution (diethyl ether / methanol / 1M citric acid (volume ratio = 30/4/1)) at −20 ° C.

  50 μL of the upper layer (organic solvent phase) after the reaction was stopped was applied to a TLC plate and developed at −20 ° C. for 45 minutes (developing agent: diethyl ether / methanol / acetic acid (volume ratio = 90/2/1)). After drying the plate, the imaging plate was exposed for 1 hour to overnight, and the radioactivity corresponding to prostaglandin D2 was analyzed with an image analyzer (Fujifilm). The ratio (%) of the band of prostaglandin D2 per lane was calculated, and the 50% inhibitory concentration (IC50) of the compound against hematopoietic prostaglandin D synthase was calculated from the inhibition rate against the Control group provided in each experiment. Value). In addition, when the IC50 value could not be obtained, it was expressed as the inhibition rate of the compound 100 μM. The results are shown in Tables 1-4.

  The following are examples of formulations containing the compound of the present invention as an active ingredient.

Formulation Example 1 Tablet 50 mg of the compound of Example 3
Corn starch 50mg
Microcrystalline cellulose 50mg
Hydroxypropylcellulose 15mg
Lactose 47mg
Talc 2mg
Magnesium stearate 2mg
Ethylcellulose 30mg
Unsaturated glyceride 2mg
Titanium dioxide 2mg
According to a conventional method at the above blending ratio, 250 mg tablets per tablet were prepared.

Formulation Example 2 Granules Compound of Example 19 300 mg
Lactose 540mg
Corn starch 100mg
Hydroxypropylcellulose 50mg
Talc 10mg
In the above blending ratio, 1000 mg of a granule was prepared per package according to a conventional method.

Formulation Example 3 Capsules Compound of Example 20 100 mg
Lactose 30mg
Corn starch 50mg
Microcrystalline cellulose 10mg
Magnesium stearate 3mg
193 mg capsules per capsule were prepared according to a conventional method at the above blending ratio.

Formulation Example 4 Injectable Compound of Example 21 100 mg
Sodium chloride 3.5mg
Appropriate amount of distilled water for injection (2 ml per ampoule)
An injection was prepared according to a conventional method at the above blending ratio.

Formulation Example 5 Syrup agent Compound of Example 27 200 mg
60g refined white sugar
Ethyl parahydroxybenzoate 5mg
Butyl parahydroxybenzoate 5mg
Syrup was prepared in accordance with a conventional method at an appropriate amount of perfume, an appropriate amount of coloring, an appropriate amount of purified water, and an appropriate amount of purified water.

Formulation Example 6 Suppository Compound of Example 35 300 mg
Witepsol W-35 1400mg
(Registered trademark, mono-, di- and tri-glyceride mixtures of saturated fatty acids from lauric acid to stearic acid, manufactured by Dynamite Nobel)
A suppository was prepared according to a conventional method at the above blending ratio.

  According to the present invention, a pyrimidine compound represented by the above general formula (I) or a salt thereof useful as a prostaglandin D synthase inhibitor is provided.

  The pyrimidine compound of the present invention or a salt thereof has excellent prostaglandin D synthase inhibitory activity.

  Therefore, the pyrimidine compound or a salt thereof of the present invention is based on its excellent prostaglandin D synthase inhibitory activity, and can prevent and / or prevent diseases involving prostaglandin D2, such as allergic diseases or inflammatory diseases. It is useful as a therapeutic agent, a suppressor for exacerbation of Alzheimer's disease and brain damage, and other useful effects can be expected.

