WO2017155018A1 - THERAPEUTIC AGENT FOR Trk INHIBITOR-RESISTANT CANCER - Google Patents

Abstract

The present invention provides a therapeutic agent for Trk inhibitor-resistant cancer. A compound represented by general formula (I) (wherein each of the symbols has the same meaning as that described in the description), a salt, N-oxide or solvate of the compound or a prodrug of the compound or the salt, N-oxide or solvate is useful as an active ingredient of a therapeutic agent for Trk inhibitor-resistant cancer.

Description

Trk inhibitor resistant cancer therapeutic agent

The present invention relates to a Trk inhibitor-resistant cancer therapeutic agent. Specifically, the general formula (I)

(Wherein all symbols have the same meanings as described later), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof (hereinafter referred to as the compound of the present invention). The present invention relates to a cancer therapeutic agent contained as an active ingredient.

The Tropomyosin receptor kinase (hereinafter abbreviated as Trk) family belongs to the receptor tyrosine kinase, TrkA, which is a high affinity receptor for nerve growth factor (hereinafter abbreviated as NGF), brain-derived trophic factor (BDNF), and It is classified into neurotrophin (hereinafter abbreviated as NT) -4/5 high-affinity receptor TrkB and NT-3 high-affinity receptor TrkC. TrkA, TrkB and TrkC proteins are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. All Trk receptors are highly expressed in nerve tissue and are involved in the differentiation and function maintenance of nerve cells (see Non-Patent Document 1).

On the other hand, Trk receptor is also expressed in cancer cells such as neuroblastoma, lung cancer, breast cancer, pancreatic cancer, colon cancer, gastric cancer, liver cancer, ovarian cancer, prostate cancer, head and neck cancer, neuroendocrine tumor, and blood cancer. The possibility of being involved in cancer cell survival, proliferation, migration, and metastasis has been reported (Non-Patent Documents 2 to 8).

Furthermore, from some cancer patients such as lung cancer, colon cancer, intrahepatic cholangiocarcinoma, thyroid cancer, skin cancer, breast cancer, head and neck cancer, renal cancer, sarcoma, brain tumor, salivary gland tumor and blood cancer, the NTRK gene 3 ' NTRK fusion gene in which a part on the side and a part on the 5 'side of another gene (partner gene) are fused has been found, and it has been confirmed that this fusion gene has cancerigenic potential (Non-Patent Documents 9 to 11) ).

In the NTRK1 fusion gene, MPRIP, CD74, RABGAP1L, TPM3, TPR, TFG, PPL, CHTOP, ARHGEF2, NFASC, BCAN, LMNA and TP53 have been reported. Similarly, in the NTRK2 fusion gene, QKI, NACC2, VCL, AGBL4, TRIM24, PAN3, AFAP1 and SQSTM1 are reported, and in the NTRK3 fusion gene, ETV6, BTB1, LYN and RBPMS are reported as partner genes on the 5 ′ side, respectively. Has been. The Trk fusion protein encoded by these fusion genes is a constitutively active kinase, and promotes canceration of cells by abnormally activating intracellular signals. From these facts, a drug that inhibits Trk is expected to become a new type of anticancer drug that has never existed before. In fact, clinical trials of a plurality of Trk inhibitors are currently underway, and a tumor shrinking effect has been observed in NTRK fusion gene-positive cancer patients (Non-Patent Documents 12 to 14).

However, on the other hand, LMNA-NTRK1 fusion gene-positive colorectal cancer patients who have acquired resistance during treatment with the Trk inhibitor Enectinib have recently been reported. In the tumor of this resistant patient, G595R mutant in which glycine, which is the 595th amino acid present in the kinase domain of TrkA, was mutated to arginine, and G667C in which 667th glycine was mutated to cysteine were detected, and the G595R or G667C mutation was detected. It has been confirmed that the Trk inhibitor does not exhibit inhibitory activity against the TPM3-TrkA recombinant enzyme into which is introduced (Non-patent Document 15). Similarly, in the ETV6-NTRK3 fusion gene-positive MASC (mammary analog secretoma) patient who acquired resistance during treatment with Enlectinib, glycine, which is the 623rd amino acid in the kinase domain of TrkC, is also present in the tumor. A G623R mutant mutated to arginine was detected, and it was confirmed that the above Trk inhibitor did not show inhibitory activity against the ETV6-TrkC recombinant enzyme into which the G623R mutation was introduced (Non-patent Document 16). Similarly, it has been reported that the above Trk inhibitors do not show inhibitory activity or extremely low against these mutations (Patent Document 7). From the above, a drug having inhibitory activity on Trk having these mutations is expected to contribute to overcoming drug resistance in patients with NTRK fusion gene-positive cancer.

On the other hand, Patent Document 1 discloses a method for treating or preventing a human or other mammalian disease regulated by tyrosine kinase, wherein the human or other mammal in need thereof is represented by the following formula (Ia): And a salt thereof, an isomer thereof, or a prodrug thereof.

General formula (Ia) is

Wherein Aa is selected from the following groups (i) to (iii);
(I) phenyl optionally ^{Ra 1,} ORa 1, substituted by 1 to 3 substituents independently selected from the group such as a halogen;
(Ii) naphthyl optionally substituted with 1 to 3 substituents independently selected from the group of Ra ¹ , ORa ¹ , halogen and the like;
(Iii) 1 to 3 independently selected from the group consisting of O, N and S, optionally substituted with 1 to 3 substituents independently selected from the group of Ra ¹ , ORa ¹ , halogen and the like 5- and 6-membered monocyclic heteroaryl groups having heteroatoms;
Ba is selected from the following groups (i) to (iii);
(I) phenyl optionally substituted with 1 to 3 substituents independently selected from the group of -La-Ma, C ₁ -C ₅ linear or branched alkyl, halogen, etc .;
(Ii) naphthyl optionally substituted with 1 to 3 substituents independently selected from the group of -La-Ma, C ₁ -C ₅ linear or branched alkyl, halogen, etc .;
(Iii) A group consisting of O, N and S, optionally substituted with 1 to 3 substituents independently selected from the group of -La-Ma, C ₁ -C ₅ linear or branched alkyl, halogen, etc. 5- and 6-membered monocyclic heteroaryl groups having 1 to 3 heteroatoms independently selected from
La is selected from the group such as — (CH ₂ ) _ma —O— (CH ₂ ) _la —, — (CH ₂ ) _ma —C (O) — (CH ₂ ) _la —, where the variables ma and la Is an integer independently selected from 0 to 4;
Ma is selected from the following groups (i) to (iii);
(I) phenyl optionally substituted with 1 to 3 substituents independently selected from the group of Ra ¹ , ORa ¹ , halogen and the like;
(Ii) naphthyl optionally substituted with 1 to 3 substituents independently selected from the group of Ra ¹ , ORa ¹ , halogen and the like;
(Iii) 1 to 3 independently selected from the group consisting of O, N and S, optionally substituted with 1 to 3 substituents independently selected from the group of Ra ¹ , ORa ¹ , halogen and the like 5- and 6-membered monocyclic heteroaryl groups having heteroatoms;
Wherein Ra ¹ is 5 with (a) hydrogen, _(b) C 1 -C ₆ alkyl, (c) phenyl, (d) O, 1 to 4 heteroatoms selected from the group consisting of N and S 1-4 selected from the group consisting of ˜6-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl, (e) C ₁ -C ₃ alkyl-phenyl, and (f) O, N and S Independently selected from the group consisting of alkyl-heteroaryls having the following heteroatoms; when Ra ¹ is not hydrogen, it is optionally C ₁ -C ₅ linear, branched or cyclic alkyl, C ₁ -C ₃ alkoxy, hydroxy , Amino, C ₁ -C ₃ alkylamino, C ₂ -C ₆ dialkylamino, substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano and nitro; Part excerpt. ).

Patent Document 2 includes general formula (Ib)

(Where
Yb is N or CH;
Lb ¹ is a bond, —O—, —S—, —SO—, —SO ₂ — and the like;
Lb ² is a bond, —NHC (O) NH—, —NHC (O) —, etc .;
Rb ¹ is (i) Rb ⁵ , or (ii) C ₁ -C ₆ alkyl optionally substituted with one or more halogens, Rb ^5, etc .;
Rb ² is (i) C ₁ -C ₆ alkyl, or (ii) aryl or heteroaryl, each group having one or more halogens, Rb ⁹ , ORb ⁹ , SRb ⁹ , N (Rb ⁹ ) ₂ , optionally substituted with C (O) Rb ^9, etc .;
Rb ³ is hydrogen, _halogen, C 1 -C ₆ alkyl and the like;
Rb ⁵ is cycloalkyl, heterocycle, aryl, heteroaryl, each group may be substituted with one or more halogen, ORb ⁶ , N (Rb ⁶ ) ₂ , Rb ⁷ , ORb ^7, etc. Often;
Rb ⁷ is cycloalkyl, heterocycle, aryl, heteroaryl, each group optionally substituted with one or more halogen, hydroxyl, N (Rb ⁶ ) _2, etc .;
Each Rb ⁶ is independently hydrogen or C ₁ -C ₄ alkyl; some group definitions are excerpted. Or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is an endogenous utrophin upregulator. Has been.

Patent Document 3 includes general formula (Ic)

(Where
Ac and Cc are each independently selected from the group consisting of optionally substituted aryl and heteroaryl;
Bc is selected from the group consisting of —N (H) C (O) N (H) — and —N (H) C (O) N (H) CH ₂ —;
Xc ¹ -Xc ⁴ is selected from the group consisting of C (Rc ² ) and N, at least one of Xc ¹ -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 optionally substituted heteroaryl and heterocycloalkyl; some definitions of groups are excerpted. Or a salt, ester, or prodrug thereof is described as having B-Raf inhibitory activity.

