JP2014237590A - 2-(pyridine-2-yl) pyrimidine-4-amine compound or a salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound useful as an active ingredient of a therapeutic pharmaceutical composition for a disease involved in RANKL/RANK signals, such as osteoporosis, osteopenia and rheumatoid arthritis.SOLUTION: The prevent inventors have been studied about a compound having RANKL/RANK signal inhibitory activity, confirmed that a 2-(pyridine-2-yl) pyrimidine-4-amine compound or a salt thereof has potent RANKL/RANK signal inhibitory activity, improves RANKL-induced bone mineral density reduction and is effective in an osteoporosis model, and completed the present invention. The 2-(pyridine-2-yl) pyrimidine-4-amine compound or a salt thereof of the present invention has RANKL/RANK signal inhibitory activity and can be used as a therapeutic agent for a disease involved in RANKL/RANK signals, such as osteoporosis, osteopenia and rheumatoid arthritis.

Description

  The present invention relates to 2- (pyridin-2-yl) pyrimidine-4 useful as an active ingredient in pharmaceutical compositions, for example, pharmaceutical compositions for the treatment of diseases involving RANKL / RANK signals such as osteoporosis, osteopenia and rheumatoid arthritis. -Relates to amine compounds or salts thereof.

  Bone metabolism is maintained by the metabolic balance between bone resorption and osteogenesis, where old bone is absorbed by osteoclasts while new bone is formed by osteoblasts (Developmental Cell, Volume 2). 389-406, 2002). Osteoporosis is a disease in which hormonal balance is lost due to aging or this balance is lost by drugs such as steroids, bone resorption exceeds bone formation, and bone weakens with a decrease in bone density and bone quality (Nature Review). Genetics, Vol. 4, 638-649, 2003).

  Osteoclasts responsible for bone resorption are cells that differentiate from monocytic cells. In 1997, Yasuda et al. Used RANKL (Receptor Activator of NF) as a differentiation inducing factor (Osteoclast Differentiation Factor (ODF)). -kappa B Ligand) (Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 7, pages 3597-3602, 1998). RANKL is a membrane protein expressed on the osteoblastic membrane and binds to RANK (Receptor Activator of NF-kappa B), a receptor expressed on the osteoclast membrane, to signal differentiation and activation of osteoclasts. Induction (Biochemistry, Vol. 72, pp. 507-525, 2000).

  Estrogen, a female hormone, is known to suppress RANKL expression, and in postmenopausal women, lack of estrogen secretion increases RANKL expression and increases osteoclast differentiation and activation In this case, bones are weakened because the balance between bone resorption and bone formation is lost. This is so-called primary osteoporosis, which is particularly common in elderly women (Lancet, 371, 760-770, 2008). In addition, steroidal (so-called secondary) osteoporosis is well known in which the balance between bone formation and bone resorption is disrupted by the administration of steroids and bone weakening is known (Clinical Nuclear Medicine, Vol. 35, No. 9, 740-742, 2010).

  As therapeutic agents for osteoporosis, bone resorption inhibitors such as bisphosphonates, selective estrogen receptor modulators (SERM), active vitamin D3 preparations, and estrogen preparations have been mainly used so far. However, although bisphosphonates have a strong bone density improving effect, 1) they act not only on osteoclasts that control bone resorption, but also on osteoblasts and suppress bone formation, so they are expected to improve bone density. The bone strength improvement effect is not seen as much as it is (so-called bone deterioration), 2) safety concerns due to accumulation in bone, and 3) gastrointestinal tract disorders. In addition, bone resorption inhibitors other than bisphosphonates are insufficient in effectiveness because the effect of improving bone density is not sufficient.

  Thus, current osteoporosis treatments are not satisfactory in terms of effectiveness and safety, and there are sufficient safety measures to improve bone strength by improving bone density and bone quality. It has been demanded.

  In view of the above situation, a RANKL / RANK signal inhibitor inhibits a RANKL / RANK signal specific to osteoclasts, and thus is expected to be an osteoporosis therapeutic agent with excellent efficacy and safety.

  In addition, rheumatoid arthritis (Arthritis & Rheumatology, 58, No. 5, 1237-1242, 2008), bone metastasis (2007 Breast Cancer Symposium, abstract 266, 2007) in clinical trials of fully anti-human RANKL antibodies September 7), osteopenia (New England Journal of Medicine, Vol.361, No.8, pp.745-755, 2009), giant cell tumor of bone (45th American Society of clinical Oncology, abstract 10510) , May-June 2002) has been reported to be effective. Therefore, RANKL / RANK signal inhibitors are expected to be therapeutic agents for these diseases.

