TW201733580A - Treating agent for cancer having TrK inhibitor resistance - Google Patents

Abstract

The present invention provides a treating agent for cancer having Trk inhibitor resistance. A compound represented by the general formula (I) (in formula, all symbols have same meanings as those described in the specification.) or its salts, its N-oxides, its solvates, or their prodrugs can be used as an effective ingredient of a treating agent for cancer having Trk inhibitor resistance.

Description

Trk inhibitor resistant cancer therapeutic agent

The present invention relates to a cancer therapeutic agent which is resistant to Trk inhibitors. In detail, there is a general formula (I)

(wherein all the symbols represent the same meaning as described below), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof (hereinafter referred to as a compound of the present invention). ) is a cancer therapeutic agent as an active ingredient.

A family of Tropomyosin receptor kinase (hereinafter referred to as Trk), which belongs to the receptor type tyrosin kinase and can be classified as a nerve growth factor (hereinafter, abbreviated as NGF). High affinity receptor TrkA, brain derived trophic factor (BDNF) and neurotrophic factor (hereinafter, abbreviated as NT.)-4/5 high affinity receptor TrkB, and TrkC of NT-3 high affinity receptor. The TrkA, TrkB and TrkC proteins are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. All of the Trk receptors are highly expressed in nerve tissues and are involved in the differentiation and function maintenance of nerve cells (refer to Non-Patent Document 1).

On the other hand, Trk receptors are also reported to be in cancer cells such as neuroblastoma, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, stomach cancer, liver cancer, ovarian cancer, prostate cancer, head and neck cancer, neuroendocrine tumors, and blood cancer. The expression may be related to survival, proliferation, migration, and metastasis of cancer cells (Non-Patent Documents 2 to 8).

Furthermore, NTRK gene 3 can also be found in cancer patients such as lung cancer, colon cancer, intrahepatic cholangiocarcinoma, thyroid cancer, skin cancer, breast cancer, head and neck cancer, kidney cancer, sarcoma, brain tumor, salivary gland tumor and blood cancer. A part of the 'end portion was fused to a part of the 5' end of another gene (partner gene) to form a NTRK fusion gene, and it was confirmed that the fusion gene has cancerigenic ability (Non-Patent Documents 9 to 11).

According to the partner gene reported in the NTRK1 fusion gene, the 5'-end partner genes are MPR1P, CD74, RABGAP1L, TPM3, TPR, TFG, PPL, CHTOP, ARHGEF2, NFASC, BCAN, LMNA and TP53. Similarly, according to the reported NTRK2 fusion gene, QK1, NACC2, VCL, AGBL4, TRIM24, PAN3, AFAP1 and SQSTM1, in the NTRK3 fusion gene, ETV6, BTB1, LYN and RBPM are the 5'-end partner genes, respectively. The Trk fusion protein encoded by these fusion genes is a constant-active kinase, and promotes canceration of cells by abnormal activation of intracellular messages. Because of these conditions, the agent that inhibits Trk can be expected to become a target. A novel type of anticancer agent that has not been available until now. In fact, clinical trials of various Trk inhibitors are currently underway, and the effect of tumor shrinkage has also been confirmed in cancer patients with positive NTRK fusion genes (Non-Patent Documents 12 to 14).

However, on the other hand, LMNA-NTRK1 fusion gene-positive colorectal cancer patients have recently been reported to be tolerated in the treatment of Trk inhibitors of Entrectinib. In the tumor of the tolerant patient, the glycine acid variability of the 595th amino acid present in the TrkA kinase domain can be detected as the G595R variant of arginine and the 667th The amino acid variability was G667C of cysteine, and the TPM3-TrkA recombinant enzyme introduced into the G595R or G667C variant confirmed that the above Trk inhibitor did not exhibit inhibitory activity (Non-Patent Document 15). Similarly, in a patient with a tolerant ETV6-NTRK3 fusion gene-positive MASC (mammary analogue secrectory carcinoma), which can be detected in the treatment with emtritinib, can be detected by the tumor. The glycine acid variation of the 623 amino acid in the TrkC kinase domain is a G623R variant of arginine, and the Trk inhibitor does not exhibit inhibitory activity on the ETG6-TrkC recombinant enzyme introduced into the G623R variant (non-patent) Document 16). Similarly, it has been reported that the above-mentioned Trk inhibitor does not exhibit inhibitory activity or is remarkably low for such variations (Patent Document 7). In view of the above, it is expected that an agent having an inhibitory activity against Trk for such mutations can contribute to the tolerance of a patient with a NTRK fusion gene-positive cancer.

On the other hand, in Patent Document 1, tyramine is described. A method for the treatment or prevention of a human or other mammalian disease by acid kinase, comprising a compound of the following formula (Ia), a salt thereof, an isomer thereof, or a prodrug thereof, for human or other mammals in need thereof The method of administration.

General formula (Ia),

(wherein Aa is selected from the group consisting of (i) to (iii) below: (i) 1 to 3 substituents independently selected from the group of Ra ¹ , ORa ¹ , halogen, etc., as needed a substituted phenyl group, (ii) a naphthyl group optionally substituted with 1 to 3 substituents independently selected from the group of Ra ¹ , ORa ¹ , halogen, etc., (iii) optionally selected from the group consisting of 1 to 3 substituents of the group of Ra ¹ , ORa ¹ , halogen, etc., and 5 and 6 membered single rings independently selected from 1 to 3 hetero atoms in groups of O, N and S heteroaromatic group; the sum of Ba is selected from (i) to (iii) or the like into groups: (i) independently selected from an optionally -La-Ma, C straight or branched chain of ₁ to C ₅ a phenyl group substituted with 1 to 3 substituents of the group of alkyl groups, halogens, etc., (ii) a linear or branched alkyl group optionally selected from -La-Ma, C ₁ to C ₅ , a naphthyl group substituted with 1 to 3 substituents of a group such as halogen, (iii) a linear or branched alkyl group optionally selected from -La-Ma, C ₁ to C ₅ , halogen, or the like, if necessary Substituted from 1 to 3 substituents of the group, and containing 5 to 6 heterocyclic rings independently selected from 1 to 3 heteroatoms of the group O, N and S Group; La is selected from _{- (CH 2) ma -O- (} CH 2) la -, - (CH 2) ma -C (O) - (CH 2) la - group, etc., wherein the variables and ma La is an integer independently selected from 0 to 4; Ma is selected from the group consisting of (i) to (iii) and the like: (i) optionally selected from the group consisting of Ra ¹ , ORa ¹ , halogen, and the like a phenyl group substituted with 1 to 3 substituents of the group, (ii) a naphthyl group optionally substituted with 1 to 3 substituents independently selected from the group of Ra ¹ , ORa ¹ , halogen, etc., (iii And optionally substituted with from 1 to 3 substituents independently selected from the group consisting of Ra ¹ , ORa ¹ , halogen, etc., and containing 1 to 3 impurities independently selected from the group consisting of O, N and S a 5- and 6-membered monocyclic heteroaryl of the atom; wherein Ra ^{1 is} independently selected from the group consisting of: (a) hydrogen, (b) C ₁ to C ₆ alkyl, (c) phenyl, ( d) 5 to 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of O, N and S, (e) C ₁ to C _{a 3-} alkyl-phenyl group, and (f) an alkyl-heteroaryl group containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S; Ra ¹ , in the case of non-hydrogen, may also be used as needed is independently selected from C ₁ to C ₅ linear, and Chain or cyclic -alkyl, C ₁ to C ₃ alkoxy, hydroxy, amino, C ₁ to C ₃ alkyl group, C ₂ to C ₆ dialkylamino, halogen, cyano and nitro Substituted in groups of 1 to 3 substituents; the definition of the radical is omitted.).

Patent Document 2 describes the general formula (Ib)

(wherein Yb is N or CH; Lb ¹ is a bond, -O-, -S-, -SO-, -SO ₂ -, etc.; Lb ² is a bond, -NHC(O)NH-, -NHC(O And Rb ¹ is (i) Rb ⁵ or (ii) a C ₁ to C ₆ alkyl group which may be substituted by one or more halogens, Rb ⁵ or the like; and Rb ² is (i) C ₁ to C ₆ An alkyl group, or (ii) an aryl group or a heteroaryl group, and each group may also have one or more halogens, Rb ⁹ , ORb ⁹ , SRb ⁹ , N(Rb ⁹ ) ₂ , C(O)Rb ⁹ or the like. Substituting; Rb ³ is hydrogen, halogen, C ₁ to C ₆ alkyl, etc.; Rb ⁵ is cycloalkyl, heterocyclic, aryl, heteroaryl, and each group may also have one or more halogens, ORb ⁶ , N(Rb ⁶ ) ₂ , Rb ⁷ , ORb ⁷ and the like are substituted; Rb ⁷ is a cycloalkyl group, a heterocyclic ring, an aryl group or a heteroaryl group, and each group may also have one or more halogens, a hydroxyl group, and N (Rb). ⁶ ) Substituted by ₂ ; each Rb ^{6 is} independently hydrogen or C ₁ to C ₄ alkyl; the definition of the radical is partially omitted.) The compound shown, or the tautomer, enantiomer, pharmaceutically acceptable Salts, hydrates, solvates, complexes, or prodrugs thereof are endogenous ultramicroactivation regulators.

Patent Document 3 describes the general formula (Ic)

(wherein, Ac and Cc are each independently selected from the group consisting of an aryl group and a heteroaryl group which may be substituted; and Bc is selected from the group consisting of -N(H)C(O)N(H)- and -N( H) C(O)N(H)CH ₂ - groups; Xc ¹ to Xc ⁴ are selected from the group consisting of C(Rc ² ) and N, and at least one of Xc ¹ to Xc ⁴ is N Xc ⁵ is C(Rc ³ )(Rc ⁴ ), N(Rc ³ ), O and S(O) _mc ; Rc ¹ is selected from the group consisting of heteroaryl and heterocycloalkyl groups which may also be substituted; The definition of the group is partially omitted.) The compound, or the salt, the ester, or the prodrug thereof, has a B-Raf inhibitory activity.

Patent Document 4 describes the general formula (Id)

(wherein, the ring C _y1d represents a monocyclic carbocyclic ring or a bicyclic carbocyclic ring of C3 to 10; R _1d represents a halogen or the like; R _2d represents a halogen or the like; A _1d and A _2d each independently represent =CR _{3d; -etc} ; A _3d , A _4d , A _5a , and A _6a each independently represent =CR _{4d -etc} ; R _3d represents a halogen or the like; R _4d represents a halogen or the like; Yd represents an oxygen atom or the like; Zd represents formation The carbon atom of the ring may be substituted by an oxygen atom or the like; the definition of the group is omitted. The compound shown, its salt, its N-oxide, its solvate, or a prodrug thereof are Trk inhibiting compounds.

Patent Document 5 describes the general formula (Ie)

(wherein the ring Cy _1e represents a monocyclic carbocyclic ring of C3 to 10, etc.; the ring Cy _2e represents a monocyclic heterocyclic ring of 4 to 10 members; R _1e represents a halogen or the like; R _2e represents a halogen or the like; A _1e and A _2e each independently represents =CR _{3 -etc} ; A _3e , A _4e , A _5e , and A _6e each independently represent =CR _{4e -etc} ; R _3e and R _4e each independently represent a hydrogen atom or the like; The definition of the group is partially omitted.) The compound shown, its salt, its N-oxide, its solvate, or the prodrug thereof are Trk inhibitor compounds.

Patent Document 6 describes 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[2- of the Trk inhibiting compound. (methylsulfonyl)-5-(trifluoromethyl)phenyl]urea, 1-{2-[4-(2-amino-5-fluoropyridin-3-yl)phenoxy]pyrimidine- 5-yl}-3-[2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl]urea, or 1-(2-(1H-pyrazol-1-yl)-5- Acid addition salt of (trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea It crystallizes.

However, in all the literatures, the compound represented by the formula (I), its salt, its N-oxide, its solvate, or the drug precursor of these drugs against Trk inhibitor are not shown. The description of the inhibitory effect on proliferation does not indicate that the compound of the present invention can be described as a therapeutic agent for cancer.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2003/068228

[Patent Document 2] International Publication No. 2010/057833

[Patent Document 3] International Publication No. 2007/076473

[Patent Document 4] International Publication No. 2013/161919

[Patent Document 5] International Publication No. 2014/129431

[Patent Document 6] International Publication No. 2016/027754

[Patent Document 7] International Publication No. 2016/196141

[Non-patent literature]

[Non-Patent Document 1] Annual Review of Biochemistry, Vol. 72, pp. 609-642, 2003

[Non-Patent Document 2] Cancer Letters, Vol. 228, pp. 143-153, 2005

[Non-Patent Document 3] Clinical Cancer Research, Vol. 15, pp. 5962-5967, 2009

[Non-Patent Document 4] Proceedings of the National Academy of Sciences, Vol. 111, pp. 10299-10304, 2014

[Non-Patent Document 5] Clinical Cancer Research, Vol. 7, pp. 105-112, 2001

[Non-Patent Document 6] Carcinogenesis, Vol. 31, pp. 1939-1947, 2010

[Non-Patent Document 7] Lung Cancer, Vol. 79, pp. 205-214, 2013

[Non-Patent Document 8] Biochemical and Biophysical Research Communications, Vol. 441, pp. 431-437, 2013

[Non-Patent Document 9] Nature Medicine, Vol. 19, pp. 1469-1474, 2013

[Non-Patent Document 10] Cancer Discovery, Vol. 5, pp. 25-34, 2015

[Non-Patent Document 11] Oncogene, Vol. 32, pp. 3698-3710, 2013

[Non-Patent Document 12] Journal of the National Cancer Institute, Vol. 108, 1-4, 2016

[Non-Patent Document 13] Journal of Thoracic Oncology, Vol. 10, pp. 1670-1674, 2015

[Non-Patent Document 14] Cancer Discovery, Vol. 5, pp. 1049-1057, 2015

[Non-Patent Document 15] Cancer Discovery, Vol. 6, 36-44, 2016

[Non-Patent Document 16] Annals of Oncology, What hides behind the MASC: Clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC)

An object of the present invention is to provide an active ingredient of a cancer therapeutic agent which is resistant to Trk inhibitors.

