WO2017155018A1 - AGENT THÉRAPEUTIQUE CIBLANT LES CANCERS RÉSISTANTS AUX INHIBITEURS DES Trk - Google Patents

AGENT THÉRAPEUTIQUE CIBLANT LES CANCERS RÉSISTANTS AUX INHIBITEURS DES Trk Download PDF

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WO2017155018A1
WO2017155018A1 PCT/JP2017/009381 JP2017009381W WO2017155018A1 WO 2017155018 A1 WO2017155018 A1 WO 2017155018A1 JP 2017009381 W JP2017009381 W JP 2017009381W WO 2017155018 A1 WO2017155018 A1 WO 2017155018A1
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Prior art keywords
trifluoromethyl
phenoxy
urea
phenyl
amino
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PCT/JP2017/009381
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English (en)
Japanese (ja)
Inventor
龍平 小崎
光希 塚本
啓 江頭
竹内　淳
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小野薬品工業株式会社
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Priority to JP2018504574A priority Critical patent/JPWO2017155018A1/ja
Publication of WO2017155018A1 publication Critical patent/WO2017155018A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to a Trk inhibitor-resistant cancer therapeutic agent. Specifically, the general formula (I)
  • the present invention relates to a cancer therapeutic agent contained as an active ingredient.
  • Trk 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).
  • 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.
  • 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.
  • Non-Patent Documents 2 to 8 The possibility of being involved in cancer cell survival, proliferation, migration, and metastasis has been reported (Non-Patent Documents 2 to 8).
  • 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) ).
  • NTRK1 fusion gene MPRIP, CD74, RABGAP1L, TPM3, TPR, TFG, PPL, CHTOP, ARHGEF2, NFASC, BCAN, LMNA and TP53 have been reported.
  • 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.
  • the Trk fusion protein encoded by these fusion genes is a constitutively active kinase, and promotes canceration of cells by abnormally activating intracellular signals.
  • Non-Patent Documents 12 to 14 a drug that inhibits Trk is expected to become a new type of anticancer drug that has never existed before.
  • 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).
  • 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.
  • 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
  • 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-membere
  • Patent Document 2 includes general formula (Ib)
  • 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
  • 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.
  • 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)
  • 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)
  • Patent Document 5 describes general formula (Ie)
  • 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.
  • 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.
  • the compound of the present invention can be a therapeutic agent for such cancer.
  • An object of the present invention is to provide an active ingredient of a Trk inhibitor-resistant cancer therapeutic agent.
  • 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
  • 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,
  • R 1 , R 2 , and R 3 may be independently the same or different.
  • 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 is general formula (IA)
  • Cy 1-B represents a C5-6 monocyclic aromatic carbocycle
  • Cy 2-B represents a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle
  • t represents an integer of 0 to 4, and the other symbols have the same meanings as those in claim 1.
  • Trk inhibitor-resistant cancer is a NTRK positive cancer and is a Trk inhibitor-resistant cancer.
  • the NTRK positive cancer is an NTRK fusion gene positive cancer.
  • the Trk inhibitor-resistant cancer is a cancer that has acquired resistance to the Trk inhibitor by administration of the Trk inhibitor.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • NRRK1 fusion gene examples 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.
  • NTRK2 fusion gene examples include QKI-NTRK2, NACC2-NTRK2, VCL-NTRK2, AGBL4-NTRK2, TRIM24-NTRK2, PAN3-NTRK2, AFAP1-NTRK2 and SQSTM1-NTRK2.
  • NRRK3 fusion gene examples include ETV6-NTRK3, BTB1-NTRK3, LYN-NTRK3 and RBPMS-NTRK3.
  • 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 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.
  • 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 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.
  • 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.
  • 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”.
  • 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)).
  • 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”.
  • 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.
  • “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, isoind
  • halogen is fluorine, chlorine, bromine, and iodine.
  • 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.
  • 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.
  • 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.