Patent Document 4 includes a general formula (Id)

(Where
Ring Cy _1d represents a C3-10 monocyclic carbocycle or bicyclic carbocycle;
R _1d represents halogen or the like;
R _2d represents halogen or the like;
A1d and A2d each independently represent = CR _3d- and the like;
A _3d , A _4d , A _5d , and A _6d each independently represent _{═CR 4d} — and the like;
R _3d represents halogen or the like;
R _4d represents halogen or the like;
Yd represents an oxygen atom or the like;
Zd is

Represents a group in which the carbon atom forming the ring is replaced by an oxygen atom, etc .; ), A salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is described as a Trk-inhibiting compound.

Patent Document 5 describes general formula (Ie)

(Where
Ring Cy _1e represents a C3-10 monocyclic carbocycle or the like;
Ring Cy _2e represents a 4- to 10-membered monocyclic heterocycle and the like;
R _1e represents halogen or the like;
R _2e represents halogen or the like;
A _1e and A _2e each independently represent ═CR ₃ — and the like;
A _3e , A _4e , A _5e , and A _6e each independently represent _{═CR 4e} — or the like;
R _3e and R _4e each independently represents a hydrogen atom or the like; a part of the definition of the group was extracted. ), A salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is described as a Trk-inhibiting compound.

Patent Document 6 discloses a Trk inhibitory compound, 1- {2- [4- (2-amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (methylsulfonyl)- 5- (trifluoromethyl) phenyl] urea, 1- {2- [4- (2-amino-5-fluoropyridin-3-yl) phenoxy] pyrimidin-5-yl} -3- [2- (pyridine- 3-yl) -5- (trifluoromethyl) phenyl] urea or 1- (2- (1H-pyrazol-1-yl) -5- (trifluoromethyl) phenyl) -3- (2- (4- An acid addition salt of (2-amino-5-chloropyridin-3-yl) phenoxy) pyrimidin-5-yl) urea and crystals thereof are described.

However, in any document, the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof suppresses the growth of cancer resistant to Trk inhibitor. There is no description or suggestion that it can have an action, and there is no description or suggestion that the compound of the present invention can be a therapeutic agent for such cancer.

International Publication No. 2003/068228 Pamphlet International Publication No. 2010/057833 Pamphlet International Publication No. 2007/076473 Pamphlet International Publication No. 2013/161919 Pamphlet International Publication No. 2014/129431 Pamphlet International Publication No. 2016/027754 Pamphlet International Publication No. 2016/196141 Pamphlet

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

As a result of diligent research to solve the above problems, the present inventors have found that a compound represented by the following general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, The present invention was completed by finding that it has a growth inhibitory action against Trk inhibitor-resistant cancer.

That is, the present invention is as follows.
[1] General formula (I)

(Where
Ring Cy ₁ represents a C3-10 monocyclic carbocycle or bicyclic carbocycle, or a 4-10 membered monocyclic heterocycle or bicyclic heterocycle,
Ring Cy ₂ represents a 4- to 10-membered monocyclic heterocycle or bicyclic heterocycle,
R ₁ is
(1) halogen,
(2) a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group optionally substituted with a substituent selected from the group consisting of (i) halogen and (ii) hydroxyl group ,
(3) a C5-6 monocyclic carbocycle optionally substituted by 1 to 2 R ₅ ,
(4) a 5- to 6-membered monocyclic heterocycle optionally substituted by 1 to 2 R ₅ ,
(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) represents a cyano group, or (13) a nitro group,
R ₅ is
(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) a cyano group,
(10) represents a nitro group, or a C1-3 alkyl group optionally substituted with a substituent selected from the group consisting of (11) (i) halogen, (ii) hydroxyl group, and (iii) oxo group ,
When R ₅ is two, R ₅ may be independently the same or different,
Further, two R ₅ are each independently a C1-3 alkyl group or a hydroxyl group, and R ₅ is adjacent to a C5-6 monocyclic carbocycle or 5- to 6-membered monocyclic heterocycle. The groups may form a ring together,
R ₆ -R ₂₇ each independently represents (1) a hydrogen atom, or (2) (i) a C1-6 alkyl group optionally substituted with a halogen or (ii) a hydroxyl group,
When R ₁₈ and R ₁₉ are each independently a C1-6 alkyl group, these groups may be taken together to form a ring;
R ₂ is
(1) halogen,
(2) (i) a C1-6 alkyl group optionally substituted with a halogen or (ii) a hydroxyl group,
(3) (i) a C3-6 cycloalkyl group optionally substituted with a halogen or (ii) a hydroxyl group,
(4) a C1-6 alkoxy group optionally substituted with halogen,
(5) -NR ₂₈ R ₂₉ ,
(6) represents a 3- to 7-membered monocyclic heterocycle, or (7) —O— (a 3- to 7-membered monocyclic heterocycle),
R ₂₈ and R ₂₉ each independently represent (1) a hydrogen atom, or (2) (i) a C1-6 alkyl group optionally substituted with a halogen or (ii) a hydroxyl group;
A ₁ and A ₂ each independently represent ═CR ₃ — or ═N—
_{A 3, A 4, A 5} , and _{A 6} are each independently, = CR ₄ - or = N- and represent,
R ₃ and R ₄ each independently represents a hydrogen atom or 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,
r represents an integer of 0-2.
However, when p, q, and r each represent an integer of 2 or more, R ₁ , R ₂ , and R ₃ may be independently the same or different. And a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof as an active ingredient, a Trk inhibitor-resistant cancer therapeutic agent.
[2] General formula (I) is general formula (IA)

Wherein Cy _1-A represents a C5-6 monocyclic aromatic carbocycle, and Cy _2-A represents a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle Wherein t represents an integer of 0 to 4, and other symbols have the same meanings as the symbols in the preceding paragraph.)
[3] General formula (I) is general formula (IB)

Wherein Cy _1-B represents a C5-6 monocyclic aromatic carbocycle, and Cy _2-B represents a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle Wherein t represents an integer of 0 to 4, and the other symbols have the same meanings as those in claim 1.), the agent according to [1].
[4] (1) 1- (2- (1H-pyrazol-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) 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) 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-triazol-1-yl) -5- (trifluoromethyl) phenyl-3- (6- (4- (2-amino-5-chloropyridine) -3-yl) phenoxy) 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-pyrazole-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-fluoro) Pyridin-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-pyrazol-1-yl) -4- (trifluoromethyl) phenyl) -3- (2- (4- (2-amino-5-chloropyridin-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- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- {5- (trifluoromethyl) -2- [ 3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} urea,
(15) 1- {2- [4- (2-amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
(16) 1- {2- [4- (2-amino-5-fluoro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
(17) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (4-chloro-1H-pyrazol-1-yl) -5- (trifluoromethyl) phenyl] urea,
(18) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- {5-chloro-2- [3- (trifluoromethyl)- 1H-pyrazol-1-yl] phenyl} urea,
(19) 1- {2- [4- (2-amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2,4-bis (trifluoromethyl) phenyl] urea,
(20) 1- (2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- [2- (4-chloro-1H-pyrazole- 1-yl) -5- (trifluoromethyl) phenyl] urea,
(21) 1- {2- [4- (2-Amino-5-fluoro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (methylsulfonyl) -5- (trifluoromethyl) phenyl ] Urea,
(22) 1- (2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- [2- (methylsulfonyl) -5- (tri Fluoromethyl) phenyl] urea,
(23) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (methylsulfonyl) -5- (trifluoromethyl) phenyl ] Urea,
(24) 2-{[(2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) carbamoyl] 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-pyridinyl) -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-pyridinyl) -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-biphenylyl] urea,
(33) 1- (2- {4- [5- (Dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5-pyrimidinyl) -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
(34) 1- (2- {4- [5- (Dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5-pyrimidinyl) -3- [3′-methyl-4- (Trifluoromethyl) -2-biphenylyl] urea or (35) 1- (2- {4- [5- (dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5 -Pyrimidinyl) -3- [2'-methyl-4- (trifluoromethyl) -2-biphenylyl] urea, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof as an active ingredient A therapeutic agent for cancer resistant to a Trk inhibitor.
[5] The agent according to any one of [1] to [4], wherein the Trk inhibitor-resistant cancer is a NTRK positive cancer and is a Trk inhibitor-resistant cancer.
[6] The agent according to any one of [1] to [5], wherein the NTRK positive cancer is an NTRK fusion gene positive cancer.
[7] The agent according to any one of [1] to [6], wherein the Trk inhibitor-resistant cancer is a cancer that has acquired resistance to the Trk inhibitor by administration of the Trk inhibitor.
[8] Any of the above [1] to [7], wherein the Trk inhibitor-resistant cancer is a cancer that has acquired resistance to the Trk inhibitor due to a mutation in the NTRK gene caused by administration of the Trk inhibitor. The agent according to crab.
[9] The agent according to [8] above, wherein the mutation in the NTRK gene is a mutation in the NTRK fusion gene.
[10] The agent according to any one of [1] to [9] above, wherein the mutation in the NTRK fusion gene is a mutation in the NTRK1 fusion gene.
[11] The agent according to any one of [1] to [10] above, wherein the mutation in the NTRK1 fusion gene is a G595R and / or G667C mutation.
[12] The agent according to any one of [1] to [11] above, wherein the mutation in the NTRK fusion gene is a mutation in the NTRK2 fusion gene.
[13] The agent according to any one of [1] to [12] above, wherein the mutation in the NTRK2 fusion gene is a G639R mutation.
[14] The agent according to any one of [1] to [13], wherein the mutation in the NTRK fusion gene is a mutation in the NTRK3 fusion gene.
[15] The agent according to any one of [1] to [14], wherein the mutation in the NTRK3 fusion gene is a G623R mutation.
[16] The Trk inhibitor is one or more drugs selected from the group consisting of Enlectinib, LOXO-101, AZD-7451, TSR-011, Crizotinib, ASP-7269, and DS-6051b. [15] The agent according to any one of [15].
[17] The above [1] to [16], wherein the cancer is lung cancer, colon cancer, intrahepatic bile duct cancer, thyroid cancer, skin cancer, breast cancer, head and neck cancer, renal cancer, sarcoma, brain tumor, salivary gland tumor or blood cancer. The agent in any one of.
[18] Alkylating agent, antimetabolite, anticancer antibiotic, anticancer plant preparation, hormone agent, platinum compound, topoisomerase inhibitor, kinase inhibitor, anti-CD20 antibody, anti-HER2 antibody, anti-EGFR antibody, And the agent according to any one of [1] to [17] above, which is used in combination with one or more agents selected from the group consisting of anti-VEGF antibodies.
[19] The agent according to any one of [1] to [18] above, which is used in combination with an EGFR inhibitor.
[20] The agent according to [19] above, wherein the EGFR inhibitor is one or more drugs selected from the group consisting of erlotinib, gefitinib and afatinib.
[21] The agent according to any one of [1] to [18], which is used in combination with a MEK inhibitor.
[22] The agent described in [21] above, wherein the MEK inhibitor is trametinib and / or selmethinib.
[23] Use of the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof for the treatment of cancer resistant to a Trk inhibitor.
[24] Use of the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof for the manufacture of a therapeutic agent for cancer resistant to a Trk inhibitor .
[25] A Trk inhibitor-resistant compound comprising administering to a subject 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. Cancer treatment method.
[26] A compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof for use in treatment of a Trk inhibitor-resistant cancer.