Claims (16)

The following general formula (I)

[Where
R ¹ represents a 5- or 6-membered nitrogen-containing unsaturated heterocyclic group which may have a substituent, or a phenyl group which may have a substituent,
R ² represents an unsaturated heterocyclic group or a phenyl group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure;
The unsaturated heterocyclic group represented by R ² has 0 to 2 R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ represents a halogen atom, a cyano group, a nitro group, a saturated or unsaturated heterocyclic ring which may have a substituent, —NR ⁴ R ⁵ group, — (C═O) —R ⁶ group, —OR ⁷ Group, or -SR ⁸ group,
R ⁴ and R ⁵ are the same or different and each have a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a substituent. An optionally substituted amino group, a saturated or unsaturated heterocyclic group which may have a substituent, an aryl group having 6 to 14 carbon atoms which may have a substituent or a carbonyl group having a substituent; Or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are each one or two selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. May form a saturated or unsaturated cyclic amino group which may have one hetero atom, the cyclic amino group may have a substituent,
R ⁶ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkenyl group having 2 to 6 carbon atoms, or a carbonyl group having a substituent. Represents
R ⁸ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms,
R ⁹ and R ¹⁰ are the same or different and are each a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon atom having 1 to 6 carbon atoms. Or an amino group which may have a substituent, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, are each one or two selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. A saturated or unsaturated cyclic amino group which may have one hetero atom may be formed, and the cyclic amino group may have a substituent. ]
Or a salt thereof (wherein R ¹ is a phenyl group substituted with a halogen atom, and R ² is a phenyl group substituted with a halogen atom) except for). R ¹ is selected from the group consisting of a pyridyl group which may have a substituent, or a halogen atom, a cyano group and a C 1-6 alkyl group which may be substituted with a halogen atom as a substituent. Represents a phenyl group optionally having one group;
R ² is a monocyclic or bicyclic unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in the ring structure, or phenyl Represents a group,
The unsaturated heterocyclic group represented by R ² has 0 to 2 R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is a halogen atom, a cyano group, a nitro group, an optionally substituted monocyclic saturated or unsaturated heterocyclic group, —NR ⁴ R ⁵ group, — (C═O) —R ⁶ group , -OR ⁷ group or -SR ⁸ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and the other of R ⁴ and R ⁵ has a hydrogen atom or a substituent. An optionally substituted alkyl group having 1 to 6 carbon atoms, a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent, and a phenyl group which may have a substituent Or a carbonyl group having a substituent, or
R ⁴ and R ⁵ , together with the adjacent nitrogen atom, are each in the ring structure one complex selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. ^May form a monocyclic or bicyclic saturated cyclic amino group which may have atoms, or R ⁴ and R ⁵ together with the adjacent nitrogen atom in the ring structure In addition to the adjacent nitrogen atom, the monocyclic or bicyclic unsaturated ring optionally having one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom An amino group may be formed, and the saturated or unsaturated cyclic amino group may have one or two substituents;
R ⁶ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an alkenyl group having 2 to 6 carbon atoms, a (C1-C6 alkyl) carbonyl group or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is a halogen atom, a hydroxyl group, An alkoxy group having 1 to 6 carbon atoms, a —NR ¹¹ R ¹² group, a phenyl group which may have a substituent, a pyridyl group which may have a substituent, and — (C═O) —R ^13. May have one or two groups selected from the group consisting of:
R ⁸ represents a C 1-3 alkyl group which may have a 5-membered or 6-membered monocyclic amino group as a substituent,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an optionally substituted alkyl group having 1 to 3 carbon atoms, and the other of R ⁹ and R ¹⁰ is a hydrogen atom, an amino group, or a substituted group. Represents an alkyl group having 1 to 6 carbon atoms which may have a group, or an alkoxy group having 1 to 3 carbon atoms which may have a substituent, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, are each one ring selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. It may form a 5-membered or 6-membered monocyclic saturated cyclic amino group which may have a hetero atom, or R ⁹ and R ¹⁰ are each taken together with an adjacent nitrogen atom. In addition to the adjacent nitrogen atom, the ring structure may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. May form a monocyclic unsaturated cyclic amino group, the saturated or unsaturated cyclic amino group may have one substituent,
R ¹¹ and R ^12, one of which represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a phenyl group, the other of R ¹¹ and R ¹² is a hydrogen atom, a phenyl group Yes An alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a 5-membered or 6-membered monocyclic saturated or unsaturated heterocyclic group, or a (C1-C6 alkyl) carbonyl group. Represent or
R ¹¹ and R ¹² , together with the adjacent nitrogen atom, are each one ring selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group [which may have a hydroxyl group] which may have a hetero atom, or R ¹¹ and R ¹² each have an adjacent nitrogen atom and Together, the ring structure may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. May form a formula unsaturated cyclic amino group [may have a methyl group]
R ¹³ represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group (R ⁹ and R ¹⁰ are the same as above). Item 1. The pyrimidine compound or a salt thereof according to Item 1, wherein R ¹ is a phenyl group substituted with a halogen atom, and R ² is a phenyl group substituted with a halogen atom. except for). R ¹ is a pyridyl group, or a halogen atom, a cyano group, or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom as a substituent at either the 2-position or the 3-position Represents a phenyl group optionally having one group selected from the group consisting of:
R ² is an unsaturated heterocyclic group selected from the group consisting of a pyridyl group, a pyrimidinyl group, a pyrrolyl group, an indolyl group, and a benzofuranyl group, or represents a phenyl group,
The unsaturated heterocyclic group represented by R ² has one or two R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the unsaturated heterocyclic group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m — groups May be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is a monocyclic saturated or unsaturated heterocyclic group optionally having a chlorine atom, a nitro group, a C 1-6 alkyl group or an oxo group as a substituent, —NR ⁴ R ⁵ Represents a group,-(C = O) -R ⁶ group, -OR ⁷ group, or -SR ⁸ group,
R ⁴ and R ^5, one of which represents a hydrogen atom, or a substituent one has to have also a good 1 to 6 carbon atoms alkyl group, the other of R ⁴ and R ⁵ are hydrogen atom, a substituted An alkyl group having 1 to 6 carbon atoms which may have one group, a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have one substituent, and 1 substituent. Represents a phenyl group which may have one carbonyl group or one substituent, or
R ⁴ and R ⁵ , together with the adjacent nitrogen atom, are each in the ring structure one complex selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group which may have an atom, or R ⁴ and R ⁵ , together with the adjacent nitrogen atom, form a ring 5-membered monocyclic ring which may have one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as a constituent atom in addition to the adjacent nitrogen atom in the structure An unsaturated cyclic amino group may be formed, the saturated cyclic amino group or the unsaturated cyclic amino group may have one or two substituents;
R ⁶ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom, an allyl group, a tert-butylcarbonyl group, or an alkyl group having 1 to 6 carbon atoms. One selected from the group consisting of —NR ¹¹ R ¹² group, an optionally substituted phenyl group, an optionally substituted pyridyl group, and — (C═O) —R ^13; May have two groups,
R ⁸ represents a C 1-3 alkyl group which may have a morpholino group as a substituent,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other of R ⁹ and R ¹⁰ may have a hydrogen atom, an amino group, or a substituent. Represents an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms, or
R ⁹ and R ¹⁰ together with the adjacent nitrogen atom each have one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group, or R ⁹ and R ¹⁰ together with the adjacent nitrogen atom may be combined with the adjacent nitrogen atom in the ring structure. In addition, a 5- or 6-membered unsaturated cyclic amino group which may have 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom as a constituent atom may be formed. The saturated cyclic amino group or unsaturated cyclic amino group may have one substituent,
