WO2013100672A1 - Dérivé d'indazole 3,6-disubstitué ayant une activité d'inhibition de protéine kinase - Google Patents

Dérivé d'indazole 3,6-disubstitué ayant une activité d'inhibition de protéine kinase Download PDF

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WO2013100672A1
WO2013100672A1 PCT/KR2012/011655 KR2012011655W WO2013100672A1 WO 2013100672 A1 WO2013100672 A1 WO 2013100672A1 KR 2012011655 W KR2012011655 W KR 2012011655W WO 2013100672 A1 WO2013100672 A1 WO 2013100672A1
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methyl
carboxamide
indazole
phenyl
fluoro
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Korean (ko)
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정경윤
최진석
김민경
박영민
심태보
노은주
진세호
이용실
김선미
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제이더블유중외제약㈜
한국과학기술연구원
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Publication of WO2013100672A1 publication Critical patent/WO2013100672A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel 3, 6-disubstituted indazole derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition effective for inhibiting protein kinase containing the same as an active ingredient.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups located at tyrosine, serine and threonine residues of proteins and play an important role in the growth factor signal transduction that causes cell growth, differentiation and proliferation. Mutations or overexpression of these protein kinases disrupt the normal cellular signaling system (mainly in vivo), leading to a variety of diseases, including cancer, inflammation, metabolic diseases, and brain diseases.
  • Raf is a serine / threonine (Ser / Thr) protein kinase that is responsible for delivering biological signals from activated growth factor receptors in the cell membrane into the nucleus.
  • Raf proteins have three subtypes, A-Raf, B-Raf and C-Raf / Raf—1, which have three conserved regions (CRl, CR2, YV-terminal regulatory domain and C-terminal kinase domain). CR3).
  • CR1 contains a Ras-binding domain (RBD) such as a cysteine-rich domain (CRD), and CR2
  • 14-3-3 protein binds to the ' site (serum # 259 serine, etc.), CR3 contains a catalytic domain, two active-fragmentary phosphorylation sites (491 of Raf-1) Burn threonine and serine 494).
  • C-Raf is expressed in almost all tissues, while A-Raf is expressed mainly in the genitourinary tissues (kidney, uterus and prostate), and B-Raf is mainly expressed in nerves, spleen and hematopoietic tissues.
  • Mutations in B-Raf are approximately related to all human cancers. In particular, mutations of B-Raf have been observed with high frequency in melanoma, a type of skin cancer.
  • the B-Raf-V600E mutant in which valine 600, located at axon 15, is mutated to glutamic acid, is mainly known to cause melanoma.
  • B-Raf-V600E induces hyperactivation of the MAPK kinase signaling system leading to cancer.
  • the reason for the high kinase activity of B-Raf—V600E is as follows. Glutamic acid 600, substituted by point mutation, acts as a phosphate model between the phosphorylation sites (threonine 598 and serine hexavalent) located in the activation segment, resulting in a conformal conformation of the always active B-Raf kinase domain.
  • the B-Rai mutant species identified so far is about Forty individuals have a significantly lower incidence of mutant species other than V600E.
  • B-Raf is always activated when activated H-Ras binds. It is formed through the phosphorylation of serine 445.
  • the phosphorylation of C—Raf serine 338 corresponds to the phosphorylation of B-Raf serine 445.
  • the B—Raf V600E mutant interferes with the self-suppressive mechanism of B-Raf and remains active at all times.
  • B-Raf-V600E mutant species are also found with high frequency in papillary thyroid cancer. At the same time, B-Raf—V600E mutant species are closely associated with colon and uterine cancers.