The present inventors have deliberately studied to solve the above problems and found a compound represented by the above formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, to Trk. The inhibitor-resistant cancer has a proliferation inhibiting effect, and the present invention has been completed.

That is, the present invention is as follows.

[1] A therapeutic agent for cancer resistant to Trk inhibitor, which comprises a compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof Active ingredients,

Wherein the ring Cy ₁ represents a C 3 to 10 monocyclic carbocyclic ring or a bicyclic carbocyclic ring, or a 4 to 10 membered monocyclic heterocyclic ring or a bicyclic heterocyclic ring; and the ring Cy ₂ represents a 4 to 10 membered monocyclic ring. a heterocyclic or bicyclic heterocyclic ring; R ₁ represents (1) halogen, (2) may be substituted with a substituent selected from the group consisting of (i) halogen and (ii) hydroxyl group, C1 to 6 alkyl, C2 To a 6 alkenyl group, or a C 2 to 6 alkynyl group, (3) a C ₅ to 6 monocyclic carbocyclic ring which may be substituted with 1 to 2 R ₅ , (4) ₅ which may be substituted by 1 to 2 R 5 To 6-membered monocyclic heterocycle, (5)-S(O) _m1 -R ₆ , (6)-SO ₂ NR ₇ R ₈ , (7)-C(O)OR ₉ , (8)-NR ₁₀ C(O)R ₁₁ , (9)-C(O)NR ₁₂ R ₁₃ , (10)-OR ₁₄ , (11)-NR ₁₅ R ₁₆ , (12) cyano, or (13) nitro; R ₅ represents (1) halogen, (2)-S(O) _{m2 -} R ₁₇ , (3)-SO ₂ NR ₁₈ R ₁₉ , (4)-C(O)OR ₂₀ , (5)-NR ₂₁ C ( O) R ₂₂ , (6)-C(O)NR ₂₃ R ₂₄ , (7)-OR ₂₅ , (8)-NR ₂₆ R ₂₇ , (9) cyano, (10) nitro, or (11) a C1 to 3 alkyl group which may be substituted with a substituent selected from the group consisting of (i) halogen, (ii) hydroxyl group, and (iii) pendant oxy group. When R ₅ is 2, R _{5 is} independently The same or different, and 2 R _{5 are} each independently a C1 to 3 alkyl group or a hydroxyl group. And when the R ₅ position is adjacent to a carbon atom on a C5 to 6 monocyclic carbocyclic ring or a 5 to 6 membered monocyclic heterocyclic ring, the groups may also form a ring; R ₆ to R ₂₇ , each independently And (2) a C1 to 6 alkyl group which may be substituted by (i) a halogen or (ii) a hydroxyl group, and each of R ₁₈ and R _{19 is} independently an alkyl group of C1 to 6 It is also possible to form a ring together; R ₂ is (1) halogen, (2) C1 to 6 alkyl group which may be substituted by (i) halogen or (ii) hydroxyl group, (3) may be (i) halogen or (ii) a C3 to 6 cycloalkyl group substituted by a hydroxy group, (4) a C1 to 6 alkoxy group which may be substituted by a halogen, (5)-NR ₂₈ R ₂₉ , a (6) 3 to 7 membered monocyclic heterocyclic ring, or (7)-O-(3 to 7 membered monocyclic heterocyclic ring); R ₂₈ and R ₂₉ each independently represent (1) a hydrogen atom, or (2) may be substituted by (i) a halogen or (ii) a hydroxyl group. C1 to 6 alkyl; A ₁ and A ₂ each independently represent =CR ₃ - or =N-; A ₃ , A ₄ , A ₅ , and A ₆ each independently represent =CR ₄ - or =N-; R ₃ and R ₄ each independently represent a hydrogen atom or a halogen; m1 represents an integer of 0 to 2; m2 represents an integer of 0 to 2; p represents an integer of 0 to 7, q represents an integer of 0 to 7, and r represents 0 to An integer of 2.

However, when each of p, q, and r represents an integer of 2 or more, R ₁ , R ₂ , and R ₃ are each independently and may be the same or different.

[2] The agent according to the above [1], wherein the formula (I) is as shown in the formula (IA),

Wherein Cy _1-A represents a C5 to 6 monocyclic aromatic carbocyclic ring; Cy _2-A represents a 5 to 10 membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring; t represents 0 to 4 An integer, the other token indicates the same meaning as the token of the preceding clause.

[3] The agent according to the above [1], wherein the formula (I) is as shown in the formula (IB),

Wherein Cy _1-B represents a C5 to 6 monocyclic aromatic carbocyclic ring; Cy _2-B represents a 5 to 10 membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring; t represents 0 to 4 Integers, other symbols indicate the same meaning as the symbols described in [1].

[4] A therapeutic agent for cancer resistant to Trk inhibitor, which comprises: (1) 1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)- 3-(2-(4-(2-Amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea, (2) 1-(2-(4-(2-amine) 5--5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2- (4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea, (3) 1-(2-(4-(2-amine) 5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-pyrazole -1-yl)phenyl)urea, (4) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-( 2-chloro-5-(trifluoromethyl)phenyl)urea, (5) 1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl-3-( 6-(4-(2-Amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea, (6) 1-(2-(1H-1,2,3-tri) Zin-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl Urea, (7) 1-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)-3-(2-(pyridine-3- 5-(3-trifluoromethyl)phenyl)urea, (8) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidine-5- 3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea, (9) 1-(2-(1H-1, 2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy) Pyrimidine-5-yl)urea, (10) 1-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2) -(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, 11) 1-(2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridine-3) -yl)phenoxy)pyrimidin-5-yl)urea, (12) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl -3-(2-fluoro-4-(trifluoromethyl)phenyl)urea, (13) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy) ()pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea, (14) 1-(2-{4-[2-amino-5-(three Fluoromethyl)-3-pyridyl]phenoxy}-5-pyrimidine (pyridyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea, (15) 1-{2- [4-(2-Amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2-biphenyl]urea, 16) 1-{2-[4-(2-Amino-5-fluoro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2- Biphenyl]urea, (17) 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[2-(4 -chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea, (18) 1-{2-[4-(2-amino-5-chloro-3-pyridine Phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea, (19)1 -{2-[4-(2-Amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[2,4-bis(trifluoromethyl)phenyl] Urea, (20) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridyl]phenoxy}-5-pyrimidinyl)-3-[2-( 4-Chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea, (21) 1-{2-[4-(2-amino-5-fluoro-3- Pyridyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl)urea, (22) 1-(2{4- [2-Amino-5-(trifluoromethyl)-3-pyridyl]phenoxy}-5-pyrimidinyl-3-[2-(methylsulfonyl)-5-(trifluoromethyl) Phenyl]urea (23) 1-{2-[4-(2-Amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)- 5-(trifluoromethyl)phenyl]urea, (24) 2-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridyl]phenoxy} -5-pyrimidinyl)aminemethanyl]amino}N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide, (25) 1-(2-(4-(5-( Azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl) Phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (26) 1-(2-(4-(5) -(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl- 1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea, (27) 1-(2-(4-(5-methoxypyrazolo[1,5-a]] Pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (28) 1-(2 -(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoro Methyl)phenyl)urea, (29) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}- 5-pyrimidinyl-3-[2-(3-pyridyl)-5-(trifluoromethyl)phenyl]urea, (30) 1-(2-{4-[5-(dimethylamine) Pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl-3-[2-(1-methyl-1H-pyrazole-5-yl)- 5-(Trifluoromethyl)phenyl]urea, (31) 1-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]- 5-pyrimidinyl}-3-[2-(3-pyridyl)-5-(trifluoromethyl)phenyl]urea, (32) 1-(2-{4-[5-(ethylamino) Pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3'-methyl-4-(trifluoromethyl)-2-biphenyl Urea, (33 1-(2-{4-[5-(Dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[4 -(trifluoromethyl)-2-biphenyl]urea, (34) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3 -yl]phenoxy}-5-pyrimidinyl-3-[3'-methyl-4-(trifluoromethyl)-2-biphenyl]urea, or (35)1-(2-{ 4-[5-(Dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl-3-[2'-methyl-4- (Trifluoromethyl)-2-biphenyl]urea, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof Effective ingredients.

[5] The agent according to any one of the items [1] to [4] wherein the Trk inhibitor-resistant cancer is a Trk inhibitor-resistant cancer belonging to NTRK-positive cancer.

[6] The agent according to any one of the items [1] to [5] wherein the NTRK-positive cancer is a NTRK fusion gene-positive cancer.

[7] The agent according to any one of the items [1] to [6] wherein the Trk inhibitor-resistant cancer is a cancer which is resistant to a Trk inhibitor by administration of a Trk inhibitor.

[8] The agent according to any one of the items [1] to [7] wherein the Trk inhibitor-resistant cancer is a variation in the NTRK gene generated by administration of the Trk inhibitor, and the Trk is obtained. Inhibitor resistant cancer.

[9] The agent according to the above [8], wherein the variation in the NTRK gene is a variation in the NTRK fusion gene.

[10] The agent according to any one of [1] to [9] wherein the variation in the NTRK fusion gene is a variation in the NTRK1 fusion gene.

[11] The agent according to any one of [1] to [10] wherein the variation in the NTRK1 fusion gene is G595R and/or G667C variation.

[12] The agent according to any one of the items [1] to [11] wherein the variation in the NTRK fusion gene is a variation in the NTRK2 fusion gene.

[13] The agent according to any one of [1] to [12] wherein the variation in the NTRK2 fusion gene is a G639R mutation.

[14] The agent according to any one of the items [1] to [13] wherein the variation in the NTRK fusion gene is a variation in the NTRK3 fusion gene.

[15] The agent according to any one of the items [1] to [14] wherein the variation in the NTRK3 fusion gene is a G623R mutation.

[16] The agent according to any one of the items [1] to [15] wherein the Trk inhibitor is from Ertrozinib, LOXO-101, AZD-7451, TSR-011, Crizotinib ( More than one agent selected from the group consisting of Crizotinib), ASP-7269 and DS-6051b.

[17] The agent according to any one of the items [1] to [16] wherein the cancer is lung cancer, colorectal cancer, intrahepatic cholangiocarcinoma, thyroid cancer, skin cancer, breast cancer, head and neck cancer, kidney cancer , sarcoma, brain tumor, salivary gland tumor or blood cancer.

[18] The agent according to any one of the items [1] to [17], which is used in combination with an alkylating agent, a metabolic antagonist, an anticancer antibiotic, an anticancer botanical preparation, a hormone drug One or more selected from the group consisting of a platinum compound, a topoisomerase inhibitor, a kinase inhibitor, an anti-CD20 antibody, an anti-HER2 antibody, an anti-EGFR antibody, and an anti-VEGF antibody.

[19] The agent according to any one of the items [1] to [18], wherein an EGFR inhibitor is used in combination.

[20] The agent according to the above [19], wherein the EGFR inhibitor is a group selected from the group consisting of erlotinib, gefitinib, and afatinib. The above medicines.

[21] The agent according to any one of the items [1] to [18], wherein a MEK inhibitor is used in combination.

[22] The agent according to the above [21], wherein the MEK inhibitor is trametinib and/or simetintinib.

[23] a compound represented by the above formula (I), a salt thereof, an N-oxide thereof, or the like The use of a solvate, or a prodrug thereof, for the treatment of cancer resistant to Trk inhibitors.

[24] Use of a compound represented by the above formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, for use in a Trk inhibitor-resistant cancer The manufacture of therapeutic agents.

[25] A method for treating a cancer resistant to Trk inhibitor, which comprises administering to a subject an effective amount of a compound represented by the above formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or the like Prodrugs.

[26] a compound represented by the above formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, which is used in the treatment of cancer resistant to Trk inhibitors. use.

The active ingredient of the therapeutic agent of the present invention is a compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, which can be used as a resistance to a Trk inhibitor. The active ingredient of a therapeutic agent for cancer.

Hereinafter, the present invention will be described in detail.