One of R ¹¹ and R ¹² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a phenyl group, and the other of R ¹¹ and R ¹² represents a hydrogen atom or a phenyl group. An optionally substituted alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, or
R ¹¹ and R ¹² together with the adjacent nitrogen atom each have one heterocyclic atom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a monocyclic saturated cyclic amino group (which may have a hydroxyl group), or R ¹¹ and R ¹² may be combined with an adjacent nitrogen atom, respectively. In the ring structure, in addition to the adjacent nitrogen atom, a monocyclic unsaturated cyclic amino group optionally having one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom [ May have a methyl group]
The pyrimidine compound or a salt thereof according to claim 1, wherein R ¹³ represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group (R ⁹ and R ¹⁰ are the same as above). R ¹ is a phenyl group substituted with a halogen atom, and R ² is a phenyl group substituted with a halogen atom (except for the compound represented by the general formula (I)). R ¹ represents a pyridyl group or a phenyl group,
R ² represents a 3-pyridyl group, an indolyl group or a phenyl group,
The 3-pyridyl group and indolyl group represented by R ^{2 have} one or two R ³ — (CH ₂ ) _m — groups,
The phenyl group represented by R ² has an R ³ — (CH ₂ ) _m — group at one or both of the 3-position and 4-position thereof,
When the 3-pyridyl group, indolyl group or phenyl group represented by R ² has two R ³ — (CH ₂ ) _m — groups, two R ³ — (CH ₂ ) _m The groups may be the same or different,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ represents a nitro group, a tetrahydropyridazinyl group or an imidazolyl group optionally having any of an alkyl group having 1 to 6 carbon atoms or an oxo group as a substituent, a —NR ⁴ R ⁵ group, — ( C = O) -R ⁶ group, or -OR ⁷ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
The other of R ⁴ and R ⁵ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a monocyclic or bicyclic unsaturated heterocyclic group or substituent having 1 or 2 nitrogen atoms as constituent atoms. A carbonyl group having one group, the alkyl group having a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a mono- or di (C1-C6 alkyl) amino group, a (C1-C6 alkoxy) carbonyl group, a substituent as a substituent. One selected from the group consisting of a 5-membered or 6-membered monocyclic saturated or unsaturated heterocyclic group which may have one, or a phenyl group which may have one sulfamoyl group as a substituent May have a group,
The carbonyl group having one substituent is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a carbon number which may have 1 to 3 substituents as the substituent. 1 to 6 alkoxy groups and one group selected from the group consisting of monocyclic saturated or unsaturated heterocyclic rings, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom each have one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group, or R ⁴ and R ⁵ together with the adjacent nitrogen atom may form a ring structure. A 5-membered monocyclic unsaturated cyclic amino group optionally having one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom And the saturated cyclic amino group or unsaturated cyclic amino group may have one or two substituents,
R ⁶ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a (C1-C6 alkyl) carbonyl group, and the alkyl group includes a fluorine atom, a hydroxyl group, A C1-C3 alkoxy group, a carboxyl group, a (C1-C6 alkoxy) carbonyl group, a carbonyl group having a 5- or 6-membered monocyclic saturated heterocyclic group, and an optionally substituted 5-membered group Alternatively, it may have one or two groups of a 6-membered monocyclic unsaturated heterocyclic group, or a —NR ¹¹ R ¹² group,
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁹ and R ¹⁰ represents a hydrogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or a pyridyl group, and the alkyl group is substituted with a hydroxyl group as a substituent. An optionally substituted alkoxy group having 1 to 6 carbon atoms, a mono- or di (C1-C6 alkyl) amino group, a 5-membered or 6-membered monocyclic unsaturated heterocyclic group optionally having a substituent, It may have either a 5-membered or 6-membered saturated cyclic amino group which may have a substituent, or