  As the 2- (pyridin-2-yl) pyrimidin-4-amine compound, for example, the following compounds are known, and each has antimalarial activity based on an inhibitory action on methionine aminopeptidase 1b (non-malaria) Patent Document 1), having methionine aminopeptidase inhibitory action to inhibit cancer cell proliferation (Patent Document 1), and being useful for iron metabolism disorders such as anemia based on hepcidin antagonistic activity action (Patent Document 2) In addition, it has been reported that it has a skin or mucous membrane cooling action based on the TRPM8 regulating action (Patent Document 3). However, these references do not specifically disclose the compounds of the present invention, nor do they disclose the possibility of treating RANKL / RANK signal inhibition or osteoporosis.

International Publication Pamphlet WO2009 / 064388 International publication pamphlet WO2011 / 026835 International publication pamphlet WO2011 / 061330

Proceedings of the National Academy of Sciences of the United States of America, 103, 39, 14548-14553, 2006

  The present invention provides a compound useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating a disease involving RANKL / RANK signals such as osteoporosis, osteopenia, rheumatoid arthritis and the like.

  As a result of intensive studies on compounds having RANKL / RANK signal inhibitory activity, the present inventors have found that 2- (pyridin-2-yl) pyrimidin-4-amine compounds or salts thereof have potent RANKL / RANK signal inhibitory activity. Thus, the present invention has been completed by finding that it improves RANKL-induced bone mineral density reduction and is effective in an osteoporosis model.

That is, the present invention relates to the following.
[1] A compound of the formula (I) or a salt thereof.

(Where
R ¹ is phenyl _optionally substituted with C _1-6 alkyl, —C _1-6 alkylene-OC _1-6 alkyl, —C _1-6 alkylene-OH, or C _1-6 alkyl;
R ² is pyrrolidin-1-yl, 2-azabicyclo [2.2.1] heptan-2-yl, adamantan-2-ylamino, decahydroisoquinolin-2-yl, 4- (4-chlorophenyl) -1,4- Diazepan-1-yl,

Is;
R ³ is F, Cl or CF ₃ ;
R ⁴ and R ⁵ are the same or different and are H, F or Cl;
n is 1 or 2;
However, when R ² is pyrrolidin-1-yl, R ¹ is a group other than methyl. )
[2] R ² is

Or a salt thereof according to [1].
[3] The compound or salt thereof according to [2], wherein R ¹ is C _1-6 alkyl.
[4] R ² is

Or a salt thereof according to [1].
[5] The compound or salt thereof according to [4], wherein R ¹ is C _1-6 alkyl.
[6] 5-methoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
N- [4-fluoro-2- (trifluoromethyl) benzyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
5-methoxy-2- (pyridin-2-yl) -N- [2- (trifluoromethyl) benzyl] pyrimidin-4-amine,
5-ethoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
2-{[2- (pyridin-2-yl) -4-{[2- (trifluoromethyl) benzyl] amino} pyrimidin-5-yl] oxy} ethanol,
5-isopropoxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine,
N- (2-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- [2- (2,4-dichlorophenyl) ethyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- (2-chloro-6-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- (2,4-difluorobenzyl) -5- (2-methoxyethoxy) -2- (pyridin-2-yl) pyrimidin-4-amine,
5- (2-methoxyethoxy) -2- (pyridin-2-yl) -N- [2- (trifluoromethyl) benzyl] pyrimidin-4-amine,
N- (2-cycloheptylethyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
rel- (1R, 4S) -2- [5-methoxy-2- (pyridin-2-yl) pyrimidin-4-yl] -2-azabicyclo [2.2.1] heptane,
5- (2-methoxyethoxy) -2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine,
N- [4-chloro-2- (trifluoromethyl) benzyl] -5- (2-methylphenoxy) -2- (pyridin-2-yl) pyrimidin-4-amine,
5-phenoxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine,
rel-N-[(1R, 3R, 5R, 7R) -adamantan-2-yl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
5-ethoxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine,
2-{[2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidin-5-yl] oxy} ethanol,
rel- (4aR, 8aS) -2- [5-methoxy-2- (pyridin-2-yl) pyrimidin-4-yl] decahydroisoquinoline, and
The compound according to [1], selected from the group consisting of 1- (4-chlorophenyl) -4- [5-methoxy-2- (pyridin-2-yl) pyrimidin-4-yl] -1,4-diazepane Or a salt thereof.
[7] 5-methoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
N- [4-fluoro-2- (trifluoromethyl) benzyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
5-methoxy-2- (pyridin-2-yl) -N- [2- (trifluoromethyl) benzyl] pyrimidin-4-amine,
5-ethoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
2-{[2- (pyridin-2-yl) -4-{[2- (trifluoromethyl) benzyl] amino} pyrimidin-5-yl] oxy} ethanol,
N- (2-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- [2- (2,4-dichlorophenyl) ethyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- (2-chloro-6-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- (2,4-difluorobenzyl) -5- (2-methoxyethoxy) -2- (pyridin-2-yl) pyrimidin-4-amine, and
The compound according to [1], selected from the group consisting of 5- (2-methoxyethoxy) -2- (pyridin-2-yl) -N- [2- (trifluoromethyl) benzyl] pyrimidin-4-amine Or a salt thereof.
[8] 5-methoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
N- [4-fluoro-2- (trifluoromethyl) benzyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
2-{[2- (pyridin-2-yl) -4-{[2- (trifluoromethyl) benzyl] amino} pyrimidin-5-yl] oxy} ethanol,
N- (2-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine, and
The compound or a salt thereof according to [1], selected from the group consisting of N- (2-chloro-6-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine.
[9] A pharmaceutical composition comprising the compound or a salt thereof according to [1] and a pharmaceutically acceptable excipient.
[10] The pharmaceutical composition according to [9], which is a pharmaceutical composition for treating a disease involving RANKL / RANK signals.
[11] The pharmaceutical composition according to [10], wherein the disease involving RANKL / RANK signal is osteoporosis, osteopenia or rheumatoid arthritis.
[12] The compound or salt thereof according to [1] for the treatment of a disease involving RANKL / RANK signal.
[13] Use of the compound or a salt thereof according to [1] for the manufacture of a pharmaceutical composition for treating a disease involving RANKL / RANK signals.
[14] Use of the compound according to [1] or a salt thereof for the treatment of a disease involving RANKL / RANK signals.
[15] A method for treating a disease involving a RANKL / RANK signal, comprising administering an effective amount of the compound or salt thereof according to [1] to a subject.

Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol indicates the same meaning.
In addition, the “subject” is a human or other animal in need of the treatment, and in one embodiment, is a human in need of the treatment.

  The compound of formula (I) or a salt thereof has RANKL / RANK signal inhibitory activity and can be used as a therapeutic agent for diseases involving RANKL / RANK signal such as osteoporosis, osteopenia, rheumatoid arthritis and the like.

Hereinafter, the present invention will be described in detail.
In the present specification, “C _1-6 alkyl” means linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl, tert-butyl, n-pentyl, n-hexyl and the like. In another embodiment, it is C _1-3 alkyl, in yet another embodiment, methyl, ethyl or isopropyl, and in yet another embodiment, methyl.

“C _1-6 alkylene” means linear or branched C _1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1, 2-dimethylethylene, 1,1,2,2-tetramethylethylene and the like. Another embodiment is C _1-3 alkylene, yet another embodiment is methylene or ethylene, and yet another embodiment is ethylene.

  In the present specification, “optionally substituted” means unsubstituted or substituted with 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.

Certain embodiments of the compound of formula (I) are shown below.
(1) A compound wherein R ¹ is C _1-6 alkyl.
(2) The compound wherein R ¹ is methyl, ethyl or isopropyl.
(3) A compound in which R ¹ is methyl.
(4) The compound wherein R ¹ is methyl, ethyl, isopropyl, 2-methoxyethyl, 2-hydroxyethyl, phenyl or 2-methylphenyl.
(5) R ² is

A compound that is
(6), R ² is

A compound that is
(7) R ² is 2,4,6-trifluorobenzylamino, 4-fluoro-2- (trifluoromethyl) benzylamino, 2-fluorobenzylamino, 2- (2,4-dichlorophenyl) ethylamino, 2 A compound which is-(trifluoromethyl) benzylamino, 2-chloro-6-fluorobenzylamino, 2,4-difluorobenzylamino or 4-chloro-2- (trifluoromethyl) benzylamino.
(8) A compound that is a combination of two or more of the groups described in (1) to (7) above.

  The compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

  Furthermore, this invention also includes the pharmaceutically acceptable prodrug of the compound shown by a formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include, for example, Progress in Medicine, Volume 5, pages 2157-2161, 1995, and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. And the groups described.

  The salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I). The compound of formula (I) may form an acid addition salt depending on the type of the substituent. 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 with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Examples include salts.

Furthermore, the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
(Production method)
The compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.

  Moreover, the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate, or reacts further using the obtained compound of the formula (I) in the same manner as the protecting group. Can be manufactured. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.

Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.
(First manufacturing method)

(In the formula, L ₁ represents a leaving group.)
The compound (I) of the present invention can be obtained by reacting the compound (1) with the amine compound (2). Here, examples of the leaving group for L ₁ include halogen, methylsulfinyl group and the like.