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

Hereinafter, the present invention will be described in detail.

In the present invention, “trk inhibitor resistant cancer” includes, for example, a cancer whose progress has been confirmed after treatment with a Trk inhibitor, a cancer that has acquired resistance to a Trk inhibitor by administration of the Trk inhibitor, One or more mutations selected from the group consisting of cancers that have acquired resistance to Trk inhibitors due to mutations in the NTRK gene caused by administration of inhibitors, G595R mutations, G667C mutations, G639R mutations, and G623R mutations described below Examples include cancers that are resistant to Trk inhibitors. The Trk inhibitor refers to a drug having an inhibitory activity against Trk protein, and as an embodiment, it is a Trk inhibitor excluding the compound represented by the general formula (I) or a salt thereof. In another aspect, one or more selected from the group consisting of Enlectinib (RXDX-101), LOXO-101, AZD-7451, TSR-011, Crizotinib, Altiratinib, ASP-7269, DS-6051b and VM-902 It is a drug.

In the present invention, “NTRK positive cancer” refers to a cancer in which expression of NTRK gene (including NTRK1 gene, NTRK2 gene and NTRK3 gene) or Trk protein (including TrkA protein, TrkB protein and TrkC protein) can be confirmed. Show. Examples of the NTRK gene include wild type and mutant NTRK1 gene, NTRK2 gene and NTRK3 gene. Furthermore, examples of mutant NTRK genes include NTRK fusion genes (including NTRK1 fusion genes, NTRK2 fusion genes, and NTRK3 fusion genes). “NTRK positive cancer” includes cancers in which the Trk protein is permanently activated by overexpression of a wild type NTRK gene or expression of a mutant NTRK gene.

Examples of the “NTRK1 fusion gene” include MPRIP-NTRK1, CD74-NTRK1, RABGAP1L-NTRK1, TPM3-NTRK1, TPR-NTRK1, TFG-NTRK1, PPL-NTRK1, CHTOP-NTRK1, ARHGEF2-NTRKNTR, NFASCNTR, -NTRK1, LMNA-NTRK1 and TP53-NTRK1. Examples of the “NTRK2 fusion gene” include 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 mutation” refers to the residue of the 595th amino acid of the wild-type TrkA protein (TrkA isoform2 (RefSeq: NP_002320.2)) as a result of base substitution in the wild-type or mutant NTRK1 gene. A group or a corresponding amino acid residue (for example, a corresponding amino acid residue in another TrkA isoform or a mutant TrkA protein) is a mutation in which glycine is converted to arginine. The G595R mutation in the NTRK1 fusion gene means that the amino acid residue of the TrkA fusion protein corresponding to the 595th amino acid residue of the wild-type TrkA protein (TrkA isoform2 (RefSeq: NP_002320.2)) is from glycine to arginine. Indicates a mutation that has been converted to.

In the present invention, the “G667C mutation” refers to the residue of the 667th amino acid of the wild type TrkA protein (TrkA isoform2 (RefSeq: NP — 002320.2)) as a result of base substitution in the wild type or mutant NTRK1 gene. A group or an amino acid residue corresponding thereto (for example, an amino acid residue corresponding to another TrkA isoform or a mutant TrkA protein) is converted from glycine to cysteine. The G667C mutation in the NTRK1 fusion gene refers to the amino acid residue of the TrkA fusion protein corresponding to the 667th amino acid residue of the wild-type TrkA protein (TrkA isoform2 (RefSeq: NP_002320.2)) from glycine to cysteine. And the mutation that is converted.

In the present invention, the “G639R mutation” refers to the 639th amino acid of the wild type TrkB protein (TrkB isoform a (RefSeq: NP_006171.2)) as a result of the base substitution in the wild type or mutant NTRK2 gene. This shows a mutation in which a residue or an amino acid residue corresponding thereto (for example, an amino acid residue corresponding to another TrkB isoform or a mutant TrkB protein) is converted from glycine to arginine. The G639R mutation in the NTRK2 fusion gene refers to the amino acid residue of the TrkB fusion protein corresponding to the 639th amino acid residue of the wild-type TrkB protein (TrkB isoform a (RefSeq: NP_006171.2)) from glycine to arginine. Indicates a mutation that has been converted to. The “G639R mutation” is a mutation in the TrkB protein corresponding to the aforementioned “G595R mutation”.

In the present invention, the “G623R mutation” refers to a wild type or mutant NTRK3 gene resulting in a base substitution, resulting in a wild type TrkC protein (TrkC isoform a (RefSeq: NP — 00101233388.1) or TrkC isoform b (RefSeq). : NP_002521.2)), or its corresponding amino acid residue (for example, the corresponding amino acid residue in other TrkC isoforms and mutant TrkC proteins) is converted from glycine to arginine. Showing the mutation. The G623R mutation in the NTRK3 fusion gene corresponds to the 623rd 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 mutation in which the amino acid residue of the TrkC fusion protein is converted from glycine to arginine is shown. The “G623R mutation” is a mutation in the TrkC protein corresponding to the aforementioned “G595R mutation”.

In the present invention, the “C3-10 monocyclic carbocycle or bicyclic carbocycle” includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, Cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, And perhydronaphthalene ring.

In the present invention, “4- to 10-membered monocyclic or bicyclic heterocycle” means, for example, oxetane, azetidine, pyrrolidine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piper Perazine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole , Thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, in Sol, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzodioxol, benzooxathiol, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline , Pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine , Dihydroazepine, Trahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrothiophene , Tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepin, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydro Thiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine) , Dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, par Hydroxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, Dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadi Zepin, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, Dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, Dihydroquinoxaline, tetrahydroquinoxaline, perch Loquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzo Oxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dioxaindane, benzodioxane, thiochroman, dihydrobenzodioxin, dihydrobenzoxathiine, chroman, pyrazolopyrimidine, imidazopyridazine, imidazo Pyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolo Such as pyrimidine, imidazopyridine, and triazolopyridine rings.

In the present invention, “halogen” is fluorine, chlorine, bromine, and iodine.

In the present invention, the “C1-6 alkyl group” means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-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-ethylpropyl 1-ethylbutyl and 2-ethylbutyl groups.

In the present invention, the “C2-6 alkenyl group” means, for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl. , 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and Such as a 5-hexenyl group.

In the present invention, the “C2-6 alkynyl group” means, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl 4-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl groups.

In the present invention, the “C5-6 monocyclic carbocycle” includes, for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene ring.

In the present invention, the “5- to 6-membered monocyclic heterocycle” means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine, pyridazine, furan, pyran. Thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, Pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine , Dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydro Isoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), Dihydrooxazine, tetrahydrooxazine Such as dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, and oxathian ring .

In the present invention, the “C1-3 alkyl group” means methyl, ethyl, n-propyl, and isopropyl groups.

In the present invention, the “C 3-6 cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl group.

In the present invention, the “C1-6 alkoxy group” means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, tert-butoxy, isobutoxy, pentyloxy, 1-methylbutoxy, 2-methyl Butoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, hexyloxy, 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-dimethylbutoxy 2,2-dimethylbutoxy, 1-ethyl-2- Chirupuropokishi, and the like 2-ethyl-2-methyl-propoxy, and 1-ethylbutoxy groups.

In the present invention, “3- to 7-membered monocyclic heterocycle” means, for example, aziridine, oxetane, azetidine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine , Pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine , Thiadiazepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, di Dropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, per Hydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydro Thiepin, Perhydrothiepin, Dihydrooxazole, Tetrahydrooxazo (Oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydro Oxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine , Perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolid ), Dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, Such as morpholine, thiomorpholine, and oxathian ring.

In the present invention, “5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle” means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine , Diazepine, furan, oxepin, thiophene, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazepine, oxadiazepine, thiadiazole, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, iso Benzothiophene, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, Nzochiazoru, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, and the like pyrazolopyrimidine, imidazopyridine and triazolopyridine ring.

In the present invention, the “5- to 6-membered monocyclic aromatic heterocycle” means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, Thiazole, isothiazole, furazane, oxadiazole, and thiadiazole rings.

In the present invention, “two R ₅ are each independently a C 1-3 alkyl group or hydroxyl group, and R ₅ is a C 5-6 monocyclic carbocycle or 5- to 6-membered monocyclic heterocycle” When they are located on the adjacent carbon atoms above, these groups may be joined together to form a ring, "for example, refers to the following groups.

(Wherein ring Cy ₃ represents a monocyclic heterocycle monocyclic carbocyclic or 5-6 membered C5 ~ 6, arrow denotes 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 C1-6 alkyl group, these groups are combined to form a ring. “May be,” for example, refers to the following groups.

In the present invention, the ring Cy ₁ is preferably a C5-6 monocyclic carbocycle or a 5-6 membered monocyclic heterocycle.

In the present invention, the ring Cy ₁ is more preferably cyclopentane, cyclohexane, benzene, pyran, thiopyran, pyrrolidine, piperidine, piperazine, imidazoline, imidazolidine, morpholine, thiomorpholine, and a 5- to 6-membered single member. A cyclic aromatic heterocycle.