In the present invention, the "Trk inhibitor-resistant cancer" may be a cancer that has been confirmed to be a disease after treatment with a Trk inhibitor, and a cancer that is resistant to a Trk inhibitor by administration of a Trk inhibitor. Inhibition of Trk due to mutations in the NTRK gene produced by Trk inhibitor administration The cancer resistant to the agent, and the cancer which is resistant to the Trk inhibitor due to one or more mutations selected from the group of the G595R mutation, the G667C mutation, the G639R mutation, and the G623R mutation described later. The Trk inhibitor refers to an agent which exhibits an inhibitory activity against the Trk protein, and one aspect of the present invention is a Trk inhibitor other than the compound represented by the formula (I) or a salt thereof. Other aspects of the invention are from Entrectinib (RXDX-101), LOXO-101, AZD-7451, TSR-011, Crizotinib, Altiratinib ), one or more agents selected from the group consisting of ASP-7269, DS-6051b, and VM-902.

In the present invention, "NTRK-positive cancer" refers to a cancer which can express the expression of NTRK gene (including NTRK1 gene, NTRK2 gene and NTRK3 gene) or Trk protein (including TrkA protein, TrkB protein, TrkC protein). The NTRK gene includes, for example, the wild type and variant NTRK1 gene, NTRK2 gene and NTRK3 gene. Further, the variant NTRK gene includes, for example, an NTRK fusion gene (including a NTRK1 fusion gene, a NTRK2 fusion gene, and a NTRK3 fusion gene). "NTRK-positive cancer" also includes cancers that constantly activate Trk protein due to overexpression of the wild-type NTRK gene and the expression of the variant NTRK gene.

"NTRK1 fusion gene", for example, may be MPRIP-NTRK1, CD74-NTRK1, RABGAP1L-NTRK1, TPM3-NTRK1, TPR-NTRK1, TFG-NTRK1, PPL-NTRK1, CHTOP-NTRK1, ARHGEF2-NTRK1, NFASC-NTRK1, BCAN -NTRK1, LMNA-NTRK1 and TP53-NTRK1. "NTRK2 fusion gene", for example, QKI-NTRK2, NACC2-NTRK2 VCL-NTRK2, AGBL4-NTRK2, TRIM24-NTRK2, PAN3-NTRK2, AFAP1-NTRK2 and SQSTM1-NTRK2. Examples of the "NTRK3 fusion gene" include ETV6-NTRK3, BTB1-NTRK3, LYN-NTRK3, and RBPMS-NTRK3.

In the present invention, the "G595R variant" refers to the result of substitution of a base in the wild type or variant NTRK1 gene, such that the wild type TrkA protein (TrkA isoform 2 (RefSeq: NP_002320.2)) a 595 amino acid residue, or an equivalent amino acid residue thereof (eg, an amino acid residue equivalent in other TrkA isoforms and variant TrkA proteins), converted from glycine to refined Amino acid variation. Further, the G595R mutation in the NTRK1 fusion gene refers to the 595 amino acid residue of the wild type TrkA protein (TrkA isoform 2 (RefSeq: NP_002320.2)), which is equivalent to the amino acid residue of the TrkA fusion protein. , converted from glycine to arginine.

In the present invention, "G667C variant" refers to the result of substitution of a base in the wild type or variant NTRK1 gene, such that the wild type TrkA protein (TrkA isoform 2 (RefSeq: NP_002320.2)) a 667 amino acid residue, or an equivalent amino acid residue thereof (eg, an equivalent amino acid residue in other TrkA isoforms and variant TrkA proteins), converted from glycine to cysteamine Acidic variation. Further, the G667C mutation in the NTRK1 fusion gene refers to the amino acid residue of the equivalent TrkA fusion protein of the 667 amino acid residue of the wild type TrkA protein (TrkA isoform 2 (RefSeq: NP_002320.2)). Conversion from glycine to cysteine.

In the present invention, "G639R mutation" refers to a result of substitution of a base in a wild type or a variant NTRK2 gene, such that wild type The 639 amino acid residue of the TrkB protein (TrkB isoform a (RefSeq: NP_006171.2)), or its equivalent amino acid residue (eg, in other TrkB isoforms and variant TrkB proteins) A comparable amino acid residue), converted from glycine to arginine. Further, the G639R mutation in the NTRK2 fusion gene refers to an amino acid residue of a TrkB fusion protein equivalent to the 639 amino acid residue of the wild type TrkB protein (TrkB isoform a (RefSeq: NP_006171.2)). Conversion from glycine to arginine. The "G639R variant" is a variation of the TrkB protein corresponding to the aforementioned "G595R variant".

In the present invention, the "G623R variant" refers to the result of substitution of a base in the wild type or variant NTRK3 gene, such that the wild type TrkC protein (TrkC isoform a (RefSeq: NP_001012338.1) or TrkC is the same. The 623 amino acid residue of the work form b (RefSeq: NP_002521.2)), or its equivalent amino acid residue (for example, the equivalent amino acid in other TrkC isoforms and variant TrkC proteins) Residue), converted from glycine to arginine. Further, the G623R mutation in the NTRK3 fusion gene refers to the 623 amino acid residue of the wild type TrkC protein (TrkC isoform a (RefSeq: NP_001012338.1) or TrkC isoform b (RefSeq: NP_002521.2)). The amino acid residue of the equivalent TrkC fusion protein is converted from glycine to arginine. The "G623R variant" is a variant of the TrkC protein corresponding to the aforementioned "G595R variant".

In the present invention, the "C3 to 10 monocyclic carbocyclic ring or bicyclic carbocyclic ring" means, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclodecane. , cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, Benzene, pentene, perhydrogenated pentene, anthracene, perhydroanthracene, anthracene, perhydroanthracene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene ring.

In the present invention, the "4 to 10 membered monocyclic heterocyclic ring or bicyclic heterocyclic ring" means, for example, oxetane, azetidine, pyrrolidine, pyrrole, imidazole, triazole, tetrazole. , pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine, pyridazine, azepanene, diazepine, furan, piper, oxeene, thiophene, thiopyran, Thiosene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thia Diazole, thiazine, thiadiazine, thiazepine, thiadiazepine, anthracene, isoindole, porphyrin, benzofuran, isobenzofuran, benzothiophene , isobenzothiophene, carbazole, quinoline, isoquinoline, quinolizine, anthraquinone, pyridazine, acridine, Pyridine, quinoxaline, quinazoline, porphyrin, benzoxazole, benzothiazole, benzimidazole, benzobisoxazole, benzoxathiale, benzopyran, benzofuran Anthraquinone, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolium, triazoline, triazole, tetrazoline, tetrazolidine, pyrazoline, pyrazole, two Hydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine Alkene, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran , dihydropyran, tetrahydropyran, dihydrocycloheptene, tetrahydrooxepane, perhydroheterocyclene, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetra Hydrothiazepine, dihydrothiazepine, tetrahydrothiene heptane, perhydrothiene heptene, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, Tetraisoxazole (isoxazole), dihydrothiazole, tetrahydrogen Thiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), two Hydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxa azepine, perhydrooxazepene , dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazole) ), dihydrothiazine, tetrahydrothiazide, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiene heptane, perhydrothiecycloheptene, dihydrogen Thiadiazepine, tetrahydrothiazepine, perhydrothiazepine, morpholine, thiomorpholine, oxathiane, porphyrin, Isoporphyrin, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, All hydrogen isobenzothiophene, dihydrocarbazole, perhydrocarbazole, dihydroquinoline, tetrahydroquine , Perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydro isoquinoline, phthalazine dihydro, tetrahydro-phthalazine, phthalazine perhydro, dihydro Pyridine, tetrahydrogen Pyridine, all hydrogen Pyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydroporphyrin, tetrahydroporphyrin, perhydrogen Porphyrin, benzothiazepine, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzene Thiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dioxa dihydroanthracene, benzodioxane , benzothiopyran, dihydrobenzodioxan, dihydrobenzooxa heterohexene, Anthracene, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyridinopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, pyrimidopyridine, and triazolopyridine ring, and the like.

In the present invention, "halogen" means fluorine, chlorine, bromine, and iodine.

In the present invention, "C1 to 6 alkyl", for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, isobutyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, Hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 2-methyl-2-ethyl Propyl, 1-ethylbutyl, and 2-ethylbutyl.

In the present invention, "C2 to 6 alkenyl group", for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group , 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butene A group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, and the like.

In the present invention, "C2 to 6 alkynyl", for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentyl Alkynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.

In the present invention, "C5 to 6 monocyclic carbon ring", for example, Cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene ring.

In the present invention, "5 to 6 membered monocyclic heterocyclic ring", for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine, pyridazine, furan, piperidine Norm, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine , imidazoline, imidazolium, triazoline, triazole, tetrazoline, tetrazole, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, two Hydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, Dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazole), dihydrothiazole, tetra Hydrothiazole (thiazopyridine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), Dihydrooxazine, tetrahydrooxazine, Hydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazide, tetrahydrothiazide, dihydrothiadiazine, tetrahydrothiazide , morpholine, thiomorpholine, and oxathiane ring.

In the present invention, the "C1 to 3 alkyl group" means a methyl group, an ethyl group, a n-propyl group, and an isopropyl group.

In the present invention, the "C3 to 6 cycloalkyl group" means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

In the present invention, "C1 to 6 alkoxy group", for example, methoxy Base, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, tert-butoxy, isobutoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, Oxyl, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy, 1,2- Dimethylbutoxy, 1,3-dimethylbutoxy, 1-methyl-1-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1,2-dimethyl Butyloxy, 2,2-dimethylbutoxy, 1-ethyl-2-methylpropoxy, 2-ethyl-2-methylpropoxy, and 1-ethylbutoxy Wait.

In the present invention, the "3 to 7 membered monocyclic heterocyclic ring", for example, aziridine, oxetane, azetidine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, Piperidine, piperazine, pyrazine, pyrimidine, pyridazine, azepanene, diazepine, furan, piper, oxeene, thiophene, thiopyran, thiene, Oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, Thiadiazine, thiazepine, thiadiazepine, pyrroline, pyrrolidine, imidazoline, imidazolium, triazoline, triazole, tetrazoline, tetrazolidine, pyr Oxazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydrohydroquinone Pyrazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine Heptene, dihydrofuran, tetrahydrofuran, two Pyran, tetrahydropyran, di-heptene heterocyclic hydroxide, tetra-heptene hydroxide heterocyclic, heterocyclic hydroxide full-heptene, dihydro-thiophene, tetrakis Hydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiazepine, tetrahydrothiene, perhydrothienene, dihydrooxazole, tetrahydrooxazole Zolidine, dihydroisoxazole, tetrahydroisoxazole (isoxazole), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), two Hydrofuroxan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, two Hydroxoxazepine, tetrahydrooxazepine, perhydrooxazepene, dihydrooxazepene, tetrahydrooxazacycloheptene , all-hydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazide, tetrahydrothiazide, dihydrothiadiazine, tetrahydrothiazide Pyrazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiazepine, tetrahydrothiazepine Cycloheptene, perhydrothiazepine, morpholine, thiomorpholine, and oxathiane ring.

In the present invention, the "5 to 10 membered monocyclic aromatic heterocyclic ring or bicyclic aromatic heterocyclic ring", for example, pyridinium, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, anthracene Azine, azepanene, diazepine, furan, oxeene, thiophene, thiene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, Oxacycloheptene, oxadiazepine, thiadiazole, anthracene, isoindole, pyridazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, Carbazole, quinoline, isoquinoline, quinolizine, anthraquinone, pyridazine, acridine, Pyridine, quinoxaline, quinazoline, porphyrin, benzoxazole, benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, pyrazolopyrimidine, imidazolium Pyrazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, pyrimidopyridine, and triazolopyridine ring, and the like.

In the present invention, the "5 to 6 membered monocyclic aromatic heterocyclic ring", for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, Isoxazole, thiazole, isothiazole, furazan, oxadiazole, and thiadiazole ring.

In the present invention, "2 R _{5 are} each independently a C1 to 3 alkyl group or a hydroxyl group, and a carbon adjacent to a C5 to 6 monocyclic carbocyclic ring or a 5 to 6 membered monocyclic heterocyclic ring in the R ₅ position. In the case of an atom, the group may also form a ring together, for example, a base or the like described below.

(wherein Cy ₃ represents a C5 to 6 monocyclic carbocyclic ring or a 5 to 6 membered monocyclic heterocyclic ring; and an arrow indicates a bond to the ring Cy ₁ .)

In the present invention, when R ₅ is -SO ₂ NR ₁₈ R ₁₉ and R ₁₈ and R _{19 are} each independently a C1 to 6 alkyl group, the group may form a ring together, for example, the following groups.

In the present invention, the ring Cy _{1 is} preferably a C5 to 6 monocyclic carbocyclic ring or a 5 to 6 membered monocyclic heterocyclic ring.

In the present invention, the ring Cy _{1 is more} preferably cyclopentane, cyclohexane, benzene, piperazine, thiopyran, pyrrolidine, piperidine, piperazine, imidazoline, imidazolium, morpholine, thiomorpholine, and 5- to 6-membered monocyclic aromatic heterocyclic ring.