  • Sorafenib (BAY 43—9006, trade name Nexavar), developed jointly by Bayer and Onyx, strongly inhibits both C-Raf and wild-type or mutant B-Rai. Sorafenib also contains platelet-derived growth factor receptors, vascular endothelial growth factor receptors 1/2/3 and fibroblast growth factor receptors, receptor tyrosine kinases. fibroblast growth factor receptor), Fit-3, c-Kit, and RET block kinase activity. Sorafenib inhibits kinases through a mechanism by which the DGF motif of the kinase domain is stabilized to have an inactive conf ormat ion. Sorafenib
  • Sorafenib was approved in 2005 for the treatment of advanced renal cell carcinoma. Sorafenib's renal cancer treatment is due to the complex inhibition of several kinases including vascular endothelial growth factor receptor 1/2/3 rather than Raf inhibition.
  • the maximum tolerated dose of Sorafenib in phase II trials was 400 mg (twice daily). Sorafenib at 600 mg (twice daily) causes grade 3 skin toxic side effects.
  • a common side effect of Sorafenib is the hand-foot syndrome of skin peeling and redness and edema.
  • Sorafenib was approved for the treatment of Hepatocellular Carcinoma (HCC) in 2008. Sorafenib
  • Sorafenib has been shown to be effective in treating thyroid cancer, hormonal refractory prostate cancer and breast cancer in phase II trials. However, Sorafenib is not effective in treating melanoma, a skin cancer.
  • PLX4720 a derivative of 7-azains from Plexxikon, is 1205Lu.
  • CHIR265 is currently a Phase 1 clinical trial in patients with melanoma
  • a substituent-substituted at the same time as the present invention is substituted at the C3 and C6 positions of the indazole parent nucleus, and a carboxamido group is particularly substituted at the C3 position.
  • Substituted indazole compounds have not been synthesized.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention and treatment of abnormal cell growth diseases containing the novel compounds as an active ingredient.
  • a ⁇ - is an arylene group; Biarylene group; Divalent heteroaromatic ring groups; Or 2
  • Ar 2 is a single bond line; Arylene group; Biarylene group; Divalent heteroaromatic ring groups; Or a divalent heteroaliphatic ring group,
  • X and L are the same or different from each other and are a single bond line; C (0)-; -NR 5- ;
  • R 1 and R 2 are the same as or different from each other and are a hydrogen atom; — N0 2 ; -OR "; -NR3 ⁇ 4 fi ; -NR 5 C (0) R 8 ;
  • R 1 and R 2 are bonded to each other heteroaromatic ring group
  • R 3 is a hydrogen atom; Halogen atom; CN; -N0 2 ; -OR 4 ; -SR 4 ; -NR 5 R R ; -NR 5 (CC 10 alkylene-OR 4 ); -NR ⁇ dd ,, alkylene -NR ⁇ ); -NR : '(heteroaliphatic ring); (heteroaromatic ring); -NR 5 (CC 10 alkylene-heteroaliphatic ring); -NR r ' ( CC 10 alkylene-heteroaromatic ring); -NR ⁇ dC, alkylene-heteroaromatic ring); ⁇ NR3 ⁇ 4 (0) -heteroaliphatic ring; one NR3 ⁇ 4 (0) -heteroaromatic ring; — NR (0) R 8 ; -NR3 ⁇ 4 (0) 0R, -NR 5 C (0)-(C r C 1 ()
  • Alkylene—NR : ⁇ ); -C (0) 8 ; -C (0) 0R 4 ; Halogen, -CN, -N0 2) -OR ", -NRR (i , -NR 5 (dC 1 (1 alkylene -NR3 ⁇ 4 (i ), N (0H), NR 5 C (0) 0R 4 ,- Linear, branched or cyclic unsubstituted or substituted with substituents selected from the group consisting of C (0) R 8 , -C (0) 0R 4
  • arylene In addition, arylene, biarylene, aryl,
  • Heteroaromatic rings, or heteroaliphatic rings are each independently a hydrogen atom
  • Halogen atom Linear, branched or cyclic saturated or unsaturated alkyl groups
  • R 4 is a hydrogen atom; Linear, branched or cyclic saturated or unsaturated d-, alkyl groups; Cr ′′ C containing 1 to 10 halogen atoms (; haloalkyl group; d— C 1 () alkylene— O — ⁇ -Cu, alkyl);-(Cr ′′ C 10 alkylene) NR3 ⁇ 4 «; -(d—Cu ) alkylene) —heteroaliphatic ring; -(Ct-do alkylene) —heteroaromatic ring; heteroaliphatic ring group; or heteroaromatic ring group;
  • R 5 , R t; , R 7 and R 8 are the same as or different from each other and are a hydrogen atom; Linear, branched or cyclic saturated or unsaturated C-doalkyl groups; Or an aryl group;
  • the aryl or arylene used in the above substituent definition consists of a monocyclic, bicyclic or tricyclic, and has an aromatic hydrocarbon group of 5 to 15 nuclear atoms.