In the present invention, the ring Cy ₁ is preferably benzene and a 5- to 6-membered monocyclic aromatic heterocycle.

In the present invention, the ring Cy ₁ is more preferably a 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 more preferably a benzene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, and pyridazine ring.

In the present invention, the ring Cy ₁ is more preferably a benzene, pyrazole, and pyridine ring.

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

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

In the present invention, ring Cy ₂ is more preferably pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, quinolidine, purine, Phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyra Zolopyrimidine, imidazopyridine, and triazolopyridine rings.

In the present invention, the ring Cy ₂ is more preferably pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, indolizine, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, On benzoxazole, benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, imidazopyridine, and triazolopyridine rings is there.

In the present invention, the ring Cy ₂ is more preferably pyridine, pyrazine, pyrimidine, pyridazine, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, imidazopyridine, and triazolo It is a pyridine ring.

In the present invention, ring Cy ₂ is still more preferably a pyridine, pyrimidine, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, and pyrazolopyridine ring.

In the present invention, the ring Cy ₂ is most preferably a pyridine and pyrazolopyrimidine ring.

In the present invention, R ₁ is preferably (1) halogen, (2) a C1-3 alkyl group optionally substituted with halogen, and (3) optionally substituted by 1-2 R _5. A benzene ring, (4) a 5- to 6-membered monocyclic aromatic heterocycle optionally substituted with 1 to 2 R ₅ , (5) a methylsulfonyl group, and (6) N, N-dimethylsulfone Amide.

In the present invention, R ₁ is more preferably (1) halogen, (2) methyl group, (3) trifluoromethyl group, (4) difluoromethyl group, (5) monofluoromethyl group, (6) trichloromethyl. A group, (7) a dichloromethyl group, (8) a monochloromethyl group, (9) a benzene ring optionally substituted with 1 to 2 R ₅ , (10) substituted with 1 to 2 R ₅ Pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, and thiadiazole ring, (11) methyl A sulfonyl group, and (12) N, N-dimethylsulfonamide.

In the present invention, R ₁ is more preferably (1) halogen, (2) methyl group, (3) trifluoromethyl group, (4) difluoromethyl group, (5) monofluoromethyl group, (6) benzene ring. , (7) indane ring, (8) tolyl group, (9) dimethylbenzene ring, (10) an imidazole, triazole, pyrazole, and pyridine ring optionally substituted with 1-2 R ₅ , and ( 11) A methylsulfonyl group.

In the present invention, R ₁ is more preferably (1) halogen, (2) trifluoromethyl group, (3) difluoromethyl group, (4) benzene ring, (5) indane ring, (6) tolyl group, ( 7) a dimethylbenzene ring, (8) an imidazole, triazole, pyrazole, and pyridine ring optionally substituted with 1-2 methyl, difluoromethyl, or trifluoromethyl groups, and (9) methylsulfonyl It is a group.

In the present invention, even more preferably as _{R 1,} (1) a trifluoromethyl group, (2) a difluoromethyl group, (3) a benzene ring, and (4) 1-2 group, difluoromethyl group or, A triazole, pyrazole, and pyridine ring, which may be substituted with a trifluoromethyl group, and (5) a methylsulfonyl group.

In the present invention, R ₁ is most preferably (1) a trifluoromethyl group, and (2) a triazole optionally substituted by 1 to 2 methyl groups, a difluoromethyl group, or a trifluoromethyl group, Pyrazole and pyridine rings.

In the present invention, R ₅ is preferably (1) a halogen, (2) a methyl group optionally substituted with a halogen, and (3) a C1-3 alkyl optionally substituted with a hydroxyl group or an oxo group. It is a group.

In the present invention, R ₅ is more preferably a methyl group, a trifluoromethyl group, a difluoromethyl group, an acetyl group, or a hydroxyethyl group.

In the present invention, R ₅ is most preferably a methyl group, a trifluoromethyl group, or a difluoromethyl group.

In the present invention, R ₂ is preferably (1) a halogen, (2) a C1-3 alkyl group optionally substituted with a halogen or a hydroxyl group, (3) a C3-6 cycloalkyl group, (4) C1 To 3 alkoxy groups, (5) amino group, (6) optionally substituted with a hydroxyl group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, sec- Butylamino, tert-butylamino, isobutylamino, and dimethylamino groups, (7) 3-7 membered monocyclic heterocycle, and (8) -O- (3-7 membered monocyclic heterocycle Ring).

In the present invention, R ₂ is more preferably halogen, methyl group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, hydroxymethyl group, hydroxyethyl group, 2-methyl-hydroxyethyl group, cyclopropyl group, A methoxy group, an ethoxy group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a 2-methyl-2-hydroxypropylamino group, an oxetanyloxy group, an azetidine ring, a pyrrolidine ring, and a piperidine ring.

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

In the present invention, R ₂ is more preferably a halogen, a methyl group, an amino group, an azetidine ring, or a pyrrolidine ring.

In the present invention, R ₂ is most preferably fluorine, chlorine, a methyl group, an amino group, and 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 C1-3 alkyl group which may be substituted with halogen.

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

In the present invention, R ₇ and R ₈ are preferably each independently a C1-3 alkyl group which may be substituted with a hydrogen atom or 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, an n-propyl group, an isopropyl group, or a 2-hydroxypropyl group.

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

In the present invention, R ₉ is preferably a hydrogen atom, a methyl group, or an ethyl group.

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

In the present invention, R ₁₇ is preferably a C1-3 alkyl group which may be substituted with halogen.

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

In the present invention, R ₁₈ and R ₁₉ are preferably each independently a C1-3 alkyl group optionally substituted with a hydrogen atom or 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, an n-propyl group, an isopropyl group, or a 2-hydroxypropyl group.

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

In the present invention, R ₂₀ is preferably a hydrogen atom, a methyl group, or an ethyl group.

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

In the present invention, m1 is preferably an integer of 2.

In the present invention, m2 is preferably an integer of 2.

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

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

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

In the present invention, R _2-a and R _2-b each independently have the same meaning as R _2, and preferred groups are the same as R ₂ .

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

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

In the present invention, the general formula (I) is preferably the ring Cy ₁ , ring Cy ₂ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R _2-a , R _2-b , m1, Preferred combinations of each of m2, p, q, r, t, qa, and qb.

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

Wherein Cy _1-A represents a C5-6 monocyclic aromatic carbocycle, and Cy _2-A represents a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle And other symbols have the same meanings as those described in [1] above), salts thereof, N-oxides thereof, solvates thereof, or prodrugs thereof.

In another embodiment, the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably represented by formula (IB)

Wherein Cy _1-B represents a C5-6 monocyclic aromatic carbocycle, and Cy _2-B represents a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle. Represents a ring, and the other symbols have the same meanings as those described in the above [1].), A salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

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

(In the formula, ring Cy _2-a and ring Cy _2-b represent a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle, and other symbols are those described in [1] above. And a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, as the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, the general formula (Ic) or the general formula (I -D)

(Wherein the ring Cy _2-c and the ring Cy _2-d are 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. And other symbols have the same meanings as those described in [1] above), salts thereof, N-oxides thereof, solvates thereof, or prodrugs thereof.

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

(In the formula, ring Cy _1-e and ring Cy _1-f represent a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle, and other symbols have the same meanings as those described in [1] above. Or a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, as the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, the general formula (Ig) or the general formula (I -H)

(In the formula, ring Cy _1-g and ring Cy _1-h represent a benzene ring, a pyridine ring, or a pyrazole ring, and other symbols have the same meanings as those described in [1] above). A compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

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

Wherein ring Cy _2-j and ring Cy _2-k represent a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle, and ring Cy _1-j and ring Cy _{1- k} represents a benzene ring or a 5- to 6-membered monocyclic aromatic heterocyclic ring, and the other symbols have the same meanings as described in the above [1]), salts thereof, N— It is an oxide form, a solvate thereof, or a prodrug thereof.

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

(Wherein the ring Cy _2-m and the ring Cy _2-n are 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 each} represents a benzene ring, a pyridine ring, or a pyrazole ring, and the other symbols have the same meanings as those described in the above [1]. Its salt, its N-oxide, its solvate, or their prodrugs.

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

(Wherein all symbols have the same meanings as described in [1] above), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

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

(In the formula, ring Cy _1- ia and ring Cy _1-ii-b represent a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle, and other symbols are those described in [1] above. Or a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

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

(In the formula, ring Cy _1-ic and ring Cy _1-ii-d represent a benzene ring, a pyridine ring, or a pyrazole ring, and other symbols have the same meanings as those described in [1] above. ), A salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In another embodiment, the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably represented by the general formula (I-iii) Or general formula (I-iv)

(Wherein all symbols have the same meanings as described in [1] above), salts thereof, N-oxides thereof, solvates thereof, or prodrugs thereof.