  • the “C5-6 monocyclic carbocycle” includes, for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene ring.
  • the “5- to 6-membered monocyclic heterocycle” means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine, pyridazine, furan, pyran.
  • C1-3 alkyl group means methyl, ethyl, n-propyl, and isopropyl groups.
  • the “C 3-6 cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl group.
  • 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.
  • “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, imidazoline,
  • “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, naphthy
  • 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.
  • 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”
  • R 5 is a C 5-6 monocyclic carbocycle or 5- to 6-membered monocyclic heterocycle
  • ring Cy 3 represents a monocyclic heterocycle monocyclic carbocyclic or 5-6 membered C5 ⁇ 6, arrow denotes a bond to the ring Cy 1.
  • 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.
  • the ring Cy 1 is preferably a C5-6 monocyclic carbocycle or a 5-6 membered monocyclic heterocycle.
  • 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 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 is more preferably cyclopentane, cyclohexane, benzene, pyran, thiopyran, pyrrolidine, piperidine, piperazine, imidazoline, imidazolidine, morpholine, thiomorph
  • the ring Cy 1 is preferably benzene and a 5- to 6-membered monocyclic aromatic heterocycle.
  • the ring Cy 1 is more preferably a benzene, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, and isothiazole ring.
  • the ring Cy 1 is more preferably a benzene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, and pyridazine ring.
  • the ring Cy 1 is more preferably a benzene, pyrazole, and pyridine ring.
  • the ring Cy 1 is most preferably a benzene and pyridine ring.
  • the ring Cy 2 is preferably a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle.
  • 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.
  • 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,
  • anzoxazole benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, imidazopyridine, and triazolopyridine rings is there.
  • 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.
  • ring Cy 2 is still more preferably a pyridine, pyrimidine, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, pyrrolopyridine, imidazopyrazine, and pyrazolopyridine ring.
  • the ring Cy 2 is most preferably a pyridine and pyrazolopyrimidine ring.
  • 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.
  • R 1 is more preferably (1) halogen, (2) methyl group, (3) trifluoromethyl group, (4) difluoromethyl group, (5) monofluoromethyl group, (6) trichloromethyl.
  • 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.
  • 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.
  • R 1 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.
  • 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.
  • 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.
  • R 5 is more preferably a methyl group, a trifluoromethyl group, a difluoromethyl group, an acetyl group, or a hydroxyethyl group.
  • R 5 is most preferably a methyl group, a trifluoromethyl group, or a difluoromethyl group.
  • 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).
  • 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.
  • 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.
  • R 2 is more preferably a halogen, a methyl group, an amino group, an azetidine ring, or a pyrrolidine ring.
  • R 2 is most preferably fluorine, chlorine, a methyl group, an amino group, and an azetidine ring.
  • R 3 is preferably hydrogen and fluorine, and most preferably hydrogen.
  • R 4 is preferably hydrogen and fluorine, and most preferably hydrogen.
  • R 6 is preferably a C1-3 alkyl group which may be substituted with halogen.
  • R 6 is more preferably a methyl group, an ethyl group, or an n-propyl group.
  • 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.
  • 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.
  • R 7 and R 8 are more preferably each independently a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group.
  • R 9 is preferably a hydrogen atom, a methyl group, or an ethyl group.
  • each of R 10 to R 16 is preferably independently a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group.
  • R 17 is preferably a C1-3 alkyl group which may be substituted with halogen.
  • R 17 is more preferably a methyl group, an ethyl group, or an n-propyl group.
  • R 18 and R 19 are preferably each independently a C1-3 alkyl group optionally substituted with a hydrogen atom or a hydroxyl group.
  • 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.
  • R 18 and R 19 are more preferably each independently a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group.
  • R 20 is preferably a hydrogen atom, a methyl group, or an ethyl group.
  • each of R 21 to R 29 is preferably independently a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group.
  • m1 is preferably an integer of 2.
  • m2 is preferably an integer of 2.