In the present invention, the ring Cy _{1 is} further preferably a benzene and a 5- to 6-membered monocyclic aromatic heterocyclic ring.

In the present invention, the ring Cy ₁ is preferably benzene, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, and isothiazole ring.

In the present invention, the ring Cy _{1 is} further preferably a benzene, an imidazole, a pyrazole, a pyridine, a pyrazine, a pyrimidine, or a pyridazine ring.

In the present invention, the ring Cy _{1 is} further more preferably a benzene, a pyrazole, or a pyridine ring.

In the present invention, the ring Cy _{1 is} most preferably a benzene ring and a pyridine ring.

In the present invention, the ring Cy _{2 is} preferably a 5- to 10-membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring.

In the present invention, the ring Cy _{2 is more} preferably a pyridine, a pyrazine, a pyrimidine, a pyridazine, an anthracene, an isoindole, a pyridazine, a benzofuran, an isobenzofuran, a benzothiophene, an isobenzothiophene or an anthracene. Azole, quinoline, isoquinoline, quinolizine, anthraquinone, pyridazine, acridine, Pyridine, quinoxaline, quinazoline, porphyrin, benzoxazole, benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, pyrazolopyrimidine, imidazolium Pyrazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, pyrimidopyridine, and triazolopyridine ring.

In the present invention, the ring Cy ₂ is preferably pyridine, pyrazine, pyrimidine, pyridazine, anthracene, isoindole, pyridazine, oxazole, quinoline, isoquinoline, quinolizine, anthracene, pyridazine, Acridine, Pyridine, quinoxaline, quinazoline, porphyrin, benzoxazole, benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, pyrazolopyrimidine, imidazolium Pyrazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, pyrimidopyridine, and triazolopyridine ring.

In the present invention, the ring Cy _{2 is} further preferably pyridine, pyrazine, pyrimidine, pyridazine, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyridinium Azolopyrimidine, pyrimidopyridine, and triazolopyridine ring.

In the present invention, the ring Cy _{2 is} further more preferably a pyridine, a pyrimidine, a pyrazolopyrimidine, an imidazopyridazine, an imidazopyridine, a pyrrolopyridine, an imidazopyrazine, or a pyrazolopyridine ring.

In the present invention, the ring Cy _{2 is} most preferably a pyridine or pyrazolopyrimidine ring.

In the present invention, R _{1 is} preferably (1) halogen, (2) C1 to 3 alkyl group which may be substituted by halogen, (3) benzene ring which may be substituted by 1 to 2 R ₅ , (4) A 5- to 6-membered monocyclic aromatic heterocyclic ring substituted with 1 to 2 R ₅ , (5) methylsulfonyl, and (6) N,N-dimethylsulfonamide.

In the present invention, R _{1 is more} preferably (1) halogen, (2) methyl, (3) trifluoromethyl, (4) difluoromethyl, (5) monofluoromethyl, (6) trichloromethane. a (7) dichloromethyl group, (8) a monochloromethyl group, (9) a benzene ring which may be substituted by 1 to 2 R ₅ , (10) a pyrrole which may be substituted by 1 to 2 R ₅ , imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, and thiadiazole ring And (11) methylsulfonyl, and (12) N,N-dimethylsulfonamide.

In the present invention, R _{1 is} further preferably (1) halogen, (2) methyl, (3) trifluoromethyl, (4) difluoromethyl, (5) monofluoromethyl, (6) benzene ring. , (7) indoline, (8) tolyl, (9) dimethylbenzene ring, (10) imidazole, triazole, pyrazole, and pyridine ring which may be substituted with 1 to 2 R ₅ , And (11) methylsulfonyl.

In the present invention, R _{1 is} further preferably (1) halogen, (2) trifluoromethyl, (3) difluoromethyl, (4) benzene ring, (5) indoline ring, (6) tolyl group. , (7) dimethylbenzene ring, (8) imidazole, triazole, pyrazole, and pyridine ring which may be substituted by 1 to 2 methyl, difluoromethyl or trifluoromethyl, and (9) ) methylsulfonyl.

In the present invention, R _{1 is} further more preferably (1) trifluoromethyl, (2) difluoromethyl, (3) benzene ring, and (4) may be 1 to 2 methyl, difluoromethyl, Or a triazole, a pyrazole, and a pyridine ring substituted with a trifluoromethyl group, and (5) a methylsulfonyl group.

In the present invention, R _{1 is} preferably (1) a trifluoromethyl group, and (2) a triazole or pyrazole which may be substituted with 1 to 2 methyl groups, difluoromethyl groups or trifluoromethyl groups, and Pyridine ring.

In the present invention, R _{5 is} preferably (1) halogen, (2) a methyl group which may be substituted by halogen, and (3) a C1 to 3 alkyl group which may be substituted by a hydroxyl group or a pendant oxy group.

In the present invention, R _{5 is more} preferably a methyl group, a trifluoromethyl group, a difluoromethyl group, an ethyl fluorenyl group, or a hydroxyethyl group.

In the present invention, R _{5 is} most preferably a methyl group, a trifluoromethyl group, and a difluoromethyl group.

In the present invention, R _{2 is} preferably (1) halogen, (2) C1 to 3 alkyl group which may be substituted by halogen or hydroxy group, (3) C3 to 6 cycloalkyl group, (4) C1 to 3 alkoxy group. , (5) an amine group, (6) a methylamino group which may be substituted by a hydroxyl group, an ethylamino group, a n-propylamino group, an isopropylamino group, an n-butylamino group, a second butylamino group , tert-butylamino, isobutylamino, and dimethylamino, (7) 3 to 7 membered monocyclic heterocyclic ring, and (8)-O- (3 to 7 membered monocyclic hetero ring).

In the present invention, R _{2 is more} preferably halogen, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, hydroxymethyl, hydroxyethyl, 2-methyl-hydroxyethyl, cyclopropyl, Methoxy, ethoxy, amine, methylamino, ethylamino, dimethylamino, 2-methyl-2-hydroxypropylamino, oxetanyloxy, nitrogen A heterocyclic butane ring, a pyrrolidine ring, and a piperidine ring.

In the present invention, R ₂ is preferably halogen, methyl, cyclopropyl, methoxy, amine, dimethylamino, oxetanyloxy, azetidine, pyrrolidine. Ring, and piperidine ring.

In the present invention, R _{2 is} further preferably a halogen, a methyl group, an amine group, an azetidine ring, and a pyrrolidine ring.

In the present invention, R _{2 is} most preferably a fluorine, a chlorine, a methyl group, an amine group or an azetidine ring.

In the present invention, R _{3 is} preferably hydrogen and fluorine, and most preferably hydrogen.

In the present invention, R _{4 is} preferably hydrogen and fluorine, and most preferably hydrogen.

In the present invention, R _{6 is} preferably a C1 to 3 alkyl group which may be substituted by halogen.

In the present invention, R _{6 is more} preferably a methyl group, an ethyl group or a n-propyl group.

In the present invention, R ₇ and R ₈ are each preferably independently a hydrogen atom and a C1 to 3 alkyl group which may be substituted with a hydroxyl group.

In the present invention, R ₇ and R _{8 are more} preferably each independently a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, and a 2-hydroxypropyl group.

In the present invention, R ₇ and R _{8 are} further preferably each independently a hydrogen atom, a methyl group, an ethyl group, and a n-propyl group.

In the present invention, R _{9 is} preferably a hydrogen atom, a methyl group, and an ethyl group.

In the present invention, R ₁₀ to R _{16 are} preferably each independently a hydrogen atom, a methyl group, an ethyl group, and a n-propyl group.

In the present invention, R _{17 is} preferably a C1 to 3 alkyl group which may be substituted by halogen.

In the present invention, R _{17 is more} preferably a methyl group, an ethyl group or a n-propyl group.

In the present invention, R ₁₈ and R _{19 are} preferably each independently a hydrogen atom and a C1 to 3 alkyl group which may be substituted with a hydroxyl group.

In the present invention, R ₁₈ and R _{19 are more} preferably each independently a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, and a 2-hydroxypropyl group.

In the present invention, R ₁₈ and R _{19 are} further preferably each independently a hydrogen atom, a methyl group, an ethyl group, and a n-propyl group.

In the present invention, R _{20 is} preferably a hydrogen atom, a methyl group, and an ethyl group.

In the present invention, R ₂₁ to R _{29 are} preferably each independently a hydrogen atom, a methyl group, an ethyl group, and a n-propyl group.

In the present invention, m1 is preferably an integer of two.

In the present invention, m2 is preferably an integer of two.

In the present invention, p is preferably an integer of from 0 to 3.

In the present invention, q is preferably an integer of from 0 to 3.

In the present invention, r is preferably an integer of from 0 to 1.

In the present invention, R _2−a and R _2−b are each independently the same as R ₂ , and a preferred group is also the same as R ₂ .

In the present invention, q-a is preferably an integer of from 0 to 1.

In the present invention, q-b is preferably an integer of from 0 to 1.

In the present invention, the general formula (I) preferably has the above ring Cy ₁ , ring Cy ₂ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R _2-a , R _2−b , m1 . Combinations of preferred definitions of m2, p, q, r, t, qa, and qb are preferred.

In the present invention, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof are preferably of the formula (IA).

(wherein, Cy _1-A represents a C5 to 6 monocyclic aromatic carbocyclic ring; and Cy _2-A represents a 5- to 10-membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring; A compound represented by the above formula (1), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In still other aspects, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably of the formula (IB).

(wherein, Cy _1-B represents a C5 to 6 monocyclic aromatic carbocyclic ring; Cy _2-B represents a 5 to 10 membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring; A compound represented by the above formula (1), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

Still another aspect, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably a formula (Ia) or a formula ( Ib)

(wherein, the ring Cy _2-a and the ring Cy _2-b represent a 5- to 10-membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring; the other symbols represent the symbols recited in the above [1] The same meaning.) A compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is more preferably a formula (Ic) or a formula (Id).

(wherein Cy _2-c and Cy _2-d represent a pyridine ring, a pyrimidine ring, a pyrazolopyrimidine ring, an imidazopyridazine ring, an imidazopyridine ring, a pyrrolopyridine ring, an imidazopyrazine ring, Or a pyrazolopyridine ring; the other symbols indicate the same as those described in the above item [1]. The compound, the salt thereof, the N-oxide thereof, the solvate thereof, or the like Precursor.

Still another aspect, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably a formula (Ie) or a formula ( If)

(wherein, the ring Cy _1-e and the ring Cy _1-f represent a benzene ring or a 5- to 6-membered monocyclic aromatic heterocyclic ring; the other symbols indicate the same meaning as the symbols described in the above item [1].) a compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is more preferably a formula (Ig) or a formula (Ih).

(wherein, the ring Cy _1-g and the ring Cy _1-h represent a benzene ring, a pyridine ring or a pyrazole ring; and the other symbols indicate the same meaning as the symbols described in the above item [1].) , a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

Still another aspect, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably a formula (Ij) or a formula ( Ik)

(wherein, ring Cy _2-j and ring Cy _2-k represent a 5- to 10-membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring; ring Cy _1-j and ring Cy _1-k , a benzene ring or a 5- to 6-membered monocyclic aromatic heterocyclic ring; the other symbols indicate the same meaning as the one described in the above item [1], the salt thereof, the salt thereof, the N-oxide thereof, and the solvent thereof. a substance, or a prodrug of such a substance.

In the present invention, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is more preferably a formula (Im) or a formula (In).