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

Wherein ring Cy _1-iii-a and ring Cy _1-iv-b represent a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle, and other symbols are those described in [1] above Or a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by the general formula (I-iii) or the general formula (I-iv), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is more preferably used. (I-iii-c) or general formula (I-iv-d)

(Wherein, Cy _1-iii-c and Cy _1-iv-d represent a benzene ring or a pyridine ring, and other symbols have the same meanings as those described in [1] above). A compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably used.
(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) pyrimidin-5-yl) -3- (3- (trifluoromethyl) phenyl) urea,
(5) 1- (2- (4- (2-Amino-5-chloropyridin-3-yl) phenoxy) pyrimidin-5-yl) -3- (2-chloro-5- (trifluoromethyl) phenyl) Urea,
(6) 1- (2- (4- (2-Amino-5-chloropyridin-3-yl) phenoxy) pyrimidin-5-yl) -3- (2-fluoro-5- (trifluoromethyl) phenyl) Urea,
(7) 1- (2- (1H-pyrazol-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) pyrimidin-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-chloropyridine) -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- Pyridinyl) -5- (trifluoromethyl) phenyl] urea,
(13) 1- {6- [4- (5-Methoxypyrazolo [1,5-a] pyrimidin-3-yl) phenoxy] -3-pyridinyl} -3- [2- (3-pyridinyl) -5 -(Trifluoromethyl) phenyl] urea,
(14) 1- {2- [4- (2-Amino-5-fluoro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (methylsulfonyl) -5- (trifluoromethyl) phenyl ] Urea,
(15) 1- (2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- [2- (methylsulfonyl) -5- (tri Fluoromethyl) phenyl] urea,
(16) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) 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] pyridazin-3-yl ] Phenoxy} -5-pyrimidinyl) urea, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In another embodiment, the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably used.
(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) 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-triazol-1-yl) -5- (trifluoromethyl) phenyl-3- (6- (4- (2-amino-5-chloropyridine) -3-yl) phenoxy) 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-pyrazole-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-fluoro) Pyridin-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-pyrazol-1-yl) -4- (trifluoromethyl) phenyl) -3- (2- (4- (2-amino-5-chloropyridin-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- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- {5- (trifluoromethyl) -2- [ 3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} urea,
(15) 1- {2- [4- (2-amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
(16) 1- {2- [4- (2-amino-5-fluoro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
(17) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (4-chloro-1H-pyrazol-1-yl) -5- (trifluoromethyl) phenyl] urea,
(18) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- {5-chloro-2- [3- (trifluoromethyl)- 1H-pyrazol-1-yl] phenyl} urea,
(19) 1- {2- [4- (2-amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2,4-bis (trifluoromethyl) phenyl] urea,
(20) 1- (2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- [2- (4-chloro-1H-pyrazole- 1-yl) -5- (trifluoromethyl) phenyl] urea,
(21) 1- {2- [4- (2-Amino-5-fluoro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (methylsulfonyl) -5- (trifluoromethyl) phenyl ] Urea,
(22) 1- (2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- [2- (methylsulfonyl) -5- (tri Fluoromethyl) phenyl] urea,
(23) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (methylsulfonyl) -5- (trifluoromethyl) phenyl ] Urea,
(24) 2-{[(2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) carbamoyl] 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-pyridinyl) -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-pyridinyl) -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-biphenylyl] urea,
(33) 1- (2- {4- [5- (Dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5-pyrimidinyl) -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
(34) 1- (2- {4- [5- (Dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5-pyrimidinyl) -3- [3′-methyl-4- (Trifluoromethyl) -2-biphenylyl] urea or (35) 1- (2- {4- [5- (dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5 -Pyrimidinyl) -3- [2'-methyl-4- (trifluoromethyl) -2-biphenylyl] urea, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

In the present invention, all isomers are included unless otherwise specified. For example, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and the like include a straight chain group and a branched chain group. Furthermore, isomers (R, S, α, β, enantiomers, diastereomers), optical rotatory power, isomers in rings, condensed rings (E, Z, cis, trans), asymmetric carbons, etc. Optically active substance (D, L, d, l form), polar form (high polar form, low polar form) by chromatographic separation, equilibrium compound, rotamer, a mixture of these in any proportion, racemic mixture, All are included in the present invention. In the present invention, all isomers by tautomerism are also included.

In the present invention, unless otherwise specified, the symbols as will be apparent to those skilled in the art:

Indicates binding to the other side of the page (ie, α-configuration) and the symbol:

Indicates binding to the front side of the paper (ie, β-configuration), and symbol:

Represents α-configuration or β-configuration, symbol:

Represents a mixture in any ratio of α-configuration and β-configuration.

[salt]
The compound represented by the general formula (I) is converted into a salt by a known method.

The salt is preferably a pharmaceutically acceptable salt.

The salt is preferably water-soluble.

Examples of the salt include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, and amine salts.

Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoic acid. Organic acid salts such as salt, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, or gluconate Can be mentioned.

Examples of the alkali metal salt include potassium and sodium.

Examples of alkaline earth metal salts include calcium and magnesium.

Examples of ammonium salts include tetramethylammonium.

Examples of amine salts include triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, and N-methyl-D- Examples include glucamine.

In addition, the compound represented by the general formula (I) and a salt thereof can be converted into an N-oxide form by an arbitrary method. The N-oxide is a compound in which the nitrogen atom of the compound represented by the general formula (I) and a salt thereof is oxidized, specifically, A of the compound represented by the general formula (I) and a salt thereof. _{When 1} , A ₂ , A ₃ , A ₄ , A ₅ , or A ₆ is ═N—, the nitrogen atom is oxidized. Alternatively, when Cy ₁ or Cy ₂ is a nitrogen-containing heterocyclic ring, the nitrogen atom is oxidized. Furthermore, it represents an oxidized amino group.

The compound represented by the general formula (I) and a salt thereof can be converted into a solvate. The solvate is preferably non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water or alcohol solvents (for example, ethanol).

[Prodrug]
The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body. As a prodrug of the compound represented by the general formula (I), for example, when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example, The amino group of the compound represented by the general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranyl , Pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated compounds, etc.); when the compound represented by formula (I) has a hydroxyl group, the hydroxyl group is acylated, alkyl , Phosphorylated, and borated compounds (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoyl Propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compound, etc.); when the compound represented by the general formula (I) has a carboxy group, Esterified, amidated compounds (for example, the carboxy group of the compound represented by the general formula (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified 1-{(ethoxycarbonyl) oxy} ethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, 1-{[(cyclohexyloxy) Carbonyl] oxy} ethyl esterification, methylamidation Such compounds), and the like. These compounds can be produced by a method known per se. The prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate. In addition, the prodrug of the compound represented by the general formula (I) has a general formula under physiological conditions as described in Yodogawa Shoten 1990, “Development of Pharmaceuticals”, Volume 7 “Molecular Design”, pages 163 to 198. It may be changed to the compound represented by (I).

Further, each atom constituting the compound represented by the general formula (I) is an isotope (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.).
[Method for producing compound of the present invention]
A compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof may be produced by the method described in WO2014 / 129431, WO2016 / 027754. Can be produced according to the methods described in No. 1, known methods, and methods analogous thereto. The starting material compound may be used as a salt. As such salts, those described as pharmaceutically acceptable salts of general formula (I) are used.

[toxicity]
The toxicity of the compound of the present invention is sufficiently low. The compound of the present invention is, for example, a compound that does not exhibit hepatotoxicity or gastrointestinal tract disorder and has low brain transferability. Therefore, this invention compound can be safely used as a pharmaceutical.

[Application to pharmaceutical products]
Since the compound of the present invention has a growth inhibitory action against Trk inhibitor-resistant cancer, it is useful as a therapeutic agent for Trk inhibitor-resistant cancer.

Examples of cancers resistant to Trk inhibitors include breast cancer, ovarian cancer, colon cancer (eg, colon cancer), lung cancer (eg, non-small cell lung cancer), prostate cancer, head and neck cancer (eg, oral squamous cell carcinoma, Head and neck squamous cell carcinoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, acoustic schwannoma, etc.), skin cancer (eg, melanoma (malignant melanoma), etc.), lymphoma (eg, B cell lymphoma, T cell lymphoma, etc.) ), Brain tumor, glioma, pituitary adenoma, uveal malignant melanoma, meningioma, thymoma, mesothelioma, esophageal cancer, stomach cancer, liver cancer (eg, hepatocellular carcinoma), cholangiocarcinoma (eg, liver) Internal bile duct cancer), gallbladder cancer, pancreatic cancer, renal cancer (eg renal cell cancer, renal pelvis / ureter cancer), bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, malignant bone tumor Sarcomas (eg soft tissue sarcoma, chondrosarcoma, pulmonary sarcoma, osteosarcoma, congenital fibrosarcoma) ), Blood cancer (for example, leukemia, etc.), myelodysplastic syndrome, multiple myeloma, salivary gland tumor, MASC (mammary analgesic carcinoma), neuroendocrine tumor, neuroblastoma, medulloblastoma, glioblastoma, eye Examples include retinoblastoma, small intestine cancer, inflammatory myofibroblastic tumor, congenital mesoderm nephroma, and adrenocortical carcinoma.

The compound of the present invention
1) complementation and / or enhancement of the prophylactic and / or therapeutic effect of the compound,
2) Improving the kinetics / absorption of the compound, reducing the dose, and / or 3) reducing the side effects of the compound may be combined with other drugs and administered as a concomitant drug.

The concomitant drug of the compound of the present invention and another drug may be administered in the form of a combination drug containing both components in one preparation, or may be administered in separate preparations. When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, administration with a time difference may be such that the compound of the present invention is administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. Each administration method may be the same or different.

The disease that exerts a preventive and / or therapeutic effect by the above concomitant agent is not particularly limited as long as it is a disease that complements and / or enhances the preventive and / or therapeutic effect of the compound of the present invention.

Examples of other agents for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present invention on cancer include, for example, alkylating agents, antimetabolites, anticancer antibiotics, anticancer plant preparations, Hormone agent, platinum compound, topoisomerase inhibitor, kinase inhibitor, anti-CD20 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-VEGF antibody, proteasome inhibitor, HDAC inhibitor, immune checkpoint inhibitor (eg, anti-CTLA-4 Antibody, anti-PD-1 antibody, anti-PD-L1 antibody, etc.), immunomodulator, and other anticancer agents.

Examples of the alkylating agent include cyclophosphamide, ifosfamide, dacarbazine, nimustine hydrochloride, ranimustine, bendamustine, thiotepa, and carbocon.

Antimetabolites include, for example, methotrexate, pemetrexed, fluorouracil, tegafur, tegafur uracil, tegafur gimestat otastat potassium, doxyfluridine, capecitabine, cytarabine, gemcitabine hydrochloride, fludarabine, nelarabine, carmofur and the like .

Examples of the anticancer antibiotics include mitomycin C, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin, chromomycin A3, bleomycin, pepromycin sulfate, and terarubicin.

Examples of the anticancer plant preparation include irinotecan hydrochloride, etoposide, vincristine sulfate, vinblastine sulfate, vindesine sulfate, vinorelbine tartrate, docetaxel hydrate, eribulin mesylate, and paclitaxel.