In this reaction, the compound (1) and the amine compound (2) are used in the same amount or in excess, and the mixture is used in a solvent inert to the reaction or in the absence of a solvent, under cooling to heating under reflux. Preferably, the mixture is stirred at 0 ° C. to 90 ° C. for usually 0.1 hour to 5 days. Examples of the solvent used here include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane and 1,2-dichloroethane. And halogenated hydrocarbons such as chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. The reaction is carried out in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide. May be advantageous.
(Second manufacturing method)

(In the formula, L ₂ represents a leaving group.)
The compound (I) of the present invention can be obtained by reacting the compound (3) with the compound (4). Here, examples of the leaving group for L ₂ include halogen, methanesulfonyloxy, p-toluenesulfonyloxy group, and the like.

In this reaction, the compound (3) and the compound (4) are used in the same amount or in excess, and the mixture is preferably cooled to heated under reflux in a solvent inert to the reaction in the presence of a base. Is stirred at 0 ° C. to 80 ° C., usually for 0.1 hour to 5 days. Examples of the solvent used here include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane and 1,2-dichloroethane. Halogenated hydrocarbons such as chloroform, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof. Examples of bases include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, organic bases such as n-butyllithium, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride, etc. Of inorganic bases. It may be advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride.
(Raw material synthesis)
The raw material compound used in the above production method may be a commercially available product as it is, and the method described in the below-mentioned production examples, a method obvious to those skilled in the art, or a modified method thereof is applied using a commercially available product. It can also be manufactured.

  The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances. The salt of the compound of the formula (I) can also be produced by subjecting it to a conventional salt formation reaction.

Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

The pharmacological activity of the compound of formula (I) was confirmed by the following test.
Test Example 1 Suppression of differentiation of mouse monocyte-derived cell line RAW264 cells into osteoclasts by stimulating soluble RANKL (sRANKL) (RANKL / RANK signal inhibitory activity)
DMEM containing mouse monocyte-derived cell line RAW264 cells (RIKEN) in 96-well plates, 1.5 × 10 ⁴ per well, 5% FBS (Fetal bovine serum, fetal bovine serum, Nicherei Bioscience, catalog number 171012) (Dulbecco's Modified Eagle Medium, Dulbecco's Modified Eagle Medium, SIGMA, Catalog No. D5795). A solution of a test compound diluted with the above medium to various concentrations was added to each well, and a sRANKL (Oriental Yeast Industry) solution diluted with the above medium was added to a final concentration of 8 ng / ml. After the culture, the inhibitory effect on the osteoclast differentiation by the test compound was evaluated by the number of tartrate-resistant acid phosphatase (TRAP) positive cells. The number of TRAP positive cells was determined by adding 1% Triton X-100, staining the cells using LEUKOCYTE ACID PHOSPHATASE kit (Sigma, catalog number 387-A), and measuring the absorbance ratio at 550 nm and 430 nm. The IC ₅₀ value is determined by ₅₀ % inhibition from the inhibition rate (%) at each concentration of the test compound (100- (absorbance ratio of 550 nm and 430 nm when the test compound is added / absorbance ratio of 550 nm and 430 nm when the solvent is added) X100). Test compound concentration was determined. The results are shown in Table 1 for some compounds of formula (I). In the table, Ex represents an example number described later (the same applies hereinafter).

Test Example 2 Improvement of bone mineral density reduction in sRANKL-induced osteopenia model
The test was conducted in accordance with the method of WO2008 / 044379. SRANKL (Oriental Yeast Co., Ltd.) was intraperitoneally administered to female C57BL / 6 mice (Nippon Charles River) at a dose of 40 μg / body / day for 2 days to produce osteopenia model mice. The group composition was sRANKL untreated group, solvent administration group and test compound administration group, and the test compound (3 mg / kg) or solvent was orally administered once a day on the same day as sRANKL administration. Three days after the start of sRANKL administration, femurs were collected and the bone mineral content was measured. The measurement was performed with a micro X-ray computed tomography apparatus manufactured by Rigaku Corporation. The measurement area was an area from the primary cancellous bone just below the growth plate at the distal part of the femur to 5 mm toward the proximal part. Bone mineral content reduction rate (%) is expressed by the formula ((Bone mineral content of test compound administration group−Bone mineral content of solvent administration group) / (Bone mineral content of sRANKL untreated group−Bone mineral content of solvent administration group)) Obtained with X100. The results are shown in Table 2 for some compounds of formula (I).