  • the heteroaromatic ring used in the above substituent definition includes 1 to 4 heteroatoms selected from N, 0 and S, and may be selected from monocyclic, bicyclic or tricyclic.
  • An aromatic heterohydrocarbon group having 5 to 15 nuclear atoms The heteroaliphatic ring used in the above substituent definition includes 1 to 4 heteroatoms selected from N, 0, and S, monocyclic, bicyclic or tricyclic
  • an aliphatic heterohydrocarbon group having 5 to 15 nuclear atoms which may or may not contain an unsaturated carbon chain.
  • novel 3,6—disubstituted indazole derivatives of the present invention or pharmaceutically acceptable salts thereof have excellent ability to inhibit the activity of protein kinases.
  • Abnormal cell growth diseases that can be prevented and treated from the compounds according to the present invention include gastric cancer lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, Sclerotic adenoma, cervical cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid gland, kidney cancer, sarcoma, prostate cancer, urethral cancer.
  • Bladder cancer leukemia, multiple myeloma,
  • tumor diseases selected from hematological cancers such as myelodysplastic syndrome, lymphomas such as Hodgkin's disease and non-Hodgkin's lymphoma, or fibroadenoma, and the like.
  • Pharmaceutically acceptable salts of 3, 6-disubstituted indazole derivatives represented by Formula 1 according to the present invention may be prepared by conventional methods in the art. Pharmaceutically acceptable salts are of low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound.
  • Pharmaceutically acceptable salts include pharmaceutically usable free acids and acid addition salts of base compounds of formula (I), alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), and organic salts and carboxyl compounds of formula (I). It is composed of organic base addition salt of acid and amino acid addition salt.
  • Free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic acids and organic acids.
  • the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like.
  • Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, / luenesulfonic acid and fumaric acid.
  • Maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used.
  • Organic bases that can be used for the preparation of organic base addition salts are tris (hydroxymethyl) methylamine, dicyclonuxylamine and the like.
  • Amino acids that can be used to prepare amino acid addition bases are natural amino acids such as alanine, glycine and the like.
  • the 3,6-disubstituted indazole derivatives represented by Chemical Formula 1 according to the present invention include all hydrates and solvates in addition to the pharmaceutically acceptable salts described above.
  • the pharmaceutically acceptable salts described above may be prepared by the conventional methods described below.
  • the base compound of Formula 1 may be dissolved in a solvent which may be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallized or recrystallized after adding a free acid or free base.
  • the 3, 6-disubstituted indazole derivatives represented by Formula 1 according to the present invention may have one or more asymmetric centers, and in the case of such compounds, enantiomers or diastereomers may be present. Accordingly, the present invention includes each isomer or a mixture of these isomers. Different isomers can be separated or resolved by conventional methods, or any given isomer can be obtained by conventional synthesis or by stereospecific or asymmetric synthesis.
  • the present invention includes a radioactive derivative of the compound represented by Formula 1 according to the present invention, these radioactive compounds are useful in the field of biological research.
  • halogen atom in the present invention means chloro, fluoro, bromo, iodo.