Examples of the hormone agent include estramustine phosphate sodium, flutamide, bicalutamide, goserelin acetate, leuprorelin acetate, tamoxifen citrate, toremifene citrate, anastrozole, letrozole, exemestane, mepithiostane, medroxyprogesterone acetate, Examples include epithiostanol, phosfestol, fadrozol hydrochloride hydrate, abiraterone, fulvestrant, and aminoglutethimide.

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

Examples of topoisomerase inhibitors include, for example, topotecan and sobuzoxane.

Examples of the kinase inhibitor include EGFR inhibitor erlotinib, gefitinib, afatinib, HER2 inhibitor lapatinib, BCR-ABL inhibitor imatinib, ALK inhibitor crizotinib, multikinase inhibitor regorafenib, And dasatinib, MEK inhibitors trametinib, selmethinib, and CDK4 / 6 inhibitors include parvocyclib and the like.

Examples of the anti-CD20 antibody include rituximab, ibritumomab, ibritumomab tiuxetan, and ocrelizumab.

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

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

Examples of anti-VEGF antibodies include bevacizumab.

Examples of proteasome inhibitors include bortezomib.

Examples of HDAC inhibitors include vorinostat and the like.

Examples of anti-CTLA-4 antibodies include ipilimumab and tremelimumab.

Examples of anti-PD-1 antibodies include nivolumab and pembrolizumab.

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

Examples of the immunomodulating agent include thalidomide, lenalidomide, and pomalidomide.

The mass ratio between the compound of the present invention and other drugs is not particularly limited.

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

In addition, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention include not only those that have been found so far, but also those that will be found in the future based on the above-mentioned mechanism. It is.

In order to use the compound of the present invention or the concomitant agent of the compound of the present invention and another drug for the above purpose, it is usually formulated as an appropriate pharmaceutical composition together with a pharmaceutically acceptable carrier, and then systemically or locally. Orally or parenterally.

The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually administered orally once to several times a day in the range of 1 mg to 1000 mg per adult. Or per parental dose, parenterally administered once or several times daily, in the range of 0.1 to 100 mg, or intravenously in the range of 1 to 24 hours per day Be administered.

Of course, as described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient or may be necessary beyond the range.

When administering the compound of the present invention or a combination of the compound of the present invention and another drug, a solid preparation for internal use for oral administration, a liquid preparation for internal use, and an injection, a preparation for external use, a sitting for parenteral administration. Used as an agent, eye drops, inhalant, etc.

固 形 Solid preparations for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. Tablets include sublingual tablets, buccal adhesive tablets, buccal quick disintegrating tablets and the like.

In such solid preparations for internal use, one or more active substances are left as they are, or excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxylpropylcellulose, polyvinylpyrrolidone, And mixed with disintegrating agents (such as calcium calcium glycolate), lubricants (such as magnesium stearate), stabilizers, solubilizing agents (such as glutamic acid, aspartic acid), etc. Used by formulating. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxylpropylcellulose, hydroxylpropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Also included are capsules of absorbable substances such as gelatin.

Oral solutions for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such a solution, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (such as purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

External dosage forms for parenteral administration include, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops, and Including nasal drops. These contain one or more active substances and are prepared by known methods or commonly used formulations.

Sprays, inhalants and sprays are buffers that provide isotonicity with stabilizers such as sodium bisulfite in addition to commonly used diluents, such as sodium chloride, sodium citrate or citric acid. An isotonic agent may be contained. The production method of the spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355.

Included as injections for parenteral administration are solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent. Examples of the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, this injection may contain a stabilizer, a solubilizing agent (such as glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative, and the like. . These are sterilized in the final process or manufactured by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.

Other compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration, which contain one or more active substances and are prescribed by conventional methods.

Unless defined otherwise, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto. The compound of the present invention is a compound described in WO2014 / 129431 and WO2016 / 027754, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, and a crystal thereof. is there.

In addition, the compounds used as Enlectinib and LOXO-101 in Pharmacological Experimental Examples 3 and 4 are the following compounds.

Examples of pharmacological experiments:
Pharmacological Experiment Example 1 Measurement of TrkA Kinase Inhibitory Activity Using Human TrkA-Expressing Cells Inhibitory activity against TrkA kinase in a cell line was determined by CHO-K1 cells (CellSensor ^™ TrkA-NFAT) expressing human TrkA and NFAT-bla. -Bla CHO-K1 cells (Invitrogen)).

The day before the assay, CellSenser ^™ TrkA-NFAT-bla CHO-K1 cells were assayed with 0.5 vol% dialyzed fetal calf serum (Invitrogen), 0.1 mM nonaminative amino acids (Invitrogen), 1 mM sodium pyruvate (Invitrogen). And Opti-MEM1 Reduced Serum Medium (Invitrogen) containing antibiotics (100 U / mL penicillin and 100 μg / mL streptomycin (Invitrogen)) and suspended in 2.4 × 10 ⁴ cells / 40 μL / well In a 96-well clear bottom plate (Corning, product number: 3882). In addition, 40 μL / well of assay medium alone was added to some wells (cell free). On the day of the assay, 10 mM of the compound of the present invention (DMSO solution) was dispensed into a 96-well plate (Costar, product number: 3363) and then serially diluted with DMSO to prepare a 3-fold common ratio dilution series. The dilution series was diluted 100-fold with an assay 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 added at 5 μL / well to the plate seeded with cells, and incubated in a CO ₂ incubator at 5% CO ₂ , 95% Air, 37 ° C. for 30 minutes. For the control and blank, 5 μL / well of assay medium containing 1 vol% DMSO was added instead of the compound solution of the present invention. Then, 5 μL / well of assay medium containing NGF (mouse 2.5 s, natural type, Invitrogen) was added to the plate (final concentration of NGF: 50 ng / ml), and 5% CO ₂ , 95% Air, 37 ° C. Incubated for 5 hours in a CO ₂ incubator. In the blank group, 5 μL / well of assay medium was added instead of NGF. After adding 10 μL / well of a reporter assay detection reagent to the plate, the plate was incubated at room temperature for 120 minutes in the dark. The reagent for reporter assay detection was prepared using LiveBLAzer ^™ -FRET B / G Loading Kit (Invitrogen). Using Analyst GT (Molecular Device Japan Co., Ltd.), excitation light of 405 nm was swept to each well, and fluorescence intensity of 460 nm and 530 nm was measured. The time-resolved fluorescence resonance energy transfer (TR-FRET) ratio of each well was calculated using the following formula.

A _460X: the invention compounds, control or blank 460nm fluorescence intensity A _460f: cell-free 460nm fluorescence intensity A _530`x`: present compound, control or blank 530nm fluorescence intensity A _530F: cell-free fluorescence intensity of 530nm of The TR-FRET inhibition rate (%) of the compound of the present invention was calculated using the following formula.

A _X : TR-FRET ratio at the time of addition of the compound of the present invention A _B : TR-FRET ratio of blank A _C : TR-FRET ratio of control The IC ₅₀ value of the compound of the present invention represents the inhibition rate at each concentration of the compound of the present invention. Calculated from the inhibition curve based.

As a result, the IC ₅₀ value of the compound of the present invention was 0.5 μM or less, and it was found that the compound of the present invention has TrkA inhibitory activity. For example, the IC ₅₀ values of some of the compounds of the present invention are as shown in the following table.

Pharmacological Experiment Example 2: Enzyme inhibitory activity test against other kinases other than Trk (selectivity experiment)
The test substance (the compound of the present invention) was dissolved in dimethyl sulfoxide to prepare a solution having a concentration 100 times the test concentration of 3 μM. The solution was further diluted 25-fold with an assay buffer (20 mM HEPES, 0.01 vol% Triton X-100, 2 mM DTT, pH 7.5) to obtain a test substance solution. A positive control substance solution was prepared in the same manner as the positive control substance.

Mix 5 μL of 4 × test substance solution adjusted with assay buffer, 5 μL of 4 × substrate / ATP / metal solution (Mg) and 10 μL of 2 × kinase solution in wells of a polypropylene 384 well plate, The reaction was allowed to proceed for 1 hour at room temperature. 60 μL Termination Buffer (QuickScout Screening Assist MSA; Carna Biosciences) was added to stop the reaction. The substrate peptide and phosphorylated peptide in the reaction solution were separated and quantified. The kinase reaction was evaluated by the product ratio (P / (P + S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P). As other kinases, for example, kinase selectivity experiments were carried out using b-Raf and KDR kinases. The following table shows the substrate, substrate concentration, ATP concentration, and positive control substance used in each kinase enzyme inhibitory activity test.

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

From these results, it was found that the compounds of the present invention showed strong inhibition against TrkA with weak inhibition against other kinases other than TrkA, such as b-Raf and KDR kinases. In other words, the compound of the present invention has a strong IC ₅₀ against TrkA inhibition of 0.5 μM or less based on the results of Pharmacological Example 1, while 3 μM for the above kinases other than TrkA based on the results of Pharmacological Example 2. Even a compound at a concentration of 1 to 0 inhibits only about 0% to about 58%. Therefore, it was found that the compound of the present invention has high selectivity for TrkA inhibition and excellent kinase selectivity.

Pharmacological experiment example 3: Growth inhibition test against Trk inhibitor resistant cell line
(1) The use of ectrinib, which is a Trk inhibitor, using KM12 (ATCC, product number: RBC0805), which is an established human colon cancer cell line of ectectinib and LOXO-101 resistant KM12 cell lines (KM12-ER and KM12-LR) A strain resistant to LOXO-101 was established. Prepared as DMEM (Life technologies), stock number: 1165, containing 10 vol% inactivated fetal bovine serum (FBS) and 1 vol% Penicillin-Streptomycin liquid (Life technologies). Thawed KM12 was suspended in the medium and centrifuged at 180 g for 3 minutes at room temperature. After removing the supernatant by aspiration, the cell sediment was resuspended in a medium to make a total volume of 50 mL, seeded in a 225 cm ² flask (Asahi Glass), and allowed to stand at 37 ° C., 5% CO ₂ , and 95% Air. . Thereafter, KM12 grown to a confluent state was suspended using 0.25% Trypsin-EDTA (Invitrogen), collected in a centrifuge tube, and then centrifuged at 180 g at room temperature for 3 minutes. The cell sediment was suspended in DMEM medium, a part of the cell suspension was collected, and the number of viable cells was counted. A part of the cell suspension was seeded in a 225 cm ² flask, and the total amount of the medium was 50 mL. 50 μL of Enlectinib or LOXO-101 dissolved in DMSO was added to the DMEM medium and allowed to stand under conditions of 37 ° C., 5% CO ₂ , and 95% Air. Thereafter, the culture in the presence of the drug was continued while being subcultured. The concentration of Enlectinib started from 1 nM and increased gradually to 10 nM. On the other hand, LOXO-101 was continuously subcultured at 30 nM. Cells that had grown stably in the presence of 10 nM Enectinib or 30 nM LOXO-101 were cryopreserved and designated KM12-ER and KM12-LR, respectively.