(wherein, Cy _2-m and Cy _2-n represent a pyridine ring, a pyrimidine ring, a pyrazolopyrimidine ring, an imidazopyridazine ring, an imidazopyridine ring, a pyrrolopyridine ring, an imidazopyrazine ring, Or a pyrazolopyridine ring; a ring Cy _1-m and a ring Cy _1-n represent a benzene ring, a pyridine ring or a pyrazole ring; the other symbols indicate the same meaning as the symbols described in the above item [1]. a compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In still another aspect, in the present invention, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably of the formula (Ii). Or general formula (I-ii)

(In the formula, all the symbols indicate the same as those described in the above item [1], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by the formula (Ii) or the formula (I-ii), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is more preferably a formula ( Iia) or formula (I-ii-b)

Wherein the ring Cy _1-ia and the ring Cy _1-ii-b represent a benzene ring or a 5- to 6-membered monocyclic aromatic heterocyclic ring; the other symbols indicate the same meaning as the symbols described in the above [1]. .) a compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by the formula (Ii) or the formula (I-ii), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof are further preferably a general formula. (Iic) or formula (I-ii-d)

(wherein the ring Cy _1-ic and the ring Cy _1-ii-d represent a benzene ring, a pyridine ring or a pyrazole ring; the other symbols indicate the same meaning as the symbols described in the above item [1].) a compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

Still another aspect, in the present invention, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably a formula (I- Iii) or formula (I-iv)

(In the formula, all the symbols indicate the same as those described in the above item [1], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by the formula (I-iii) or the formula (I-iv), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof are more preferably passed Formula (I-iii-a) or formula (I-iv-b)

(wherein, the ring Cy _1-iii-a and the ring Cy _1-iv-b represent a benzene ring or a 5- to 6-membered monocyclic aromatic heterocyclic ring; the other symbols represent the symbols described in the above [1] The same meaning.) A compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by the formula (I-iii) or the formula (I-iv), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof are further preferably Formula (I-iii-c) or Formula (I-iv-d)

(wherein the ring Cy _1-iii-c and the ring Cy _1-iv-d represent a benzene ring or a pyridine ring; the other symbols indicate the same meaning as the symbols described in the above item [1], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof are preferably (1) 1-(2-(4- (2-Amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl) Urea, (2) 1-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl) -5-(Trifluoromethyl)phenyl)urea, (3) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl -3-(3-(trifluoromethyl)phenyl)urea, (4) 1-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidine- 5-yl)-3-(3-(trifluoromethyl)phenyl)urea, (5) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy) Pyrimidine-5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea, (6) 1-(2-(4-(2-amino-5-chloropyridine)- 3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, (7) 1-(2-(1H-pyrazole-1) -yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea (8) 1-(2-(4-(2-Amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)- 2-(3-(Trifluoromethyl)-1H-pyrazol-1-yl)phenyl)urea, (9) 1-(2-(1H- Pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidine-5 -yl)urea, (10) 1-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl) Phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (11) 1-(2-(1H-1, 2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy) Pyridin-3-yl)urea, (12) 1-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]pyridazin-3-yl] Phenoxy}-5-pyrimidinyl-3-[2-(3-pyridyl)-5-(trifluoromethyl)phenyl]urea, (13) 1-{6-[4-(5- Methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-3-pyridyl}-3-[2-(3-pyridyl)-5-(trifluoromethyl) Phenyl]urea, (14) 1-{2-[4-(2-amino-5-fluoro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[2-(methyl Sulfhydryl)-5-(trifluoromethyl)phenyl]urea, (15) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridyl]benzene Oxy}5-pyrimidinyl)-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea, (16) 1-{2-[4-(2-amine 5--5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea, or 17) 1-(5-Chloro-2-methylphenyl)-3-(2-{4-[6-(3-oxetanyloxy)imidazo[1,2-b]indole Pyrazin-3-yl]phenoxy}-5-pyrimidinyl)urea, a salt thereof, an N-oxide thereof, a solvate thereof, or the like Wait for the drug precursor.

In still other aspects, the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof are preferably (1) 1-(2-( 1H-pyrazol-1-yl)-5-(trifluoromethyl)-phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy) Pyrimidin-5-yl)urea, (2) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2- (4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea, (3) 1-(2-(4-(2-Amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2 -(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)urea, (4) 1-(2-(4-(2-amino-5-chloropyridin-3-yl) Phenoxypyrimidine-5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea, (5) 1-(2-(1H-pyrazol-1-yl) -5-(Trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)acrid-3-yl)urea, (6 ) 1-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-) Chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea, (7) 1-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridine -3-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (8) 1-(2-(4-(2-amino-5) -chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl Urea, (9) 1-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2) -amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea, (10) 1-(2-(4-(2-amino-5-fluoropyridin-3-yl) Phenoxypyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (11) 1-(2-(1H-pyridyl) Zin-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(2-) 5-(chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea, (12) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)benzene Oxy)pyrimidin-5-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea, (13) 1-(2-(4-(2-amino-5-chloro) Pyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea, (14) 1-(2-{4-[2 -amino-5-(trifluoromethyl)-3-pyridyl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl) -1H-pyrazol-1-yl]benzene Urea, (15) 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl) (6)-biphenyl]urea, (16) 1-{2-[4-(2-amino-5-fluoro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3- [4-(Trifluoromethyl)-2-biphenyl]urea, (17) 1-{2-[4-(2-Amino-5-chloro-3-pyridyl)phenoxy]-5 -pyrimidinyl}-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea, (18) 1-{2-[4-( 2-amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyrazole-1 -yl]phenyl}urea, (19) 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy1-5-pyrimidinyl}-3-[2, 4-bis(trifluoromethyl)phenyl]urea, (20) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridyl]phenoxy}- 5-pyrimidinyl)-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea, (21) 1-{2-[4- (2-Amino-5-fluoro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl] Urea, (22) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridyl]phenoxy}-5-pyrimidinyl)-3-[2-( Methylsulfonyl)-5-(trifluoromethyl)phenyl]urea, (23) 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy] -5-pyrimidinyl}-3 -[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea, (24) 1-{[(2-{4-[2-amino-5-(trifluoromethyl) (3-pyridyl)phenoxy}-5-pyrimidinyl)amine-methylamino]amino}N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide, (25) 1-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy(pyrimidin-5-yl)-3 -(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (26) 1-(2-(4-(5-(Azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy (pyrimidin-5-yl) )-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea, (27) 1-(2-(4-(5- Methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl Phenyl)urea, (28) 1-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2- (pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (29) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5- a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridyl)-5-(trifluoromethyl)phenyl]urea, (30) 1-( 2-{4-[5-(Dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(1- Methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea, (31) 1-{2-[4-(5-methylpyrazolo[1,5- a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridyl)-5-(trifluoromethyl)phenyl]urea, (32) 1-( 2-{4-[5-(ethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl-3-[3'-methyl- 4-(trifluoromethyl)-2-biphenyl]urea, (33) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidine- 3-yl]phenoxy}-5- Pyridyl)-3-[4-(trifluoromethyl)-2-biphenyl]urea, (34) 1-(2-{4-[5-(dimethylamino)pyrazolo[1 , 5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3'-methyl-4-(trifluoromethyl)-2-biphenyl]urea, or 35) 1-(2-{4-[5-(Dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[ 2'-Methyl-4-(trifluoromethyl)-2-biphenyl]urea, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, unless otherwise specified, the isomers include such All. For example, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group or the like includes a linear one and a branched chain. Further, it includes an isomer (E, Z, cis, trans) in a ring, a condensed ring, an isomer (R, S body, α, β body, symmetrical) due to the presence of asymmetric carbon or the like. Structure, asymmetric isomer), optically active optically active (D, L, d, l body), polar body separated by chromatography (high polarity, low polarity), equilibrium compound, rotation The construct, a mixture thereof in any ratio, and racemic isomers are all included in the present invention. Further, in the present invention, all isomers of tautomerism are also included.

In the present invention, unless otherwise specified, the symbols known to those skilled in the art: Indicates that the bond is on the opposite side of the paper (ie, the α-configuration), and the mark: Indicates that the bond is on the front side of the paper (ie, the β-configuration), and the mark: Represents α-configuration or β-configuration, notation: A mixture representing the alpha-configuration and the beta-configuration in any ratio.

[salt]

The compound of the formula (I) can be converted into a salt by a generally known method.

The salt is preferably a pharmaceutically acceptable salt.

The salt is preferably water soluble.

The salt may, for example, be an acid addition salt, an alkali metal salt, an alkaline earth metal salt, an ammonium salt or an amine salt.

The acid addition salt may, for example, be a mineral acid salt of a hydrochloride, a hydrogen bromide, a hydrocyanate, a sulfate, a phosphate or a nitrate, or an acetate, a lactate or a tartrate, Benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, besylate, tosylate, isethionate, glucuronate, or gluconate Organic acid salt.

The alkali metal salt may, for example, be potassium or sodium.

Examples of the alkaline earth metal salt include calcium and magnesium.

The ammonium salt may, for example, be tetramethylammonium or the like.

The amine salt may, for example, be triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine or tris(hydroxymethylmethyl). Aminomethane, lysine, arginine, and N-methyl-D-glucosamine.

Further, the compound represented by the formula (I) and a salt thereof can be formed into an N-oxide by any method. N-oxide, which represents a nitrogen atom of the compound of the formula (I) and a salt thereof, and is oxidized, specifically, a compound represented by the formula (I) and a salt thereof, A ₁ and A ₂ , A ₃ , A ₄ , A ₅ , or A ₆ , when it is =N-, its nitrogen atom is oxidized. Further, when Cy ₁ or Cy ₂ is a nitrogen-containing hetero ring, it means that the nitrogen atom is oxidized. At the same time, it also indicates that the amine group is oxidized.

The compound represented by the formula (I) and a salt thereof can also be converted into a solvate. The solvate is preferably non-toxic and water soluble. A suitable solvate may, for example, be water or a solvate such as an alcohol solvent (for example, ethanol).

[prodrug]

The prodrug of the compound represented by the formula (I) is a compound which can be converted into a compound represented by the formula (I) by a reaction of an enzyme and gastric acid in a living body. A prodrug of a compound of the formula (I), for example, a compound which is thiolated, alkylated, or phosphorylated when the compound represented by the formula (I) contains an amine group (for example, a formula The amine group of the compound represented by (I) is an octadecyl decyl group, an aryl thiolated group, a pentylamino group carbonyl group, (5-methyl-2-oxo-1,3-dioxa compound). Cyclopentan-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation, trimethylacetoxymethylation, ethoxymethylation, tert-butylation a compound, etc.); when the compound represented by the formula (I) contains a hydroxyl group, the hydroxyl group is thiolated, alkylated, phosphorylated, or borated (for example, the hydroxyl group of the compound represented by the formula (I) Ethylation, palmitoylation, propylation, trimethylacetylation, amber thiolation, anti a compound having a butenylation, an arylation, a dimethylaminomethylcarbonylation, or the like; when the compound represented by the formula (I) contains a carboxyl group, the carboxyl group is esterified and amided. The compound (for example, the carboxyl group of the compound represented by the formula (I) is ethylated, phenyl esterified, carboxylated, methylated, dimethylaminomethylated, trimethylacetoxymethylated, 1- Ethylation of {(ethoxycarbonyl)oxy}, mercaptoesterification, methylation of (5-methyl-2-oxo-1,3-dioxolan-4-yl), Ethyl 1-{[(cyclohexyloxy)carbonyl]oxy}, methylammonium compound, etc.). These compounds can be produced by methods generally known per se. Further, the prodrug of the compound represented by the formula (I) may be optionally a hydrate or a non-hydrate. Further, the prodrug of the compound represented by the formula (I) can also be described in the "Development of Pharmaceutical Products", Vol. 7, "Molecular Design", published by the Hirokawa Shoten in 1990, pages 163 to 198. Conversion to a compound of the formula (I) under physiological conditions.

Further, each atom constituting the compound represented by the formula (I) may be an isotope thereof (for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁶ N, ¹⁷ O, ¹⁸ O, ³⁵ S). , ³⁶ Cl, ⁷⁷ Br, ¹²⁵ I, etc. were replaced.

[Method for Producing Compound of the Present Invention]

A compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof can be prepared according to the method described in International Publication No. 2014/129431, International Publication No. 2016 The method described in /027754, a generally known method, and a method according to these methods. Further, a salt may be used as the raw material compound. As such a salt, those which are described in the general formula (I) as a pharmaceutically acceptable salt can be used.

[toxicity]

The compounds of the invention are extremely toxic. The compound of the present invention, for example, does not exhibit hepatotoxicity and digestive tract obstruction, and is a compound having low brain metastasis. Therefore, the compound of the present invention can be safely used as a pharmaceutical.

[Applicability in pharmaceutical products]

Since the compound of the present invention has an inhibitory effect on proliferation of a Trk inhibitor-resistant cancer, a therapeutic agent for cancer resistant to a Trk inhibitor can be used.

Trk inhibitor-resistant cancers include breast cancer, ovarian cancer, colorectal cancer (for example, colon cancer, etc.), lung cancer (for example, non-small cell lung cancer, etc.), prostate cancer, and head and neck cancer (for example, oral squamous cell Cancer, head and neck squamous cell carcinoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, auditory nerve sheath, etc.), skin cancer (for example, melanoma (malignant melanoma), etc.), lymphoma (for example, B cells) Lymphoma, T-cell lymphoma, etc.), brain tumor, glioma, pituitary adenoma, uveal malignant melanoma, meningococcal tumor, thymoma, mesothelioma, esophageal cancer, gastric cancer, liver cancer (for example, Hepatocellular carcinoma, etc.), cholangiocarcinoma (eg, intrahepatic cholangiocarcinoma, etc.), gallbladder cancer, pancreatic cancer, renal cancer (eg, renal cell carcinoma, renal pelvic cancer/renal ureteral cancer, etc.), bladder cancer, penile cancer, Testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, malignant bone tumor, sarcoma (for example, soft tissue sarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, congenital fibrosarcoma, etc.), blood cancer (eg, leukemia, etc.), bone marrow dysplasia Syndrome, multiple myeloma , salivary gland tumor, MASC (mammary analogue secretory carcinoma), mammalian breast secretory cancer, Neuroendocrine tumors, neuroblastoma, myeloma, pleomorphic glioma, retinoblastoma, small bowel cancer, inflammatory myofibroblastic tumor, congenital mesodermal nephroma and adrenal cortical carcinoma Wait.

A compound of the invention, for use in 1) supplementation and/or enhancement of the prophylactic and/or therapeutic effect of the compound, 2) improvement in the dynamics/absorption of the compound, reduction in the amount administered, and/or 3) side effects of the compound When it is reduced, it can also be combined with other agents to be administered as a co-agent.