Test Example 3 Effects in a rat ovariectomized osteoporosis model
Inhalation anesthesia (induction and maintenance) with isoflurane (Mylan Pharmaceutical) or pentobarbital (Dainippon Sumitomo Pharma) anesthesia (5-10 mg / kg, intraperitoneal administration) to Wistar female rats (Nippon Charles River) aged 10-11 weeks Underneath, trim the hair on both sides of the animal, wipe it with Hibiten-alcohol solution (Dainippon Sumitomo Pharma), lay it on its left side or right side in a natural shape, and lower the kidney at the upper femur The skin was cut with scissors for cutting 0.5 cm. Fat and muscle were incised in order to expose the ovary, and the ovary was removed with a tightly tied ophthalmic scissors wrapped around the oviduct part 1 cm away from the ovary. The oviduct was returned to its original position, and the muscle and skin were sutured with sutures. The wound was disinfected with isodine disinfectant (Meiji Seika). The opposite side was similarly treated and the ovaries on both sides were removed. Seven days after the operation, the suture was removed under isoflurane anesthesia, and the sutured part was disinfected with isodine disinfectant. The group composition was an untreated group, a solvent administration group, and a test compound administration group. The test compound and the solvent were orally administered for 28 days from the first day after surgery, and the bone density was measured by collecting the femur 28 days after the first day. . In the bone density measurement, the position of 18% of the entire length from the distal end of the femur was used as a measurement slice plane (1 slice). The measurement was performed with a peripheral quantitative computed tomography apparatus manufactured by Norland Stratec. The bone density improvement rate (%) was determined by the formula ((bone density of test compound administration group−bone density of solvent administration group) / (bone density of untreated group−bone density of vehicle administration group)) X100. For example, the compound of Example 1 significantly and dose-dependently improved the bone density of whole bone, cortical bone and cancellous bone at 0.3-1 mg / kg, and the ED ₅₀ value in whole bone (the bone density of whole bone was 50% The improving dose) was 0.81 mg / kg.

Test Example 4 Action in Bovine Type-II Collagen-Induced Mouse Arthritis Model Bovine Type-II Collagen (Collagen Technology Research Group, Catalog No. K42) 125 μg / body Complete Freund's Adjuvant No. 014-09541) and intradermally administered to the ridges of 7-8 week old DBA / 1 mice (Nippon Charles River). This antigen sensitization is carried out on the 0th and 21st days, with the first administration day being the 0th day. The test compound and vehicle will be administered orally once a day for 21 days from the 21st day. The bone destruction of the foot can be performed using the X-ray image of the excised hind leg taken with the Acrobio X-ray machine DX50-DC12, and the ribs, talus, scaphoid, metatarsal bone, and tibia A total of seven items were scored and evaluated: the bone destruction state of the place, and the state of narrowing of the interosseous distance between the talus and the scaphoid and between the scaphoid and the wedge bone. Bone destruction score improvement rate (%) is expressed by the formula (100- (bone destruction score of test drug administration group−bone destruction score of untreated group) / (bone destruction score of solvent administration group−bone destruction score of untreated group)). X100).

  As a result of the above test, it was confirmed that some compounds of formula (I) have RANKL / RANK signal inhibitory activity, improve RANKL-induced bone mineral loss, and are effective in an osteoporosis model. Therefore, the compound of formula (I) can be used for the treatment of diseases involving RANKL / RANK signals.

  In the present specification, “disease involving RANKL / RANK signal” means a disease that is sensitive to inhibition of RANKL / RANK signal transmission, that is, its symptom is improved by inhibiting RANKL / RANK signal transmission. A disease in which the deterioration of the symptom stops, or a disease in which the deterioration of the symptom is slow.

  Here, the disease involving RANKL / RANK signal specifically means osteoporosis, rheumatoid arthritis, cancer bone metastasis, osteopenia, giant cell tumor of the bone, etc., in particular, osteoporosis, osteopenia or joint It means rheumatism.

  A pharmaceutical composition containing one or more of the compounds of formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. Can be prepared by a commonly used method.

  Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

  As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.

  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

  Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

  External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.

  Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.

  In general, in the case of oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. In the case of intravenous administration, the daily dose is appropriately about 0.0001 to 10 mg / kg per body weight, and is administered once a day or divided into multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

  Depending on the route of administration, dosage form, administration site, type of excipient or additive, the pharmaceutical composition of the present invention is 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight of the active ingredient. Or more compounds of formula (I) or salts thereof.

  The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

  Hereinafter, based on an Example, the manufacturing method of the compound of a formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is each shown in a manufacture example. Further, the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.

In this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used for naming compounds.
For convenience, the concentration mol / l is expressed as M. For example, a 1M aqueous sodium hydroxide solution means a 1 mol / l aqueous sodium hydroxide solution.

Production Example 1
Sodium methoxide (7.33 g) was added to a mixture of ethyl (2-methoxyethoxy) acetate (20.0 g) and methyl formate (99.2 ml) under ice cooling, and the mixture was stirred at the same temperature for 6 hours, and further at room temperature for 16 hours. Stir. The reaction solution was concentrated under reduced pressure, ethanol (200 ml) and pyridine-2-carboximidoamide hydrochloride (19.4 g) were added to the resulting residue, and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with a methanol / chloroform mixed solvent (1: 4). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dispersed in diisopropyl ether, and the solid was collected by filtration and dried under reduced pressure to give 5- (2-methoxyethoxy) -2- (pyridine- 2-yl) pyrimidin-4-ol (21.2 g) was obtained.