(2) Growth inhibition experiment on KM12, KM12-ER and KM12-LR The antitumor effect of the compound of the present invention was evaluated using KM12, KM12-ER and KM12-LR. Cells were subcultured in DMEM medium until subjected to experiments. The day before the compound treatment, the cells were suspended using 0.25% Trypsin-EDTA, and the cells were collected from the culture flask into a centrifuge tube. The cells were centrifuged at 180 g for 3 minutes at room temperature, and the cell pellet was suspended in 10 mL of DMEM medium. A part of the cell suspension was collected and the number of cells was counted. Then, the cells were suspended in DMEM medium at a cell density of 3 × 10 ⁴ cells / mL to prepare the cell suspension. The cell suspension was seeded at 100 μL / well on a 96-well tissue culture plate (Asahi Glass) and allowed to stand for 24 hours at 37 ° C., 5% CO ₂ and 95% Air. On the day of compound treatment, 10 mM of the compound of the present invention, Protectinib and LOXO-101 (DMSO solution) were serially diluted with DMSO to prepare a 3-fold common ratio dilution series. The dilution series and DMSO were diluted 100-fold with a medium to prepare a 10-fold concentration compound solution and a medium solution. Was added compound solution or vehicle solution prepared above into each well of a 96-well tissue culture plate cells were 24 h static culture by 11 [mu] L / well, 37 ℃, 5% CO 2 , and at 95% Air conditions The culture was stationary for 72 hours. After completion of stationary culture, the luminescence signal (relative luminescence unit, RLU) of each well was measured with a microplate reader using CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7571). The average value of RLU for 3 wells of the vehicle group (group treated with a medium solution having a compound concentration of zero (0)) was calculated, and the growth inhibition rate in each well was calculated using the following formula.

Based on the growth inhibition rate at each concentration, IC ₅₀ values of the compound of the present invention and Enectinib were inversely estimated by performing nonlinear regression analysis using a Sigmaid Emax model.

As a result, it was found that the compound of the present invention inhibits the growth of KM12-ER and KM12-LR at a treatment concentration lower than that of Enlectinib and LOXO-101. The compound of the present invention, _{IC 50} values of Entrectinib and LOXO-101 was as shown in the table below.

Pharmacological Experiment Example 4: Growth inhibition test for TrkA G595R or G667C mutation positive cell line
(1) Establishment of wild-type TPM3-TrkA and G595R or G667C mutant TPM3-TrkA-expressing Ba / F3 cell line Using wild-type TPM3-TrkA and G595R or G667C mutant type using Ba / F3, a mouse pro-B cell line Ba / F3 cell lines (Ba / F3 TrkA wild type, Ba / F3 TrkA G595R and Ba / F3 TrkA G667C) expressing TPM3-TrkA were established. 10 vol% inactivated fetal bovine serum (FBS), 1 vol% Penicillin-Streptomycin liquid (Life technologies), and 10 ng / mL IL-3 (BD Bioscience, 40 product number: 40, 35) RPMI (Life technologies, product number: 11875) was prepared as a culture medium. The thawed Ba / F3 was suspended in the culture medium. Centrifugation was performed at 400 g for 3 minutes at room temperature, and after removing the supernatant, the cell pellet was resuspended in a culture medium. The whole amount was seeded in a 150 mm untreated dish (Asahi Glass) and allowed to stand under conditions of 37 ° C., 5% CO ₂ and 95% Air. Thereafter, Ba / F3 was subcultured in a culture medium until the gene was introduced. TPM3-NTRK1 fusion gene encoding wild type TPM3-TrkA and G595R or G667C mutant TPM3-TrkA protein was artificially synthesized and subcloned into pcDNA3.1 vector. According to the package insert of Amaxa Cell line Nucleofect Kit V (Lonza, product number: VCA-1003), these three kinds of constructs were respectively introduced into Ba / F3 using Nucleofector device (Lonza). 10 vol% FBS, 1 vol% Penicillin-Streptomycin liquid (Life technologies), final concentration of 10 ng / mL IL-3 (BD Bioscience, product number: 354040) and final concentration of 500 μg / mL G418 (Wako product: RPMI containing 077-04973) was prepared as a selection medium, and Ba / F3 was statically cultured in the selection medium for 1 week after 2 days from gene introduction. Thereafter, the passage was repeated in a selective medium from which IL-3 was removed stepwise. Cells subcultured several times in a selection medium (IL-3-free selection medium) from which IL-3 was completely removed were stored in liquid nitrogen.

(2) Growth inhibition experiment on Ba / F3 TrkA wild type, Ba / F3 TrkA G595R and Ba / F3 TrkA G667C Were evaluated for their anti-tumor effects. Ba / F3 TrkA wild type, Ba / F3 TrkA G595R and Ba / F3 TrkA G667C were subcultured in IL-3-free selection medium until subjected to experiments. On the day of the growth inhibition experiment, Ba / F3 TrkA wild type, Ba / F3 TrkA G595R and Ba / F3 TrkA G667C were collected from the dish in a centrifuge tube and centrifuged at 400 g for 3 minutes at room temperature. The cell sediment was suspended in a medium, the number of cells was counted, and a cell suspension was prepared at a cell density of 3.3 × 10 ⁴ cells / mL. 10 mM of the compound of the present invention and Enectinib (DMSO solution) were serially diluted with DMSO to prepare a 3-fold common ratio dilution series. The dilution series and DMSO were diluted 100-fold with a medium to prepare a 10-fold concentration compound solution and a medium solution. The compound solution or medium solution prepared above was added at 10 μL / well to each well of the 96-well tissue culture plate. Next, the cell suspension was seeded at 90 μL / well, and statically cultured at 37 ° C., 5% CO ₂ , and 95% Air for 72 hours. For the blank, a medium containing no cells was added at 100 μL / well. After completion of static culture, the absorbance at 450 nm (A ₄₅₀ ) of each well and the absorbance at 650 nm (A ₆₅₀ ) as a control wavelength were measured with a microplate reader using Cell Counting Kit-8 (DOJINDO). A value obtained by dividing A ₆₅₀ from A ₄₅₀ (A _450-650 ) was calculated. After the average value of the _{A 450-650} blank from _{A 450-650} of each well by dividing _(A Δblank), calculates the average value of A _Derutablank in vehicle group, calculated growth inhibition rate in each well by the following equation did.

Based on the growth inhibition rate at each concentration, IC ₅₀ values of the compound of the present invention and Enectinib were inversely estimated by performing nonlinear regression analysis using a Sigmaid Emax model.

As a result, the compound of the present invention was found to inhibit the growth of Ba / F3 TrkA G595R and Ba / F3 TrkA G667C at a treatment concentration lower than that of Enectinib. The IC ₅₀ values of some of the compounds of the present invention and Enlectinib were as shown in the table below.

Pharmacological experiment example 5: Growth inhibition test against TrkC G623R mutation positive cell line
(1) Establishment of wild-type ETV6-TrkC and G623R mutant ETV6-TrkC expressing Ba / F3 cell line Using wild-type ETV6-TrkC and G623R mutant ETV6-TrkC using Ba / F3, a mouse pro-B cell line An expressing Ba / F3 cell line (Ba / F3 TrkC wild type, Ba / F3 TrkC G623R) was established. 10 vol% inactivated fetal bovine serum (FBS), 1 vol% Penicillin-Streptomycin liquid (Life technologies), and 10 ng / mL IL-3 (BD Bioscience, 40 product number: 40, 35) RPMI (Life technologies, product number: 11875) was prepared as a culture medium. The thawed Ba / F3 was suspended in the culture medium. Centrifugation was performed at 400 g for 3 minutes at room temperature, and after removing the supernatant, the cell pellet was resuspended in a culture medium. The whole amount was seeded in a 150 mm untreated dish (Asahi Glass) and allowed to stand under conditions of 37 ° C., 5% CO ₂ and 95% Air. Thereafter, Ba / F3 was subcultured in a culture medium until the gene was introduced. The ETV6-TrkC fusion gene encoding wild type ETV6-NTRK3 and G623R mutant ETV6-TrkC protein was artificially synthesized and subcloned into pcDNA3.1 vector. According to the package insert of Amaxa Cell line Nucleofect Kit V (Lonza, product number: VCA-1003), these three kinds of constructs were respectively introduced into Ba / F3 using Nucleofector device (Lonza). 10 vol% FBS, 1 vol% Penicillin-Streptomycin liquid (Life technologies), final concentration of 10 ng / mL IL-3 (BD Bioscience, product number: 354040) and final concentration of 500 μg / mL G418 (Wako product: RPMI containing 077-04973) was prepared as a selection medium, and Ba / F3 was statically cultured in the selection medium for 1 week after 2 days from gene introduction. Thereafter, the passage was repeated in a selective medium from which IL-3 was removed stepwise. Cells subcultured several times in a selection medium (IL-3-free selection medium) from which IL-3 was completely removed were stored in liquid nitrogen.