  • alkyl group means methyl, ethyl,; rpropyl, / propyl, Cyclopropyl, / ⁇ butyl, / -butyl, butyl , cyclobutyl, cyclopropylmethyl ,
  • cyclopentyl cyclobutylmethyl, / ⁇ nuclear chamber, nuclear chamber, cyclonuclear chamber, cyclopentylmethyl, heptyl, cyclonuclear methylmethyl, octyl, etc. It means an aliphatic saturated hydrocarbon group having up to 10 carbon atoms.
  • the "haloalkyl group” means an alkyl group in which a hydrogen atom is substituted by one or more halogen atoms, such as a difluoromethyl group and a trifluoromethyl group.
  • alkoxy group means methoxy, ethoxy, / ⁇ propoxy, / -propoxy, / ⁇ butoxy, 7-butoxy, group containing methoxy, C r ( 1 ( , It means a hydroxyl group in which a hydrogen atom is substituted by a substituent selected from an alkyl group.
  • aryl group in the present invention means a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group, including phenyl, naphthyl, anthracenyl, phenanthryl, and the like.
  • bias group refers to an aromatic hydrocarbon group in which two aryl groups of 5 to 7 are bonded, including biphenyl, phenoxyphenyl, benzoylphenyl, or phenyldiazenylphenyl.
  • heteromatic ring group refers to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazol3 ⁇ 4, isocazolyl, triazolyl, oxa Diazole 3 ⁇ 4, thiadiazole 3 ⁇ 4, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, indolyl, isoindolinyl, benzofuranyl, benzofurazanyl, dibenzofuranyl, Isobenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisooxazolyl, benzo [d] [1,3] dioxyl, benzothiazolyl, dibenzothiophenyl naphthyridyl,
  • 5- to 7-membered monocyclic, bicyclic, or tricyclic aromatic heterohydrocarbon groups containing one or more heteroatoms including isoquinolinyl, quinoxalinyl, phthalazinyl, chinolinyl, quinazolinyl, and the like it means.
  • heteroaliphatic ring group includes a morpholininyl, piperidine group, piperazinyl, ⁇ protected piperazinyl, and the like. It means a heterohydrocarbon ring group.
  • 6'-substituted indazole derivatives represented by the formula (1) according to the present invention preferably,
  • the silver represents an arylene group having 5 to 7 substituted or unsubstituted nuclear atoms having 1 to 4 substituents selected from the group consisting of halogen, Cr; alkyl and d-Cs haloalkyl,
  • Ar 2 is a single bond line;
  • X and L are the same as or different from each other and are a single bond line; -NH-; -N (C)-; -NHC (O)-; -C (0) ⁇ -; -C (0) NHNH-; —C (0) ′ CH 2 —; —C (0) NHCH 2 CH 2 —; -NHC (0) NH-; -NHC (0) N (CH :! )-; -NHC (S) NH-; Or ⁇ NHS0 2 —,
  • R 1 and R 2 are the same as or different from each other as a hydrogen atom; -Ah I; d-Cfi alkyl group;
  • R 2 is a mutually bonded heteroaromatic ring group; Or a heteroaliphatic ring group, wherein the aryl, heteroaromatic ring, and heteroaliphatic ring are each independently selected from the group consisting of halogen, C, -C ( ; alkyl, and C R C (; haloalkyl).
  • halogen C, -C ( ; alkyl, and C R C (; haloalkyl).
  • R 3 is a hydrogen atom; Halogen atom; CN; -N0 2 ; —OH; -SH; — NH 2 ; -NHO ⁇ -C) alkyl);
  • Alkylene — NH ( Cl - Cl0 alkyl); — ( Cl - Cl potentiallyalkylene) — N ⁇ -C K) alkyl) 2 ; -(CC 1 ()
  • -C (0) (aryl), -C (0) (heteroaromatic ring), -C00H,-(XOXXd—C 6 alkyl), -S (0) (CC (i alkyl), -SW d-Cfialkyl ), N3 ⁇ 4, NH (dC (; alkyl), and N (dC (; alkyl) 2 ) is substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of
  • the aryl or arylene used in the above substituent definition consists of a monocyclic, bicyclic or tricyclic, aromatic hydrocarbon group having 5 to 15 nuclear atoms.