The compound of the present invention and a combination of other agents may be administered in the form of a formulation in which two components are formulated in one preparation, or may be administered in the form of a separate preparation. When administered in separate formulations, it includes simultaneous administration and administration at different times. Further, when administered at different times, the compound of the present invention may be administered first, and then administered with other agents, or may be administered with other agents, and then administered with the compound of the present invention. The individual administration methods may be the same or different.

The above-mentioned concomitant agent is not particularly limited as long as it can exert a preventive and/or therapeutic effect, and may be a disease which supplements and/or enhances the preventive and/or therapeutic effect of the compound of the present invention.

Other agents for supplementing and/or enhancing the effect of the compound of the present invention on the prevention and/or treatment of cancer, for example, alkylating agents, metabolic antagonists, anticancer antibiotics, anticancer botanical preparations, hormones Drugs, platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteosome inhibitors, HDAC inhibitors, immunological checkpoint inhibitors (eg , anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, etc.), immunomodulation Preparations, and other anticancer agents.

The alkylating agent may, for example, be cyclophosphamide, ifosfamide, dacarbazine, nimustine, ranimustine, Bendamustine, thio-TEPA, and carboquone.

Antimetabolites, for example, may be methotrexate, pemetrexed, fluorouracil, tegafur, tegafur/uracil, tigafur/jimo Gimestat / otastat potassium, dexifluridine, capecitabine, cytarabine, gemcitabine, fludarabine (fludarabine), nairabine, carmofur, and procarbazine.

Anticancer antibiotics, for example, mitomycin C, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, pan-ubimycin ( Epirubicin), chromomycin A3, bleomycin, peplomycin, and theraubicin.

The anticancer plant preparation may, for example, be irinotecan hydrochloride, etoposide, vincristine sulfate, vinblastin sulfate, vindesine sulfate (vindesine). , therrubicin tartrate, the docetaxel hydrate, the eribulin mesylate, and paclitaxel.

Hormone drugs, for example, estradiol sodium sulphate, flutamide, bicalutamide, goserelin acetate, leuprolide acetate (leuprorelin), tamoxifen citrate, toremifene citrate, anastrozole, letrozole, exemestane, mepitiostane ), medroxyprogesterone, epitiostanol, fosfestrol, fadrozole hydrochloride, abiraterone, fulvestrant, And aminoglutethimide and the like.

Examples of the platinum compound include carboplatin, cisplatin, nedaplatin, and oxaliplatin.

Examples of the topoisomerase inhibitors include, for example, topotecan and sobuzuxane.

The kinase inhibitor may, for example, be an EGFR inhibitor of erlotinib, gefitinib, afatinib, a HER2 inhibitor of lapatinib, BCR- Imatinib of ABL inhibitor, crizotinib of ALK inhibitor, regorafenib of multikinase inhibitor, and dasatinib, MEK Inhibitors of trametinib, simetintinib, palbociclib of CDK4/6 inhibitors, and the like.

Rituximab (rituximab), ibritumomab, and ibritumomab tiuxetan, and olirelizumab.

Examples of the anti-HER2 antibody include trastuzumab, trastuzumab-emtansine, and pertuzumab.

Examples of the anti-EGFR antibody include cetuximab and panitumumab.

The anti-VEGF antibody may, for example, be bevacizumab or the like.

The proteosome inhibitor may, for example, be bortezomib or the like.

The HDAC inhibitor may, for example, be vorinostat or the like.

Examples of the anti-CTLA-4 antibody include ipilimumab and tremelimumab.

Examples of the anti-PD-1 antibody include nivolumab and pembrolizumab.

Examples of the anti-PD-L1 antibody include atezolizumab and avumab.

The immunomodulatory preparation may, for example, be a thalidomide, a lenalidomide, or a pomalidomide.

The mass ratio of the compound of the present invention to other pharmaceutical agents is not particularly limited.

Other drugs may be administered in combination of two or more kinds.

Further, other agents which supplement and/or enhance the preventive and/or therapeutic effects of the compounds of the present invention include not only the above-mentioned mechanism but also those which have not been found but are found in the future.

The compound of the present invention having the above object, or a combination of the compound of the present invention and another agent, usually, after being formulated into a suitable pharmaceutical composition together with a pharmaceutically acceptable carrier, may be administered systemically or locally Dosing in the form of oral or parenteral.

The dosage is different depending on the age, weight, symptoms, treatment effect, administration method, treatment time, etc. Usually, it can be administered to each adult, every time, in the range of 1 mg to 1000 mg, once a day to several times. The drug is administered intravenously or intravenously in the range of 0.1 mg to 100 mg per adult, once every other day, in the range of 0.1 mg to 100 mg; or intravenously in the range of 1 hour to 24 hours on the 1st.

Of course, as described above, the amount of administration varies depending on various conditions, and therefore, the amount which is smaller than the above-mentioned dosage is sufficient, or the case where it is necessary to exceed the range.

When the compound of the present invention or the compound of the present invention and the other agent are administered together, the solid preparation, the internal administration liquid, the injection for parenteral administration, the external preparation, and the stopper can be used for oral administration. Agents, eye drops, inhalants, etc.

For the administration of solid preparations, such as tablets, pills, capsules, powders, granules, etc., for oral administration. Capsules, including hard gelatin Capsules and soft capsules. Further lozenges include sublingual ingots, intraoral adhesive sticks, and intra-oral disintegration tablets.

In this type of internal solid preparation, one or more active substances, or with excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), and a binder (hydroxypropyl cellulose) may be directly used. , polyvinylpyrrolidone, magnesium metasilicate aluminate, etc., disintegrant (such as cellulose glycolate), slip agent (magnesium stearate, etc.), stabilizer, cosolvent (glutamic acid, aspartic acid) Etc., etc., and then formulated according to the general method. Further, it may be coated with a coating agent (white sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like) as needed, or may be coated in two or more layers. Also included are capsules of absorbable substances such as gelatin.

It is used for oral administration of oral liquids, including pharmaceutically acceptable aqueous preparations, suspensions, emulsions, syrups, elixirs and the like. In the liquid preparation, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (refined water, ethanol or a mixture thereof, etc.). Further, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifier, a sweetener, a flavor, a fragrance, a preservative, a buffer, and the like.

The dosage form for the parenteral administration, for example, an ointment, a latex, a cream, a compress, a patch, an expectorant, a spray, an inhalant, a spray, a gel, Eye drops, nose drops, etc. These may comprise one or more active substances, which are prepared in a generally known manner or in the usual manner.

Sprays, inhalants and sprays, in addition to commonly used diluents, may also contain stabilizers such as sodium bisulfite and may impart isotonicity A buffering agent such as sodium chloride, sodium citrate or citrate. The method of producing a spray is described in detail in, for example, U.S. Patent Nos. 2,868,691 and 3,095,355.

The injection for parenteral administration may contain a solution, a suspension, an emulsion, and a solid injection which is dissolved or suspended in a solvent in use. The injection may be used in a solvent by dissolving, suspending or emulsifying one or more active substances. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil such as propylene glycol, polyethylene glycol, alcohol of ethanol, or the like, or a combination thereof can be used. Further, such an injection may contain a stabilizer, a co-solvent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a pain-relieving agent, a buffering agent. , preservatives, etc. These may be sterilized or aseptically processed in the final step. Further, a sterile solid preparation, for example, a lyophilized product can be produced, and then sterilized or dissolved in sterile distilled water for injection or other solvent before use, and then used.

Other compositions for parenteral administration also include a suppository containing one or more active substances, prescribed in a conventional manner for intrarectal administration, and a pessary for intravaginal administration.

Unless otherwise defined, all technical, scientific terms, and abbreviations used in this specification have the same meaning as understood by those of ordinary skill in the art.

[Examples]

Hereinafter, the present invention will be described in detail by way of examples, but the invention is not limited thereto. The compound of the present invention is a compound described in International Publication No. 2014/129431 and International Publication No. 2016/027754, a salt thereof, Its N-oxide, its solvate, or such prodrugs, and its crystallization.

Further, Entrectinib and LOXO-101 compounds used in Pharmacological Experiments 3 and 4 are the following compounds.

Pharmacological experiment:

Pharmacological Experiment 1: Determination of TrkA Kinase Inhibitory Activity Using Human TrkA Expression Cells

Cell lines TrkA kinase inhibitory activity, the use of performance-based human TrkA, and NFAT-bla of CHO-K1 cells ^{(CellSenser TM TrkA-NFAT-bla} CHO-K1 cells, Invitrogen Corporation).

Day prior to analysis, first ^{CellSenser TM TrkA-NFAT-bla CHO} -K1 cells containing: assay medium (0.5vol% dialyzed fetal bovine serum treated (Invitrogen), 0.1 mM non-essential amino acids (Invitrogen), 1 mM sodium pyruvate (Invitrogen), and anti-biomass (containing 100 U/mL cinnamicin, and 100 μg/mL streptomycin (Invitrogen) in Opti-MEM1 reduced serum medium (Invitrogen)), 2.4× At a density of 10 ⁴ cells/40 μL/well, the cells were cultured in a 96-well clear bottom microplate (Corning, Model: 3882). Further, a part of the well was added with only the analysis medium (cell-free group) at 40 μL/well. On the day of analysis, the compound of the present invention (DMSO solution) was dispensed at 10 mM in a 96-well microplate (Costar, model: 3363), and then diluted with a DMSO gradient to prepare a dilution series of 3 times the ratio. This diluted series was further diluted 100-fold with an analysis medium to prepare a 10-fold concentration of the compound solution of the present invention (DMSO concentration: 1 vol%). The compound of the present invention was further added to a microplate of the cultured cells at 5 μL/well, and cultured in a CO ₂ incubator of 5% CO ₂ , 95% air, and 37 ° C for 30 minutes. In the control group and the blank group, the analysis medium containing 1 vol% of DMSO was added in 5 μL/well instead of the compound solution of the present invention. Then, 5 μL/well was added to the microplate (final concentration of NGF: 50 ng/mL) containing NGF (mouse 2.5 s, natural type, Invitrogen) assay medium, and at 5% CO ₂ , 95% air. The cells were cultured in a CO ₂ incubator at 37 ° C for 5 hours. In the blank group, the analysis medium was added at 5 μL/well in place of NGF. Further, the reagent for label analysis was added to the microplate at 10 μL/well, and then incubated at room temperature for 120 minutes under light-shielding. And, based marker analysis and detection reagent to ^{LiveBLAzer TM - FRET B / G Loading} Kit (Invitrogen Corporation) formulated. Thereafter, each well was scanned with 405 nm excitation light using Analyst GT (Molecular Device Japan), and the fluorescence intensity at 460 nm and 530 nm was measured. The time-resolved fluorescence resonance energy transfer (TR-FRET) ratio of each well was calculated by the following mathematical formula.

[Number 1] TR-FRET ratio = (A _{460X -} A _460F ) / (A _{530X -} A _530F )

A _460X : 460nm fluorescence intensity of the compound of the present invention, control group or blank group

A _460F : 460nm fluorescence intensity of cell-free group

A _530X : 530 nm fluorescence intensity of the compound of the present invention, control group or blank group

A _530F : 530nm fluorescence intensity of cell-free group

The TR-FRET inhibition rate (%) of the compound of the present invention is calculated by the following mathematical formula.

[Number 2] inhibition rate (%) = {1 - (A _{X -} A _B ) / (A _{C -} A _B )} × 100

A _X : TR-FRET ratio when adding the compound of the present invention

A _B : TR-FRET ratio of blank group

A _C : TR-FRET ratio of the control group

The IC ₅₀ value of the compound of the present invention is calculated from the inhibition curve according to the inhibition rate of the compound of the present invention in various concentrations.

As a result, the compound of the present invention has an IC ₅₀ value of 0.5 μM or less, and thus it is understood that the compound of the present invention has TrkA inhibitory activity. For example, several of the compounds of the present invention, IC ₅₀ values of lines such as shown in the following Table.

Pharmacological Experiment 2: Enzyme inhibition activity test on other kinases other than Trk Test (selective experiment)

The test substance (the compound of the present invention) was dissolved in dimethyl hydrazine to adjust to a 100-fold concentration solution having a test concentration of 3 μM. The solution was further diluted 25 times in assay buffer (20 mM HEPES, 0.01 vol% Triton X-100, 2 mM DTT, pH 7.5) into a test substance solution. The positive control was adjusted to the positive control substance solution in the same manner as this.

5 μL of the test substance solution adjusted to 4 times concentration with the analysis buffer, 5 times of the concentration/ATP/metal solution (Mg), and 10 μL of the 2 times concentration of the kinase solution in the pores of the 384-well microplate made of polypropylene. Mix and react at room temperature for 1 hour. The reaction was then stopped by the addition of 60 μL of Termination Buffer (QuickScout Screening Assist MSA; Carna Biosciences). The matrix peptide and the phosphorylated peptide in the reaction solution are separated and quantified. The kinase reaction was evaluated by the ratio of the product (P/(P+S)) calculated from the height of the matrix peptide (S) to the height of the phosphorylated peptide (S). Other kinases can be used for kinase selectivity experiments such as b-Raf and KDR kinases. The matrix, matrix concentration, ATP concentration, and positive control substance used in each kinase enzyme inhibitory activity test are shown in the table below.