(2) Growth Inhibition Experiment on Ba / F3 TrkC Wild Type and Ba / F3 TrkC G623R The antitumor effect of the compound of the present invention was evaluated using Ba / F3 TrkC wild type and Ba / F3 TrkC G623R. Ba / F3 TrkC wild type and Ba / F3 TrkC G623R were subcultured in IL-3-free selection medium until the experiment. On the day of the growth inhibition experiment, Ba / F3 TrkC wild type and Ba / F3 TrkC G623R were collected from the dish in a centrifuge tube and centrifuged at 400 g for 3 minutes at room temperature. The cell sediment was suspended in a medium, the number of cells was counted, and a cell suspension was prepared at a cell density of 3.3 × 10 ⁴ cells / mL. 10 mM of the present compound, Enectinib (DMSO solution) was serially diluted with DMSO to prepare a 3-fold common ratio dilution series. The dilution series and DMSO were diluted 100-fold with a medium to prepare a 10-fold concentration compound solution and a medium solution. The compound solution or medium solution prepared above was added at 10 μL / well to each well of the 96-well tissue culture plate. Next, the cell suspension was seeded at 90 μL / well, and statically cultured at 37 ° C., 5% CO ₂ , and 95% Air for 72 hours. After completion of stationary culture, the luminescence signal (relative luminescence unit, RLU) of each well was measured with a microplate reader using CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7571). The average value of RLU for 3 wells of the vehicle group (group treated with a medium solution having a compound concentration of zero (0)) was calculated, and the growth inhibition rate in each well was calculated using the following formula.

Based on the growth inhibition rate at each concentration, IC ₅₀ values of the compound of the present invention and Enectinib were inversely estimated by performing nonlinear regression analysis using a Sigmaid Emax model.

As a result, it was found that the compound of the present invention inhibits the growth of Ba / F3 TrkC G623R at a treatment concentration lower than that of Enlectinib. The IC ₅₀ values of some of the compounds of the present invention and Enlectinib were as shown in the table below.

[Formulation example]
Formulation Example 1
The following components were mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 10 mg of active ingredient.
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 (lubricant) …… 10g
・ Microcrystalline cellulose ... 870g

Formulation Example 2
The following components are mixed by a conventional method, filtered through a dust filter, filled in 5 ml aliquots, and heat sterilized in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient in one ampule.
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

The compound of general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is useful as an active ingredient of a Trk inhibitor-resistant cancer therapeutic agent.

Claims (19)

1. Formula (I)
   

   

   (Where
   Ring Cy ₁ represents a C3-10 monocyclic carbocycle or bicyclic carbocycle, or a 4-10 membered monocyclic heterocycle or bicyclic heterocycle,
   Ring Cy ₂ represents a 4- to 10-membered monocyclic heterocycle or bicyclic heterocycle,
   R ₁ is
   (1) halogen,
   (2) a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group optionally substituted with a substituent selected from the group consisting of (i) halogen and (ii) hydroxyl group ,
   (3) a C5-6 monocyclic carbocycle optionally substituted by 1 to 2 R ₅ ,
   (4) a 5- to 6-membered monocyclic heterocycle optionally substituted by 1 to 2 R ₅ ,
   (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) represents a cyano group, or (13) a nitro group,
   R ₅ is
   (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) a cyano group,
   (10) represents a nitro group, or a C1-3 alkyl group optionally substituted with a substituent selected from the group consisting of (11) (i) halogen, (ii) hydroxyl group, and (iii) oxo group ,
   When R ₅ is two, R ₅ may be independently the same or different,
   Further, two R ₅ are each independently a C1-3 alkyl group or a hydroxyl group, and R ₅ is adjacent to a C5-6 monocyclic carbocycle or 5- to 6-membered monocyclic heterocycle. The groups may form a ring together,
   R ₆ -R ₂₇ each independently represents (1) a hydrogen atom, or (2) (i) a C1-6 alkyl group optionally substituted with a halogen or (ii) a hydroxyl group,
   When R ₁₈ and R ₁₉ are each independently a C1-6 alkyl group, these groups may be taken together to form a ring;
   R ₂ is
   (1) halogen,
   (2) (i) a C1-6 alkyl group optionally substituted with a halogen or (ii) a hydroxyl group,
   (3) (i) a C3-6 cycloalkyl group optionally substituted with a halogen or (ii) a hydroxyl group,
   (4) a C1-6 alkoxy group optionally substituted with halogen,
   (5) -NR ₂₈ R ₂₉ ,
   (6) represents a 3- to 7-membered monocyclic heterocycle, or (7) —O— (a 3- to 7-membered monocyclic heterocycle),
   R ₂₈ and R ₂₉ each independently represent (1) a hydrogen atom, or (2) (i) a C1-6 alkyl group optionally substituted with a halogen or (ii) a hydroxyl group;
   A ₁ and A ₂ each independently represent ═CR ₃ — or ═N—
   _{A 3, A 4, A 5} , and _{A 6} are each independently, = CR ₄ - or = N- and represent,
   R ₃ and R ₄ each independently represents a hydrogen atom or 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,
   r represents an integer of 0-2.
   However, when p, q, and r each represent an integer of 2 or more, R ₁ , R ₂ , and R ₃ may be independently the same or different. And a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof as an active ingredient.
2. The general formula (I) is represented by the general formula (IA)
   

   

   Wherein Cy _1-A represents a C5-6 monocyclic aromatic carbocycle, and Cy _2-A represents a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle Wherein t represents an integer of 0 to 4, and the other symbols have the same meanings as those of claim 1.).
3. General formula (I) is represented by general formula (IB)
   

   

   Wherein Cy _1-B represents a C5-6 monocyclic aromatic carbocycle, and Cy _2-B represents a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle Wherein t represents an integer of 0 to 4, and the other symbols have the same meanings as those of claim 1.).
4. A compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,
   (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) 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-triazol-1-yl) -5- (trifluoromethyl) phenyl-3- (6- (4- (2-amino-5-chloropyridine) -3-yl) phenoxy) 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-pyrazole-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-fluoro) Pyridin-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-pyrazol-1-yl) -4- (trifluoromethyl) phenyl) -3- (2- (4- (2-amino-5-chloropyridin-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- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- {5- (trifluoromethyl) -2- [ 3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl} urea,
   (15) 1- {2- [4- (2-amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
   (16) 1- {2- [4- (2-amino-5-fluoro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
   (17) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (4-chloro-1H-pyrazol-1-yl) -5- (trifluoromethyl) phenyl] urea,
   (18) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- {5-chloro-2- [3- (trifluoromethyl)- 1H-pyrazol-1-yl] phenyl} urea,
   (19) 1- {2- [4- (2-amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2,4-bis (trifluoromethyl) phenyl] urea,
   (20) 1- (2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- [2- (4-chloro-1H-pyrazole- 1-yl) -5- (trifluoromethyl) phenyl] urea,
   (21) 1- {2- [4- (2-Amino-5-fluoro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (methylsulfonyl) -5- (trifluoromethyl) phenyl ] Urea,
   (22) 1- (2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) -3- [2- (methylsulfonyl) -5- (tri Fluoromethyl) phenyl] urea,
   (23) 1- {2- [4- (2-Amino-5-chloro-3-pyridinyl) phenoxy] -5-pyrimidinyl} -3- [2- (methylsulfonyl) -5- (trifluoromethyl) phenyl ] Urea,
   (24) 2-{[(2- {4- [2-Amino-5- (trifluoromethyl) -3-pyridinyl] phenoxy} -5-pyrimidinyl) carbamoyl] 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-pyridinyl) -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-pyridinyl) -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-biphenylyl] urea,
   (33) 1- (2- {4- [5- (Dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5-pyrimidinyl) -3- [4- (trifluoromethyl) -2-biphenylyl] urea,
   (34) 1- (2- {4- [5- (Dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5-pyrimidinyl) -3- [3′-methyl-4- (Trifluoromethyl) -2-biphenylyl] urea or (35) 1- (2- {4- [5- (dimethylamino) pyrazolo [1,5-a] pyrimidin-3-yl] phenoxy} -5 -Pyrimidinyl) -3- [2'-methyl-4- (trifluoromethyl) -2-biphenylyl] urea, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, Item 3. The agent according to Item 1.
5. The agent according to any one of claims 1 to 4, wherein the Trk inhibitor-resistant cancer is a NTRK positive cancer and is a Trk inhibitor-resistant cancer.
6. The agent according to any one of claims 1 to 5, wherein the Trk inhibitor-resistant cancer is a cancer that has acquired Trk inhibitor resistance by administration of the Trk inhibitor.
7. The Trk inhibitor-resistant cancer is a cancer that has acquired resistance to a Trk inhibitor due to a mutation in the NTRK gene caused by administration of the Trk inhibitor. Agent.
8. The agent according to claim 7, wherein the mutation in the NTRK gene is a mutation in the NTRK fusion gene.
9. The agent according to claim 8, wherein the mutation in the NTRK fusion gene is a mutation in the NTRK1 fusion gene.
10. The agent according to claim 9, wherein the mutation in the NTRK1 fusion gene is a G595R and / or G667C mutation.
11. The agent according to claim 8, wherein the mutation in the NTRK fusion gene is a mutation in the NTRK2 fusion gene.
12. The agent according to claim 11, wherein the mutation in the NTRK2 fusion gene is a G639R mutation.
13. The agent according to claim 8, wherein the mutation in the NTRK fusion gene is a mutation in the NTRK3 fusion gene.
14. The agent according to claim 13, wherein the mutation in the NTRK3 fusion gene is a G623R mutation.
15. The Trk inhibitor is one or more drugs selected from the group consisting of Enlectinib, LOXO-101, AZD-7451, TSR-011, Crizotinib, ASP-7269, and DS-6051b. The agent according to one item.
16. The cancer is lung cancer, colon cancer, intrahepatic cholangiocarcinoma, thyroid cancer, skin cancer, breast cancer, head and neck cancer, renal cancer, sarcoma, brain tumor, salivary gland tumor or blood cancer. The agent described.
17. Use of a compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof for the treatment of a Trk inhibitor-resistant cancer.
18. Use of a compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof for the manufacture of a therapeutic agent for cancer resistant to Trk inhibitors.
19. A Trk inhibitor-resistant cancer treatment method comprising administering an effective amount of a compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof to a subject .