  • p is preferably an integer of 0 to 3.
  • q is preferably an integer of 0 to 3.
  • r is preferably an integer of 0 to 1.
  • 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 .
  • q ⁇ a is preferably an integer of 0 to 1.
  • q ⁇ b is preferably an integer of 0 to 1.
  • 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.
  • 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)
  • Cy 1-A represents a C5-6 monocyclic aromatic carbocycle
  • Cy 2-A represents a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle
  • 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)
  • Cy 1-B represents a C5-6 monocyclic aromatic carbocycle
  • 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].)
  • 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)
  • 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.
  • 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.
  • other symbols have the same meanings as those described in [1] above), salts thereof, N-oxides thereof, solvates thereof, or prodrugs thereof.
  • 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)
  • 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.
  • 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).
  • 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)
  • ring Cy 2-j and ring Cy 2-k represent a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle
  • ring Cy 1-j and ring Cy 1- k represents a benzene ring or a 5- to 6-membered monocyclic aromatic heterocyclic ring
  • the other symbols have the same meanings as described in the above [1])
  • 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)
  • 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.
  • 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)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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.
  • 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.
  • 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).
  • the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably used.
  • the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably used.
  • 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.
  • isomers R, S, ⁇ , ⁇ , 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.
  • the salt is preferably a pharmaceutically acceptable salt.
  • the salt is preferably water-soluble.
  • salts examples include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, and amine salts.
  • 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.
  • alkali metal salt examples include potassium and sodium.
  • alkaline earth metal salts examples include calcium and magnesium.
  • ammonium salts examples include tetramethylammonium.
  • amine salts include triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, and N-methyl-D- Examples include glucamine.
  • 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.
  • 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.
  • Cy 1 or Cy 2 is a nitrogen-containing heterocyclic ring, the nitrogen atom is oxidized.
  • 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).
  • 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.
  • 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)
  • the prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate.
  • 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).
  • 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.).
  • 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.
  • those described as pharmaceutically acceptable salts of general formula (I) are used.
  • 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.
  • the compound of the present invention 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.
  • 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
  • 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.
  • simultaneous administration and administration by time difference are included.
  • 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.
  • 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.
  • alkylating agents 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
  • alkylating agent examples 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 .
  • anticancer antibiotics examples include mitomycin C, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin, chromomycin A3, bleomycin, pepromycin sulfate, and terarubicin.
  • anticancer plant preparation examples include irinotecan hydrochloride, etoposide, vincristine sulfate, vinblastine sulfate, vindesine sulfate, vinorelbine tartrate, docetaxel hydrate, eribulin mesylate, and paclitaxel.
  • hormone agent examples 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.
  • platinum compound examples include carboplatin, cisplatin, nedaplatin, and oxaliplatin.
  • topoisomerase inhibitors examples 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.
  • anti-CD20 antibody examples include rituximab, ibritumomab, ibritumomab tiuxetan, and ocrelizumab.
  • anti-HER2 antibody examples include trastuzumab, trastuzumab emtansine, and pertuzumab.
  • anti-EGFR antibody examples include cetuximab and panitumumab.
  • anti-VEGF antibodies examples include bevacizumab.
  • proteasome inhibitors examples include bortezomib.
  • HDAC inhibitors examples include vorinostat and the like.
  • anti-CTLA-4 antibodies examples include ipilimumab and tremelimumab.
  • anti-PD-1 antibodies examples include nivolumab and pembrolizumab.
  • anti-PD-L1 antibody examples include atezolizumab and avelumab.
  • immunomodulating agent examples 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • stabilizers such as sodium bisulfite
  • 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.
  • 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.
  • the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof.
  • 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. .
  • 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.
  • 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.
  • 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.
  • the reagent for reporter assay detection was prepared using LiveBLAzer TM -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.
  • the IC 50 value of the compound of the present invention was 0.5 ⁇ M or less, and it was found that the compound of the present invention has TrkA inhibitory activity.