R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, each have a hetero atom of either a nitrogen atom or an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a saturated cyclic amino group, or R ⁹ and R ¹⁰ , together with the adjacent nitrogen atom, may be added to the adjacent nitrogen atom in the ring structure in addition to 1 An unsaturated cyclic amino group which may have one or two nitrogen atoms may be formed, and the saturated cyclic amino group or the unsaturated cyclic amino group may have a substituent. ,
One of R ¹¹ and R ¹² represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other of R ¹¹ and R ¹² may have a hydrogen atom or a phenyl group. Represents 1 to 3 alkyl groups, or
R ¹¹ and R ¹² , together with the adjacent nitrogen atom, each have a hetero atom of any one of a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure. May form a 5-membered or 6-membered monocyclic saturated cyclic amino group [which may have a hydroxyl group], or R ¹¹ and R ¹² may be combined with an adjacent nitrogen atom, respectively. The ring structure may have one or two heteroatoms selected from the group consisting of nitrogen atoms and oxygen atoms in addition to the adjacent nitrogen atoms. The pyrimidine compound or salt thereof according to claim 1, which may form a monocyclic unsaturated cyclic amino group [which may have a methyl group]. R ¹ represents a 3-pyridyl group or a phenyl group,
R ² is, R ³ in the 6-position - (CH _{2) m} - 3- pyridyl groups having group, at the 2-position _{^{R 3 - (CH 2) m}} - any indolyl group, or a 3- or 4-position with a group Represents a phenyl group having a R ^3- (CH ₂ ) _m -group,
In the R ^3- (CH ₂ ) _m -group,
m represents 0 to 4,
R ³ is 2-methyl-1-imidazolyl group, 3-oxo-2,3,4,5-tetrahydropyridazinyl group, -NR ⁴ R ⁵ group,-(C = O) -R ⁶ group, or an -OR ⁷ group,
One of R ⁴ and R ⁵ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁴ and R ⁵ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a monocyclic or bicyclic unsaturated heterocyclic group having one nitrogen atom as a constituent atom, a tert-butoxycarbonyl group, a cyclo Represents a propylcarbonyl group, an ethoxyethylcarbonyl group, a 3-acetoxy-2,2-dimethylpropionyl group, a thiophenecarbonyl group or a furylcarbonyl group, and the alkyl group is a C 1-3 alkoxy group, mono- or di-substituted as a substituent. (C1-C6 alkyl) one selected from the group consisting of an amino group, ethoxycarbonyl group, morpholino group, pyrrolidinyl group optionally having an oxo group, pyridyl group, imidazolyl group, and 4-sulfamoylphenyl group Or a group of
R ⁴ and R ⁵ together with the adjacent nitrogen atom are pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, imidazolyl group, pyrazolyl group, pyrazolinyl group, thiazolinyl group, 1,2,3-triazolyl group, Or represents any cyclic amino group of a 1,2,4-triazolyl group, the cyclic amino group may have a substituent,
R ⁶ represents a hydrogen atom, a hydroxyl group, an ethoxy group, a tert-butoxy group, or a —NR ⁹ R ¹⁰ group,
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and the alkyl group is substituted with a hydroxyl group, a methoxy group, a benzylmethylamino group, a carboxyl group, a tert-butoxycarbonyl group, a morpholinocarbonyl group, 2 -Methylimidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, pyrrolyl group, pyrrolidinyl group, morpholino group, 4-hydroxypiperidinyl group, or pyridyl group You may have
One of R ⁹ and R ¹⁰ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
The other of R ⁹ and R ¹⁰ represents a hydrogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. The alkyl group has a hydroxyethoxy group, a dimethylamino group, an oxo group as a substituent. May have one group selected from the group consisting of a pyrrolidinyl group, a morpholino group, and a pyridyl group, which may have a group, or
The pyrimidine compound or a salt thereof according to claim 1, wherein R ⁹ and R ¹⁰ together with an adjacent nitrogen atom represent a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, or pyrazolinyl group. R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position or a 3-pyridyl group having an R ³ — (CH ₂ ) _m — group at the 6-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ represents -NR ⁴ R ⁵ group, or -OR ⁷ group,
R ⁴ and R ⁵ each represents a hydrogen atom or a methyl group, and the other represents a hydrogen atom, a methoxypropyl group, a dimethylaminoethyl group, an ethoxycarbonylethyl group, a morpholinoethyl group, a 2-oxopyrrolidinylpropyl group, Pyridylethyl group, imidazolylpropyl group, 4-sulfamoylphenylethyl group, tert-butoxycarbonyl group, cyclopropylcarbonyl group, ethoxyethylcarbonyl group, 3-acetoxy-2,2-dimethylpropionyl group, thiophenecarbonyl group or furyl Represents any of the carbonyl groups, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are pyrrolidinyl group optionally having oxo group, piperidinyl group having substituent, piperazinyl group having substituent, morpholino group, carbon as substituent An imidazolyl group optionally having an alkyl group of 1 to 6, a hydroxyl group as a substituent, a pyrazolyl group optionally having one or both of a methyl group, a pyrazolinyl group, a thiazolidinyl group, 1,2, Represents either a 3-triazolyl group or a 1,2,4-triazolyl group,