  • the heteroaromatic ring used in the above substituent definition includes 1 to 4 heteroatoms selected from N, 0 and S, and may be selected from monocyclic, bicyclic or tricyclic.
  • An aromatic heterohydrocarbon group having 5 to 15 nuclear atoms The heteroaliphatic ring used in the above substituent definition includes 1 to 4 heteroatoms selected from N, 0, and S, and includes a monocyclic ring, a bicyclic ring, or a tricyclic ring.
  • An represents phenylene having 1 to 2 substituted or unsubstituted substituents selected from the group consisting of chloro, fluoro, bromo, methyl and trifluoromethyl.
  • the tax is a single bond, or chloro, fluoro, bromo, methyl and
  • X is a single bond or represents -NH-, or -N (C)-.
  • L is — NHC (O) — , — C (0) NH— , — C (0) NHNH ⁇ , — C (0) NHCH 2 — , — C (0) NHCH 2 CH 2 ⁇ ,
  • R] and R 2 are the same or different and represents hydrogen atom, a hydroxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclo propyl, cyclo nucleus group, a hydroxyl group, the molar Poly group; Morpholinoethyl group, piperidine- 4-yl group ,
  • 2-fluoropyridin-3-yl group 5—poloropyridin-3-yl group
  • 6 fluoropyridin-3-yl group
  • pyrimidin-4-yl pyrimidin-3—yl
  • pyrimidin-4—yl pyrimidin-4—yl
  • pyrimidine 5-yl
  • Imidazole-4-yl group 1—methylimidazol-4-yl group, (imidazol—2-yl) methyl group, or pyrrolidin—3—yl group, or R 1 and are bonded to each other to pipera A zyl group or a 4-methylpiperazine—1-yl group.
  • R 3 is hydrogen atom, chloro atom, fluoro atom, bromo atom, cyano group, nitro group, hydroxy group, acetyl group, methyl group, ethyl group, isopropyl group, er-butyl bromomethyl group, cyanopropyl Group, dimethylaminomethyl group ,
  • 2-methylimidazole group 4-methylimidazole group, 2,4-dimethylimidazole group, pyridinyl group, 3-hydroxypyrrolidin ⁇ 1-yl group, 3- (dimethylamino) pyridine- Diary,
  • Methyl-6_ (methyl (2-methyl-5— (3— (4—methylpiperazin—1-yl) -5— (trimulomethyl) benz amido) phenyl) amino) ⁇ 1 // — indazole -3-carboxamide (Example 15);
  • 6- (4-fluoro-2-methyl-5— (3- (methylamino) -5— (trifluoromethyl) benzamido) phenyl)- ⁇ methyl-1 ⁇ indazole-3—carbox Amides (Example 73); 6- (5— (2— (dimethylamino) — 5- (trifluoromethyl) benzamido) -4—fluoro—2-methyl phenyl)-/ V "methyl indazole-3-carboxamide ( Example 74);
  • 6- (5- (3— (1-acetylpiperidine-4-carboxamido) -5- (trifluoromethyl) benzamido) ⁇ 4 ⁇ fluoro-2-methylphenyl) methyl-1 ⁇ Indazole-3-carboxamide (Example 93); 6- (5- (3— (2— (dimethylamino) acetamido) -5- (trifluoromethyl) benzamido) -4-fluoro-2-methylphenyl) methyl indazole-3-carbox Amide (Example 94);
  • 6- (5 ′ (3 ′ (2-amino— 2-methylpropoxy) -5- (trifluoromethyl) benzamido) —4-fluorofluoro 2-methylphenyl) methyl-1 ⁇ indazol ⁇ 3 Carboxamide (Example 131); 6- (5- (3-((l ⁇ (dimethylamino) propane_2-yl) oxy) ⁇ 5- (trifluoromethyl) benzamido) -4 -fluoro- 2 —methylphenyl methyl- ;! ⁇ Indazole 3 —carboxamide
  • Trifluoroacetic acid salt (Example 190);
  • 6- (5-((3 ⁇ ((2- (dimethylamino) ethyl) amino) -5— (trifluoromethyl) phenyl) carbamoyl) -4-fluoro-2-methylphenyl) methyl-1 ⁇ is Sol-3-carboxamide (Example 229); 6- (4-fluoro— 2-methyl— 5— ((2-morpholino-5 (trifluoromethyl) phenyl) carbamoyl) phenyl) -gmethyl indazole— 3—carboxamide (implemented Example 230);