  • 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 ⁇ M.
  • 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.
  • 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
  • the inhibition rate was calculated from the average signal of each test substance test well.
  • 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.
  • the compound of the present invention has a strong IC 50 against TrkA inhibition of 0.5 ⁇ M or less based on the results of Pharmacological Example 1, while 3 ⁇ M 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.
  • FBS inactivated fetal bovine serum
  • Penicillin-Streptomycin liquid Life technologies
  • 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.
  • Trypsin-EDTA Invitrogen
  • 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 ⁇ L 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.
  • 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.
  • 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 ⁇ L / 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 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 ⁇ L / well to each well of the 96-well tissue culture plate.
  • the cell suspension was seeded at 90 ⁇ L / well, and statically cultured at 37 ° C., 5% CO 2 , and 95% Air for 72 hours.
  • a medium containing no cells was added at 100 ⁇ L / well.
  • 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).
  • DOJINDO Cell Counting Kit-8
  • 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.
  • 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.
  • 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 ⁇ L / well to each well of the 96-well tissue culture plate.
  • the cell suspension was seeded at 90 ⁇ L / well, and statically cultured at 37 ° C., 5% CO 2 , and 95% Air for 72 hours.
  • 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.
  • 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.
  • 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 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.
  • 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.

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Abstract

La présente invention concerne un agent thérapeutique pour les cancers résistants aux inhibiteurs des Trk. Un composé représenté par la formule générale (I) (où chacun des symboles a la même signification que celle décrite dans la description), un sel, N-oxyde ou solvate du composé, ou un promédicament du composé ou du sel, N-oxyde ou solvate, est utilisable comme principe actif ou agent thérapeutique contre les cancers résistants aux inhibiteurs des Trk.
PCT/JP2017/009381 2016-03-11 2017-03-09 AGENT THÉRAPEUTIQUE CIBLANT LES CANCERS RÉSISTANTS AUX INHIBITEURS DES Trk WO2017155018A1 (fr)

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US10590139B2 (en) 2008-09-22 2020-03-17 Array Biopharma Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US11267818B2 (en) 2008-10-22 2022-03-08 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US10774085B2 (en) 2008-10-22 2020-09-15 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
US10758542B2 (en) 2009-07-09 2020-09-01 Array Biopharma Inc. Substituted pyrazolo[l,5-a]pyrimidine compounds as Trk kinase inhibitors
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US10813936B2 (en) 2014-11-16 2020-10-27 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-YL)-pyrazolo[1,5-A]pyrimidin-3-YL)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10799505B2 (en) 2014-11-16 2020-10-13 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10655186B2 (en) 2015-10-26 2020-05-19 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10724102B2 (en) 2015-10-26 2020-07-28 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10907215B2 (en) 2015-10-26 2021-02-02 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US11191766B2 (en) 2016-04-04 2021-12-07 Loxo Oncology, Inc. Methods of treating pediatric cancers
US11484535B2 (en) 2016-04-04 2022-11-01 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10668072B2 (en) 2016-04-04 2020-06-02 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10588908B2 (en) 2016-04-04 2020-03-17 Loxo Oncology, Inc. Methods of treating pediatric cancers
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
WO2018081417A2 (fr) 2016-10-26 2018-05-03 Qian Zhao Procédé de préparation de pyrazolo[1,5-a]pyrimidines et de sels de celles-ci
US11091486B2 (en) 2016-10-26 2021-08-17 Array Biopharma, Inc Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
US10688100B2 (en) 2017-03-16 2020-06-23 Array Biopharma Inc. Macrocylic compounds as ROS1 kinase inhibitors
CN110305138B (zh) * 2018-03-27 2021-04-23 海创药业股份有限公司 一种治疗癌症的化合物及其用途
CN110305138A (zh) * 2018-03-27 2019-10-08 成都海创药业有限公司 一种治疗癌症的化合物及其用途

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