R ⁷ is a hydrogen atom, isobutyl group, hydroxypropyl group, carboxymethyl group, tert-butoxycarbonylmethyl group, pyrrolidinylpropyl group, 4-hydroxypiperidinylpropyl group, morpholinoethyl group, pyrrolylpropyl group, 2 -Represents any one of a methylimidazolylethyl group, a 1,2,3-triazolylethyl group, a 1,2,4-triazolylethyl group, or a morpholinocarbonylmethyl group,
The pyrimidine compound or a salt thereof according to claim 1. R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ represents -NR ⁴ R ⁵ group, or -OR ⁷ group,
R ⁴ and R ⁵ each represents a hydrogen atom or a methyl group, and the other represents a hydrogen atom, a methoxypropyl group, a 4-sulfamoylphenylethyl group, a tert-butoxycarbonyl group, a cyclopropylcarbonyl group, an ethoxyethylcarbonyl group. Represents a group, 3-acetoxy-2,2-dimethylpropionyl group, thiophenecarbonyl group or furylcarbonyl group, or
R ⁴ and R ⁵ together with the adjacent nitrogen atom are pyrrolidinyl group optionally having oxo group, piperidinyl group having substituent, piperazinyl group having substituent, morpholino group, carbon as substituent An imidazolyl group optionally having an alkyl group of 1 to 6, a hydroxyl group as a substituent, a pyrazolyl group optionally having one or both of a methyl group, a pyrazolinyl group, a thiazolidinyl group, 1,2, Represents either a 3-triazolyl group or a 1,2,4-triazolyl group,
R ⁷ is a hydrogen atom, isobutyl group, hydroxypropyl group, carboxymethyl group, tert-butoxycarbonylmethyl group, pyrrolidinylpropyl group, 4-hydroxypiperidinylpropyl group, morpholinoethyl group, pyrrolylpropyl group, 2 -Represents any one of a methylimidazolylethyl group, a 1,2,3-triazolylethyl group, a 1,2,4-triazolylethyl group, or a morpholinocarbonylmethyl group,
The pyrimidine compound or a salt thereof according to claim 1. R ¹ represents a 3-pyridyl group or a phenyl group,
R ² represents a phenyl group having an R ³ — (CH ₂ ) _m — group at the 4-position;
In the R ^3- (CH ₂ ) _m -group,
m represents 0-2,
R ³ represents a pyrrolidinyl group, a piperidinyl group having a substituent at the 4-position, a piperazinyl group having a substituent at the 4-position, a morpholino group, a 2-methylimidazolyl group, or a 1,2,4-triazolyl group,
The pyrimidine compound or a salt thereof according to claim 1. 2-phenoxy-N- (4- (1,2,4-triazol-1-ylmethyl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (2- (2-methylimidazol-1-yl) ethyl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4-tert-butoxycarbonylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4-carboxylpiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4- (1-pyrrolidinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4- (4-morpholinylcarbonyl) -piperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (4- (N-methoxy-N-methyl) -carboxamidopiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide,
2-phenoxy-N- (4- (3- (4-hydroxypiperidin-1-yl) -propoxy) phenyl) -5-pyrimidinecarboxamide,
2- (3-pyridyloxy) -N- (4- (4-hydroxypiperidin-1-yl) phenyl) -5-pyrimidinecarboxamide, or 2- (3-pyridyloxy) -N- (4- ( The pyrimidine compound or a salt thereof according to claim 1, which is 2- (morpholin-4-yl) -ethoxy) phenyl) -5-pyrimidinecarboxamide.   A pharmaceutical composition comprising an effective amount of at least one of the compounds according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.   A prostaglandin D synthase inhibitor comprising an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.   A disease involving prostaglandin D2 or a metabolite thereof, comprising an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. Preventive or therapeutic agent.   The preventive or therapeutic agent according to claim 12, wherein the disease involving prostaglandin D2 or a metabolite thereof is any of allergic diseases, inflammatory diseases, Alzheimer's disease, and brain injury.   A prophylactic or therapeutic agent for allergic diseases, comprising an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.   A prophylactic or therapeutic agent for inflammatory diseases, comprising an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.   A prophylactic and / or therapeutic agent for Alzheimer's disease or brain injury, comprising an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. .