The average of the wells of the control group containing all the reaction components The signal was 0% inhibition, and the average signal of the background group (no enzyme added) was 100% inhibition, and the inhibition rate was calculated from the average signal of the wells tested for each substance. As a result, the inhibition ratio of each kinase of the compound of the present invention at a concentration of 3 μM is shown in the following table.

From the results, it was revealed that the compounds of the present invention and other kinases other than TrkA were less potent against the kinases such as b-Raf and KDR, and stronger against TrkA. In other words, the compound of the present invention has a strong IC ₅₀ of less than 0.5 μM for TrkA inhibition as a result of pharmacological example 1, and the result of pharmacological example 2 is the concentration of the above kinase other than TrkA, even in the compound. It is also inhibited from 0% to about 58% for 3 μM. Therefore, it is understood that the compound of the present invention has high selectivity for inhibition of TrkA and excellent kinase selectivity.

Pharmacological Experiment 3: Proliferation inhibition test on Trk inhibitor resistant cell lines

(1) Construction of emetinib and LOXO-101 resistant KM12 cell lines (KM12-ER and KM12-LR)

A human colorectal cancer cell line KM12 (ATCC, model: RBC0805) was constructed to construct a resistant strain of the Trk inhibitor emtritinib or LOXO-101. The medium was prepared in a DMEM (Life Technologies, Model: 11965) containing 10 vol% of fully deactivated fetal bovine serum (Fetal Bovine Serum: FBS) and 1 vol% of Penicillin-Streptomycin liquid (Life Technologies). The thawed KM12 was suspended in the medium and centrifuged at 180 x g for 3 minutes at room temperature. After the supernatant was aspirated and removed, the cell sediment was resuspended in the culture medium to a total amount of 50 mL and the cells were cultured in a 225 cm ² flask (Asahi Glass Co., Ltd.), and placed at 37 ° C, 5% CO ₂ , and 95%. Under the conditions of air. Thereafter, KM12 which proliferated in an aggregated state was first floated with 0.25% Trypsin-EDTA (Invitrogen), and after being collected in a centrifuge tube, KM12 was centrifuged at room temperature, 180 × g, 3 minutes. After the cell sediment was suspended in DMEM medium, a part of the cell suspension was taken out, and the number of viable cells was counted. Further, a part of the cell suspension was cultured in a 225 cm ² flask, and the total amount of the medium was 50 mL. 50 μL of enchtinib or LOXO-101 dissolved in DMSO was added to DMEM medium and allowed to stand at 37 ° C, 5% CO ₂ , and 95% air. It is then continued to be cultured in the presence of the agent under subculture. The concentration of entrinib started from 1 nM and gradually increased to 10 nM. On the other hand, LOXO-101 continued to be subcultured at 30 nM. The stably proliferating cells were then cryopreserved in the presence of 10 nM of entretinib or 30 nM of LOXO-101, each of which was KM12-ER and KM12-LR.

(2) Proliferation inhibition experiments on KM12, KM12-ER and KM12-LR

The antitumor effects of the compounds of the invention were evaluated using KM12, KM12-ER and KM12LR. The cells were subcultured in DMEM medium until the experiment was provided. On the day before compound treatment, the cells were first floated with 0.25% Trypsin-EDTA, and the cells were recovered from the culture flask by a centrifuge tube. After centrifuging the cells at 180 × g for 3 minutes at room temperature, the cell sediment was suspended in 10 mL of DMEM medium. Then, a part of the cell suspension was taken, and after measuring the number of cells, the cells were suspended in DMEM medium at a cell density of 3 × 10 ⁴ cells/mL to prepare the cell suspension. Then, the cells were cultured in a 96-well tissue culture microplate (Asahi Glass Co., Ltd.) in a cell suspension of 100 μL/well, and allowed to stand at 37 ° C, 5% CO ₂ , and 95% air for 24 hours. On the day of treatment with the compound, 10 mM of the compound of the invention, octrotinib and LOXO-101 (DMSO solution) were diluted in DMSO to prepare a dilution series of 3 times the ratio. The diluted series and DMSO were further diluted 100 times in the medium to prepare a 10-fold concentration of the compound solution and the medium solution. The compound solution or the medium solution prepared above was added to each well of a 96-well tissue culture microplate which was statically cultured for 24 hours at 11 μL/well, and then at 37 ° C, 5% CO ₂ , and 95%. The culture was allowed to stand for 72 hours under air conditions. After the static culture was completed, the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7571) was used, and the luminescence signal (relative luminescence unit, RLU) of each well was measured by a microplate analyzer. First, the average value of the RLU of the three-well amount of the medium group (the group treated with the medium solution having the compound concentration of zero (0)) was calculated, and the growth inhibition rate in each well was calculated by the following mathematical formula.

[Number 3] Proliferation inhibition rate (%) = {1 - (RLU of each well / (RLU average of the medium group))} × 100

The IC ₅₀ values of the compounds of the invention and entrinib were then reversed by non-linear regression analysis using the Sigmoid Emax mode based on the proliferation inhibition rate in each concentration.

As a result, it was found that the compound of the present invention can inhibit the proliferation of KM12-ER and KM12LR at a lower treatment concentration than that of erttrium and LOXO-101. The IC ₅₀ values of the compounds of the present invention, entretinib and LOXO-101 are shown in the following table.

Pharmacological Experiment 4: Proliferation inhibition test on TrkA G595R or G667C variant positive cell lines

(1) Construction of Ba/F3 cell line expressing wild-type TPM3-TrkA and G595R or G667C variant TPM3-TrkA

A Ba/F3 cell line expressing the wild-type TPM3-TrkA and G595R or G667C variant TPM3-TrkA was constructed from Ba/F3 of mouse pro-B-cell line (Ba/F3 TrkA wild type, Ba/F3 TrkA G595R). And Ba/F3 TrkA G667C). And containing 10 vol% of fully deactivated fetal bovine serum (Fetal Bovine Serum: FBS), 1 vol% of Penicillin-Streptomycin liquid (Life Technologies) and a final concentration of 10 ng / mL of IL-3 (BD Bioscience, model: RPMI (Life Technologies, model: 11875) of 354040) was formulated into a culture medium. The thawed Ba/F3 was suspended in the culture medium. The cells were centrifuged at 400 × g for 3 minutes at room temperature, and the cell sediment was resuspended in the culture medium after aspirating the supernatant. The cells were then plated in full amount in a 150 mm untreated petri dish (Sunglass) and allowed to stand at 37 ° C, 5% CO ₂ , and 95% air. Thereafter, Ba/F3 was introduced into the culture medium by subculture until the introduction of the gene. The TPM3-NTRK1 fusion gene of wild type TPM3-TrkA and G595R or G667C variant TPM3-TrkA protein was transfected by artificial gene synthesis, and subcultured in pcDNA3.1 vector. The three constructs were introduced into each of Ba/F3 in a Nucleofector device (Lonza) according to the document attached to Amaxa Cell line Nucleofector Kit V (Lonza, model: VCA-1003). And containing 10 vol% of FBS, 1 vol% of Penicillin-Streptomycin liquid (Life Technologies), a final concentration of 10 ng/mL of IL-3 (BD Bioscience, model: 354040) and a final concentration of 500 μg/mL of G418 ( RPMI of Wako Co., Ltd., model: 077-04973) was formulated into a selection medium, and after 2 days from the introduction of the gene, Ba/F3 was allowed to stand still for one week in the selection medium. The subculture was then repeated in stages with a selection medium to remove IL-3. The cells subcultured several times in the selection medium (without IL-3 selection medium) for complete removal of IL-3 were stored in liquid nitrogen.

(2) Proliferation inhibition experiments on Ba/F3 TrkA wild type, Ba/F3 TrkA G595R and Ba/F3 TrkA G667C

The antitumor effects of the compounds of the present invention were evaluated in Ba/F3 TrkA wild type, Ba/F3 TrkA G595R and Ba/F3 TrkA G667C. Ba/F3 TrkA wild type, Ba/F3 TrkA G595R and Ba/F3 TrkA G667C were subcultured in medium without IL-3 selection until the experiment was provided. On the day of the proliferation inhibition experiment, Ba/F3 TrkA wild type, Ba/F3 TrkA G595R and Ba/F3 TrkA G667C were recovered from the culture dish in a centrifuge tube and centrifuged at 400 x g for 3 minutes at room temperature. Then, after the cell sediment was suspended in the medium, the number of cells was measured, and the cell suspension was prepared at a cell density of 3.3 × 10 ⁴ cells/mL. 10 mM of the compound of the invention and Entrectinib (DMSO solution) were diluted in DMSO to prepare a dilution series of 3 times the ratio. The diluted series and DMSO were further diluted 100 times with the medium to prepare a 10-fold concentration of the compound solution and the medium solution. The compound solution or the medium solution prepared above was added to each well of a 96-well tissue culture microplate at 10 μL/well. Next, the above cell suspension was cultured at 90 μL/well, and cultured at 37 ° C, 5% CO ₂ , and 95% air for 72 hours. The blank group was added with cell-free medium at 100 μL/well. After the static culture was completed, the Cell Counting Kit-8 (DOJINDO) was used to measure the absorbance at 450 nm (A ₄₅₀ ) and the absorbance at 650 nm (A ₆₅₀ ) at a control wavelength of each well using a microplate analyzer, and calculate the respective holes. A ₄₅₀ removes the value of A ₆₅₀ (A _450-650 ). In each hole of the A _450-650 A _450-650 is the average of the control group (A _{△ blank)} is removed, the medium is calculated in the average group of A _{△ blank,} then the following equation is calculated in each well of proliferation Inhibition rate.

[Number 4] Proliferation inhibition rate (%) = {1 - (A _{Δblank of} each hole) / (Average of A _{△ blank} of the medium group)} × 100

The IC ₅₀ values of the compounds of the invention and entrinib were then reversed by non-linear regression analysis using the Sigmoid Emax mode based on the proliferation inhibition rate in each concentration.

As a result, it was found that the compound of the present invention can inhibit the proliferation of Ba/F3 TrkA G595R and Ba/F3 TrkA G667C at a lower concentration than that of emtritinib. The IC ₅₀ values of several compounds of the invention and entrinib are shown in the table below.

Pharmacological Experiment 5: Proliferation inhibition test on TrkC G623R variant positive cell line

(1) Wild-type ETV6-TrkC and G623R variant ETV6-TrkC performance Construction of Ba/F3 cell line

A Ba/F3 cell line (Ba/F3 TrkC wild type, Ba/F3 TrkC G623R) expressing wild type ETV6-TrkC and G623R variant ETV6-TrkC was constructed by Ba/F3 of mouse original B-cell line. And completely deactivated fetal bovine serum (Fetal Bovine Serum: FBS) containing 10 vol%, 1 vol% of Penicillin-Streptomycin liquid (Life Technologies) and IL-3 with a final concentration of 10 ng/mL (BD Bioscience, model: 354040 RPMI (Life Technologies, model: 11875) was formulated into a culture medium. The thawed Ba/F3 was suspended in the culture medium. The cells were centrifuged at 400 × g for 3 minutes at room temperature, and the cell sediment was resuspended in the culture medium after aspirating the supernatant. The cells were then plated in full amount in a 150 mm untreated petri dish (Sunglass) and allowed to stand at 37 ° C, 5% CO ₂ , and 95% air. Thereafter, Ba/F3 was subcultured to the culture medium until the introduction of the gene. The ETV6-TrkC fusion gene of wild type ETV6-NTRK3 and G623R variant ETV6-TrkC protein was transfected by artificial gene synthesis and subcultured in pcDNA3.1 vector. The three constructs were introduced into each of Ba/F3 in a Nucleofector device (Lonza) according to the document attached to Amaxa Cell line Nucleofector Kit V (Lonza, model: VCA-1003). And containing 10 vol% of FBS, 1 vol% of Penicillin-Streptomycin liquid (Life Technologies), a final concentration of 10 ng/mL of IL-3 (BD Bioscience, model: 354040) and a final concentration of 500 μg/mL of G418 ( RPMI of Wako Co., Ltd., model: 077-04973) was formulated into a selection medium, and after 2 days from the introduction of the gene, Ba/F3 was allowed to stand still for one week in the selection medium. Subsequent subculture was then repeated in stages with the selection medium to remove IL-3. The cells subcultured several times in the selection medium (without IL-3 selection medium) for complete removal of IL-3 were stored in liquid nitrogen.