Production Example 2
N, N-dimethylformamide (0.1 ml) was added to a mixture of 5- (2-methoxyethoxy) -2- (pyridin-2-yl) pyrimidin-4-ol (1.0 g) and thionyl chloride (11.8 ml) under a nitrogen stream. And stirred at 60 ° C. for 3 hours. The reaction solution was carefully added to saturated aqueous sodium hydrogen carbonate solution, and the precipitate was collected by filtration and dried under reduced pressure to give 4-chloro-5- (2-methoxyethoxy) -2- (pyridin-2-yl) pyrimidine (0.531 g). Got.

Production Example 3
4-Chloro-5-methoxy-2- (pyridin-2-yl) pyrimidine (5.00 g), 2.1 M aqueous sodium thiomethoxide solution (19 ml), 1,4-dioxane (70 ml) and acetonitrile (70 ml) The mixture was stirred at 80 ° C. for 1 hour. To the reaction solution was added 5% aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium and concentrated under reduced pressure. To the resulting residue were added pyridine hydrochloride (1.6 g) and N, N-dimethylformamide (50 ml), and the mixture was stirred at 100 ° C. for 1 hour. Water was then added to the reaction mixture, and the precipitate was collected by filtration and filtered. Dried. Pyridine hydrochloride (8.5 g) and N, N-dimethylformamide (25 ml) were added to the obtained solid and stirred at 100 ° C. for 1 hour. Water was added to the reaction solution, and the precipitate was collected by filtration and dried. The obtained solid was washed with an ethyl acetate / n-hexane mixed solvent (1: 1) to give 4- (methylsulfanyl) -2- (pyridin-2-yl) pyrimidin-5-ol (2.53 g). Got.

Production Example 4
To a mixture of 4- (methylsulfanyl) -2- (pyridin-2-yl) pyrimidin-5-ol (800 mg), potassium carbonate (1.5 g) and N, N-dimethylformamide (15 ml) at room temperature Ethyl chloride (0.3 ml) was added and stirred at the same temperature for 30 minutes. Further, ethyl iodide (0.2 ml) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 5% aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate / n-hexane to obtain 5-ethoxy-4- (methylsulfanyl) -2- (pyridin-2-yl) pyrimidine (713 mg).

Production Example 5
To a mixture of 5-ethoxy-4- (methylsulfanyl) -2- (pyridin-2-yl) pyrimidine (784 mg) and methylene chloride (18 ml) was added 3-chloroperbenzoic acid (75%, 900 mg) was added, and the mixture was stirred at the same temperature for 2 hours. A 5% aqueous sodium sulfite solution (20 ml) was added to the reaction mixture, and the mixture was stirred for 5 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-ethoxy-4- (methylsulfinyl) -2- (pyridin-2-yl) pyrimidine (703 mg).

Production Example 6
Add pyridine hydrochloride (13.5 g) to a solution of 5-methoxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine (6.00 g) in N, N-dimethylformamide (60 ml). And heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and the precipitated solid was collected by filtration, washed with ethyl acetate, dried under reduced pressure, and 5-hydroxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl). ) Pyrimidine (5.26 g) was obtained.

In the same manner as in Production Examples 1 to 6, the compounds of Production Examples 7 to 12 shown in the table below were produced. The structures, physicochemical data, and production methods of the production example compounds are shown in Tables 3 and 4.
Example 1
4-Chloro-5-methoxy-2- (pyridin-2-yl) pyrimidine (5.00 g), potassium carbonate (7.0 g), acetonitrile (30 ml) and 2,4,6-trifluorobenzylamine (4.2 g) The mixture was stirred at 80 ° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 97: 3). To the resulting mixture of 5-methoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine and methanol (50 ml), add 4M hydrogen chloride / acetic acid. Ethyl solution (15 ml) was added at room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was washed with a methanol / ethyl acetate mixed solvent (1:10), dried under reduced pressure, and 5-methoxy-2- (pyridin-2-yl) -N- (2 , 4,6-trifluorobenzyl) pyrimidin-4-amine dihydrochloride (6.26 g) was obtained.

Example 2
4-chloro-5-methoxy-2- (pyridin-2-yl) pyrimidine (10 g), 4-fluoro-2- (trifluoromethyl) benzylamine (9.66 g), potassium carbonate (6.91 g) and acetonitrile ( 100 ml) was refluxed for 3 days. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether, dried under reduced pressure, and light brown powder of N- [4-fluoro-2- (trifluoromethyl) benzyl] -5-methoxy-2- (pyridin-2-yl) Pyrimidin-4-amine (14.31 g) was obtained. To a mixture of the obtained compound (5 g) and ethyl acetate (250 ml), 4M hydrogen chloride / 1,4-dioxane solution (25 ml) was added. The precipitated solid was collected by filtration, washed with ethyl acetate and recrystallized from ethanol to give N- [4-fluoro-2- (trifluoromethyl) benzyl] -5-methoxy-2- (pyridine-2- Yl) pyrimidin-4-amine hydrochloride (3.08 g) was obtained.

Example 3
A mixture of 4-chloro-5-methoxy-2- (pyridin-2-yl) pyrimidine (100 mg), 2-trifluoromethylbenzylamine (78 μl), potassium carbonate (94 mg) and acetonitrile (2.3 ml) Heated to reflux for 4 days. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 91: 9), dried under reduced pressure, and 5-methoxy-2- (pyridin-2-yl) -N- [2- ( Trifluoromethyl) benzyl] pyrimidin-4-amine (76 mg) was obtained.

Example 4
5-Ethoxy-4- (methylsulfinyl) -2- (pyridin-2-yl) pyrimidine (120 mg), potassium carbonate (126 mg), 1,4-dioxane (5 ml) and 2,4,6-tri A mixture of fluorobenzylamine (200 mg) was stirred at 95 ° C. for 3 hours. To the reaction solution was added 5% aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 100: 0 to 90:10), then chromatolex (registered trademark) NH (Fuji Silysia Chemical, product number DM1020) column chromatography (n-hexane: chloroform = 60:40 to 20:80), washed with diisopropyl ether and dried under reduced pressure to give 5-ethoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) ) Pyrimidin-4-amine (77 mg) was obtained.

Example 5
5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -4- (methylsulfinyl) -2- (pyridin-2-yl) pyrimidine (250 mg), potassium carbonate (200 mg), 1 , 4-Dioxane (5 ml) and 2-trifluoromethylbenzylamine (0.27 ml) were stirred at 95 ° C. for 16 hours. To the reaction solution was added 5% aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -2- (pyridin-2-yl) -N- [2- A crude product of (trifluoromethyl) benzyl] pyrimidin-4-amine was obtained. 1M hydrochloric acid (10 ml) and concentrated hydrochloric acid (1 ml) were added to a mixture of the obtained crude product and 1,4-dioxane (10 ml), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (70 ml) and 5% aqueous sodium chloride solution (70 ml) were added to the reaction solution, and the aqueous layer was separated. The obtained aqueous layer was made alkaline with 1M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (100 ml). The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 92: 8), washed with diisopropyl ether, dried under reduced pressure, and 2-{[2- (pyridin-2-yl ) -4-{[2- (trifluoromethyl) benzyl] amino} pyrimidin-5-yl] oxy} ethanol (32 mg) was obtained.

Example 6
5-hydroxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine (200 mg), N, N-dimethylformamide (4 ml), potassium carbonate (342 mg) and isopropyl iodide (98.9 μl) of the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (chloroform: methanol = 100: 0 to 95: 5) by chromatolex (registered trademark) NH (Fuji Silysia Chemical, product number DM1020). Wash with n-hexane mixed solvent (4: 1) and dry under reduced pressure to obtain 5-isopropoxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine (60 mg). It was.

  In the same manner as in Examples 1 to 6, the compounds of Examples 7 to 21 shown in the table below were produced. The structures and production methods of the example compounds are shown in Tables 5 to 7, and the physicochemical data are shown in Tables 8 to 10, respectively.

In the tables below, the following abbreviations are used.
Pre: Production example number, Ex: Example number, Str: Structural formula, Syn: Production method (In the above examples / production examples, production example numbers or example numbers produced in the same manner are shown. Represents production examples, and E represents an example, for example, indicates that the compound of Production Example 7 was produced in the same manner as the compound of Production Example 4, and the compound of Example 7 was the same as the compound of Example 1. indicating that produced Te), Dat:. physicochemical data (NMR1: [delta] in ¹ H NMR in _{DMSO-d 6 (ppm),} NMR2: δ in ¹ H NMR in CD ₃ OD (ppm), NMR3 : Δ (ppm) in ¹ H NMR in CDCl ₃ , ESI +: ESI-MS (positive ion), APCI / ESI +: APCI / ESI-MS (positive ion)), Me: methyl, Et: ethyl, iPr: isopropyl , TBS: tert-butyldimethylsilyl.

  The compound of formula (I) or a salt thereof has RANKL / RANK signal inhibitory activity and can be used as a therapeutic agent for diseases involving RANKL / RANK signal such as osteoporosis, osteopenia, rheumatoid arthritis and the like.

Claims (15)

A compound of formula (I) or a salt thereof.