(2) Proliferation inhibition assay of Ba/F3 TrkC wild type and Ba/F3 TrkC G623R

The antitumor effect of the compound of the present invention was evaluated by Ba/F3 TrkC wild type, Ba/F3 TrkC G623R. Ba/F3 TrkC wild type, Ba/F3 TrkC G623R, subcultured with medium containing no IL-3 selection until the experiment was provided. On the day of the proliferation inhibition experiment, Ba/F3 TrkC wild type, Ba/F3 TrkC G623R was recovered from the culture dish in a centrifuge tube, and centrifuged at 400 × g for 3 minutes at room temperature. Then, after the cell sediment was suspended in the medium, the number of cells was measured, and the cell suspension was prepared at a cell density of 3.3 × 10 ⁴ cells/mL. Further, 10 mM of the compound of the present invention and entreatinib (DMSO solution) were diluted with DMSO to prepare a dilution series of 3 times the ratio. The diluted series and DMSO were further diluted 100 times with the medium to prepare a 10-fold concentration of the compound solution and the medium solution. The compound solution or the medium solution prepared above was added to each well of a 96-well tissue culture microplate at 10 μL/well. Next, the above cell suspension was cultured at 90 μL/well, and cultured at 37 ° C, 5% CO ₂ , and 95% air for 72 hours. After the static culture was completed, the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7571) was used, and the luminescence signal (relative luminescence unit, RLU) of each well was measured by a microplate analyzer. First, the average value of the RLU of the three-well amount of the medium group (the group treated with the medium solution having the compound concentration of zero (0)) was calculated, and the growth inhibition rate in each well was calculated by the following mathematical formula.

[Number 5] Proliferation inhibition rate (%) = {1 - (RLU of each well) / (average of RLU of the medium group))} × 100

The IC ₅₀ values of the compounds of the invention and entrinib were then reversed by non-linear regression analysis using the Sigmoid Emax mode based on the proliferation inhibition rate in each concentration.

As a result, it was found that the compound of the present invention can inhibit the proliferation of Ba/F3 TrkC G623R at a lower concentration than that of emtritinib. The IC ₅₀ values of several compounds of the invention and entrinib are shown in the table below.

[Formulation Example]

Formulation Example 1

The following components are mixed in accordance with a general method, and then ingots are used to prepare a tablet of 10,000 tablets containing 10 mg of the active ingredient in one tablet.

‧1-(2-(4-(2-Amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-1, 2,3-Triazol-1-yl)-5-(trifluoromethyl)phenyl)urea. . . . . . 100g

‧Carboxymethylcellulose calcium (disintegrant). . . . . . 20g

‧ Magnesium stearate (sliding agent). . . . . . 10g

‧Microcrystalline cellulose. . . . . . 870g

Formulation Example 2

The following components were mixed according to a general method, filtered through a dust filter, and each was filled with an injection tube at 5 mL, and heated and sterilized by an autoclave to obtain 10,000 injection tubes containing 20 mg of the active ingredient in one injection tube.

‧1-(2-(4-(2-Amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-1, 2,3-Triazol-1-yl)-5-(trifluoromethyl)phenyl)urea. . . . . 200g

‧ mannitol . . . . . 20g

‧ distilled water. . . . . . 50L

[Possibility of industrial use]

The compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof can be used as an active ingredient of a therapeutic agent for cancer resistant to a Trk inhibitor.

Claims (19)

A therapeutic agent for cancer resistant to Trk inhibitor, which comprises a compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof as an active ingredient, Wherein the ring Cy ₁ represents a C 3 to 10 monocyclic carbocyclic ring or a bicyclic carbocyclic ring, or a 4 to 10 membered monocyclic heterocyclic ring or a bicyclic heterocyclic ring; and the ring Cy ₂ represents a 4 to 10 membered monocyclic ring. a heterocyclic or bicyclic heterocyclic ring; R ₁ represents (1) a halogen, (2) a C1 to 6 alkyl group, C2 which may be substituted with a substituent selected from the group consisting of (i) a halogen and (ii) a hydroxyl group. To a 6 alkenyl group, or a C 2 to 6 alkynyl group, (3) a C ₅ to 6 monocyclic carbocyclic ring which may be substituted with 1 to 2 R ₅ , (4) ₅ which may be substituted by 1 to 2 R 5 To 6-membered monocyclic heterocycle, (5)-S(O) _m1 -R ₆ , (6)-SO ₂ NR ₇ R ₈ , (7)-C(O)OR ₉ , (8)-NR ₁₀ C(O)R ₁₁ , (9)-C(O)NR ₁₂ R ₁₃ , (10)-OR ₁₄ , (11)-NR ₁₅ R ₁₆ , (12) cyano, or (13) nitro; R ₅ represents (1) halogen, (2)-S(O) _{m2 -} R ₁₇ , (3)-SO ₂ NR ₁₈ R ₁₉ , (4)-C(O)OR ₂₀ , (5)-NR ₂₁ C ( O) R ₂₂ , (6)-C(O)NR ₂₃ R ₂₄ , (7)-OR ₂₅ , (8)-NR ₂₆ R ₂₇ , (9) cyano, (10) nitro, or (11) a C1 to 3 alkyl group which may be substituted with a substituent selected from the group consisting of (i) halogen, (ii) hydroxyl group, and (iii) pendant oxy group. When R ₅ is 2, R ₅ is independently It may be the same or different, and the two R _{5 are} each independently a C1 to 3 alkyl group or a hydroxyl group. And when the R ₅ position is a C5 to 6 monocyclic carbocyclic ring or a 5 to 6 membered monocyclic heterocyclic ring adjacent to a carbon atom, the groups may also form a ring; R ₆ to R ₂₇ are each independently represented (1) a hydrogen atom, or (2) a C1 to 6 alkyl group which may be substituted by (i) a halogen or (ii) a hydroxyl group, and each of R ₁₈ and R _{19 is} independently a C1 to 6 alkyl group, and the same Rings may be formed together; R ₂ is (1) halogen, (2) C1 to 6 alkyl group which may be substituted by (i) halogen or (ii) hydroxyl group, (3) may be (i) halogen or (ii) hydroxyl group Substituted C3 to 6 cycloalkyl, (4) C1 to 6 alkoxy which may be substituted by halogen, (5)-NR ₂₈ R ₂₉ , (6) 3 to 7 membered monocyclic heterocyclic ring, or 7) -O-(3 to 7 membered monocyclic heterocyclic ring); R ₂₈ and R ₂₉ each independently represent (1) a hydrogen atom, or (2) may be substituted by (i) a halogen or (ii) a hydroxyl group. C1 to 6 alkyl; A ₁ and A ₂ each independently represent =CR ₃ - or =N-; A ₃ , A ₄ , A ₅ , and A ₆ each independently represent =CR ₄ - or =N-; ₃ and R ₄ each independently represent a hydrogen atom or a halogen; m1 represents an integer of 0 to 2; m2 represents an integer of 0 to 2; p represents an integer of 0 to 7; q represents an integer of 0 to 7, and r represents 0 to 2 Integer; only, p, q, and r 2 shows more of an integer, R _1, R _2, and R _3, independently of each may be identical or different. The therapeutic agent according to claim 1, wherein the formula (I) is as shown in the formula (IA), Wherein Cy _1-A represents a C5 to 6 monocyclic aromatic carbocyclic ring; Cy _2-A represents a 5 to 10 membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring; t represents 0 to 4 Integer; other notation indicates the same meaning as the symbol described in item 1 of the patent application. The therapeutic agent according to claim 1, wherein the general formula (I) is as shown in the general formula (IB) Wherein Cy _1-B represents a C5 to 6 monocyclic aromatic carbocyclic ring; Cy _2-B represents a 5 to 10 membered monocyclic aromatic heterocyclic ring or a bicyclic aromatic heterocyclic ring; t represents 0 to 4 Integer; other symbols indicate the same meaning as the symbols described in item 1 of the patent application. The therapeutic agent according to the above aspect of the invention, wherein the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is (1) 1-(2-(1H-Pyrazole-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridine)- 3-yl)phenoxy)pyrimidin-5-yl)urea, (2) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidine-5- 3-(2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea, (3) 1-(2 -(4-(2-Amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(3-(trifluoro) Methyl)-1H-pyrazol-1-yl)phenyl)urea, (4) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidine- 5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea, (5) 1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl) Phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea, (6) 1-(2-(1H) -1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)benzene Oxy)pyridin-3-yl)urea, (7) 1-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)-3- (2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (8) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)) Phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea, (9)1- (2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzene )-3-(2-(4-(2-Amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea, (10) 1-(2-(4-(2) -amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (11) 1-(2-(1H-Pyrazole-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridine)- 3-yl)phenoxy)pyrimidin-5-yl)urea, (12) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidine-5- base)- 3-(2-Fluoro-4-(trifluoromethyl)phenyl)urea, (13) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy) Pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea, (14) 1-(2-{4-[2-amino-5-(trifluoromethyl) Benzyl-3-pyridyl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazole-1- (phenyl)urea, (15) 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-[4-( Trifluoromethyl)-2-biphenyl]urea, (16) 1-{2-[4-(2-amino-5-fluoro-3-pyridyl)phenoxy]-5-pyrimidinyl} -3-[4-(trifluoromethyl)-2-biphenyl]urea, (17) 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy ]-5-pyrimidinyl}-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea, (18) 1-{2-[ 4-(2-Amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyridyl Zin-1-yl]phenyl}urea, (19) 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidinyl}-3- [2,4-bis(trifluoromethyl)phenyl]urea, (20) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridyl]phenoxy (5-pyrimidinyl)-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea, (21) 1-{2- [4-(2-Amino-5-fluoro-3-pyrylo) Phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl)urea, (22) 1-(2{4-[ 2-amino-5-(trifluoromethyl)-3-pyridyl]phenoxy}-5-pyrimidinyl-3-[2-(methylsulfonyl)-5-(trifluoromethyl) Phenyl)urea, (23) 1-{2-[4-(2-amino-5-chloro-3-pyridyl)phenoxy]-5-pyrimidine }[-3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)urea, (24) 2-{[(2-{4-[2-amino-5-- (trifluoromethyl)-3-pyridyl]phenoxy}-5-pyrimidinyl)amine-methylmethyl]amino}N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide , (25) 1-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidine-5- 3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (26) 1-(2-(4-(5-(azetidine)- 1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazole-5-yl) -5-(Trifluoromethyl)phenyl)urea, (27) 1-(2-(4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy Pyrimidine-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (28) 1-(2-(4-(pyrazolo) [1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea, (29) 1-(2-{4-[5-(Di-methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3 -[2-(3-pyridyl)-5-(trifluoromethyl)phenyl]urea, (30) 1-(2-{4-[5-(dimethylamino)pyrazolo[1] ,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl-3-[2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl ) Urea, (31) 1-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[ 2-(3-pyridyl)-5-(trifluoromethyl)phenyl]urea, (32) 1-(2-{4-[5-(ethylamino)pyrazolo[1,5- a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3'-methyl-4-(trifluoromethyl)-2-biphenyl]urea, (33) 1- (2-{4-[5-(Dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]benzene Oxy}-5-pyrimidinyl-3-[4-(trifluoromethyl)-2-biphenyl]urea, (34) 1-(2-{4-[5-(dimethylamino) Pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3'-methyl-4-(trifluoromethyl)-2-biphenyl Urea, or (35) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidine 3-[2'-methyl-4-(trifluoromethyl)-2-biphenyl]urea, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof . The therapeutic agent according to any one of claims 1 to 4, wherein the Trk inhibitor-resistant cancer is a Trk inhibitor-resistant cancer belonging to NTRK-positive cancer. The therapeutic agent according to any one of claims 1 to 5, wherein the Trk inhibitor-resistant cancer is a cancer resistant to a Trk inhibitor by administration of a Trk inhibitor. The therapeutic agent according to any one of claims 1 to 6, wherein the Trk inhibitor-resistant cancer obtains inhibition of Trk due to a variation in the NTRK gene generated by administration of the Trk inhibitor The drug's resistance to cancer. The therapeutic agent according to the invention of claim 7, wherein the variation in the NTRK gene is a variation in the NTRK fusion gene. The therapeutic agent according to the invention of claim 8, wherein the variation in the NTRK fusion gene is a variation in the NTRK1 fusion gene. The therapeutic agent according to claim 9, wherein the variation in the NTRK1 fusion gene is G595R and/or G667C variation. The therapeutic agent according to item 8 of the patent application, wherein NTRK fusion The variation in the gene is a variation in the NTRK2 fusion gene. The therapeutic agent according to the invention of claim 11, wherein the variation in the NTRK2 fusion gene is a G639R mutation. The therapeutic agent according to the invention of claim 8, wherein the variation in the NTRK fusion gene is a variation in the NTRK3 fusion gene. The therapeutic agent according to the invention of claim 13, wherein the variation in the NTRK3 fusion gene is a G623R mutation. The therapeutic agent according to any one of claims 1 to 14, wherein the Trk inhibitor is selected from the group consisting of Entrectinib, LOXO-101, AZD-7451, TSR-011, and ketazole. More than one agent in the group consisting of Crizotinib, ASP-7269, and DS-6051b. The therapeutic agent according to any one of claims 1 to 15, wherein the cancer is lung cancer, colon cancer, intrahepatic cholangiocarcinoma, thyroid cancer, skin cancer, breast cancer, head and neck cancer, kidney cancer, Sarcoma, brain tumor, salivary gland tumor or blood cancer. A compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, for use in the treatment of cancer resistant to Trk inhibitors. A compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, which is used for a therapeutic agent for cancer resistant to Trk inhibitors Manufacturing. A Trk inhibitor-resistant cancer treatment method comprising: an effective amount of a compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof Give the medicine to the subject.