(Where
R ¹ is phenyl _optionally substituted with C _1-6 alkyl, —C _1-6 alkylene-OC _1-6 alkyl, —C _1-6 alkylene-OH, or C _1-6 alkyl;
R ² is pyrrolidin-1-yl, 2-azabicyclo [2.2.1] heptan-2-yl, adamantan-2-ylamino, decahydroisoquinolin-2-yl, 4- (4-chlorophenyl) -1,4- Diazepan-1-yl,

Is;
R ³ is F, Cl or CF ₃ ;
R ⁴ and R ⁵ are the same or different and are H, F or Cl;
n is 1 or 2;
However, when R ² is pyrrolidin-1-yl, R ¹ is a group other than methyl. ) R ² is

The compound according to claim 1 or a salt thereof. The compound or a salt thereof according to claim 2, wherein R ¹ is C _1-6 alkyl. R ² is

The compound according to claim 1 or a salt thereof. The compound or a salt thereof according to claim 4, wherein R ¹ is C _1-6 alkyl. 5-methoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
N- [4-fluoro-2- (trifluoromethyl) benzyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
5-methoxy-2- (pyridin-2-yl) -N- [2- (trifluoromethyl) benzyl] pyrimidin-4-amine,
5-ethoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
2-{[2- (pyridin-2-yl) -4-{[2- (trifluoromethyl) benzyl] amino} pyrimidin-5-yl] oxy} ethanol,
5-isopropoxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine,
N- (2-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- [2- (2,4-dichlorophenyl) ethyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- (2-chloro-6-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- (2,4-difluorobenzyl) -5- (2-methoxyethoxy) -2- (pyridin-2-yl) pyrimidin-4-amine,
5- (2-methoxyethoxy) -2- (pyridin-2-yl) -N- [2- (trifluoromethyl) benzyl] pyrimidin-4-amine,
N- (2-cycloheptylethyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
rel- (1R, 4S) -2- [5-methoxy-2- (pyridin-2-yl) pyrimidin-4-yl] -2-azabicyclo [2.2.1] heptane,
5- (2-methoxyethoxy) -2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine,
N- [4-chloro-2- (trifluoromethyl) benzyl] -5- (2-methylphenoxy) -2- (pyridin-2-yl) pyrimidin-4-amine,
5-phenoxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine,
rel-N-[(1R, 3R, 5R, 7R) -adamantan-2-yl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
5-ethoxy-2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidine,
2-{[2- (pyridin-2-yl) -4- (pyrrolidin-1-yl) pyrimidin-5-yl] oxy} ethanol,
rel- (4aR, 8aS) -2- [5-methoxy-2- (pyridin-2-yl) pyrimidin-4-yl] decahydroisoquinoline, and
The compound of claim 1, selected from the group consisting of 1- (4-chlorophenyl) -4- [5-methoxy-2- (pyridin-2-yl) pyrimidin-4-yl] -1,4-diazepane Or a salt thereof. 5-methoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
N- [4-fluoro-2- (trifluoromethyl) benzyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
5-methoxy-2- (pyridin-2-yl) -N- [2- (trifluoromethyl) benzyl] pyrimidin-4-amine,
5-ethoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
2-{[2- (pyridin-2-yl) -4-{[2- (trifluoromethyl) benzyl] amino} pyrimidin-5-yl] oxy} ethanol,
N- (2-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- [2- (2,4-dichlorophenyl) ethyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- (2-chloro-6-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
N- (2,4-difluorobenzyl) -5- (2-methoxyethoxy) -2- (pyridin-2-yl) pyrimidin-4-amine, and
The compound of claim 1, selected from the group consisting of 5- (2-methoxyethoxy) -2- (pyridin-2-yl) -N- [2- (trifluoromethyl) benzyl] pyrimidin-4-amine Or a salt thereof. 5-methoxy-2- (pyridin-2-yl) -N- (2,4,6-trifluorobenzyl) pyrimidin-4-amine,
N- [4-fluoro-2- (trifluoromethyl) benzyl] -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine,
2-{[2- (pyridin-2-yl) -4-{[2- (trifluoromethyl) benzyl] amino} pyrimidin-5-yl] oxy} ethanol,
N- (2-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine, and
The compound or a salt thereof according to claim 1, selected from the group consisting of N- (2-chloro-6-fluorobenzyl) -5-methoxy-2- (pyridin-2-yl) pyrimidin-4-amine.   A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable excipient.   The pharmaceutical composition according to claim 9, which is a pharmaceutical composition for treating a disease involving RANKL / RANK signals.   The pharmaceutical composition according to claim 10, wherein the disease involving RANKL / RANK signal is osteoporosis, osteopenia or rheumatoid arthritis.   The compound according to claim 1 or a salt thereof for the treatment of a disease involving RANKL / RANK signals.   Use of the compound according to claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of a disease involving RANKL / RANK signals.   Use of the compound according to claim 1 or a salt thereof for the treatment of a disease involving RANKL / RANK signals.   A method for treating a disease involving a RANKL / RANK signal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to a subject.