  • 6- (5 ⁇ ((3-((2— (dimethylamino) ethyl) amino) -5- (trifluoromethyl) phenyl) carbamoyl) ⁇ 4-fluoro-2—methylphenyl) ⁇ ⁇ methyl-ly Indazole-3-carboxamide (Example 232); 6- (5 '((2-((2- (dimethylamino) ethyl) amino) -5- (trifluoromethyl) phenyl) carbamoyl) -4-fluoro-2—methylphenyl)-/ ⁇ methyl— 1 ⁇ indazole-3-carboxamide (Example 233); 6- (5— ((3—chloro-4-methoxyphenyl) carbamoyl) —4-fluoro—2-methylphenyl) methyl indazole-3-carboxamide (Example 234);
  • 6- (5- (2- (3,5-dimethoxyphenyl) acetamido) ⁇ 4-fluoro-2-methylphenyl) -methyl-1 ⁇ dazole- 3-carboxamide (Example 254); 6- (5- (2- (4-dimethoxyaminophenyl) acetamido)-4-fluoro- 2-methylphenyl) -methyl-1 ⁇ indazole-3-carboxamide (Example 255);
  • the present invention can be used as a prophylactic or therapeutic agent for diseases caused by abnormal cell growth.
  • diseases caused by abnormal cell growth include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, myeloma, breast cancer, scleroid adenomas, uterine cancer,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a 3,6-disubstituted indazole derivative represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient, and abnormal cell growth. It is characterized by the prophylaxis and treatment of various tumor diseases caused.
  • the pharmaceutical composition of the present invention is a pharmaceutically acceptable salt thereof, solvate thereof, or hydrate thereof of the 3, 6-disubstituted indazole derivative represented by Chemical Formula 1
  • Oral such as tablets, capsules, troches, liquids, suspensions, etc., which are conventional in the pharmaceutical field by adding them as an active ingredient, and adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant, and excipient thereto.
  • Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders , solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, layering agents, fragrances, and the like.
  • lactose for example, lactose, dextrose, sucrose, manni, solbi, salulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, eggs Havoc, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyridone, sodium chloride, calcium chloride, orange essence , strawberry essence, vanilla flavor Can be.
  • the dosage of the compound according to the present invention to the human body may vary according to the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally 0.01 based on an adult patient having a weight of 70 kg. ⁇ 1,000 mg / day, may be divided into once or several times a day at regular intervals depending on the judgment of the doctor or pharmacist.
  • 6-Nitrojan1-indazole (5 g) and dioxane (50 ITIL) were placed in a bottom-bottom flask. 3N NaOH solution (25 mL) was added thereto and stirred. H (8.5 g) was added to the mixture. After 4 hours, water (100 ml ) was added to react Terminated. The product resulting from the addition of water was filtered to give a yellow solid product.
  • the filtrate was distilled off under reduced pressure to obtain a solid product.
  • 6-nitrojan 1-indazol-3-carboxylic acid 280 mg
  • EtOH 4.5 niL
  • Concentrated S0 4 0.04 mL was added to the mixture and heated to 100 ° C. After 3 hours, the solvent was removed by distillation under reduced pressure, and the mixture was neutralized with IN NaOH. Solid product obtained by quenching was obtained by solid filtration. The product was washed with water and dried under nitrogen gas to give 300 mg (94%) of the product.
  • 6-Bromoqen 1 / indazole (5 g) and dioxane (50 ill) were placed in a bottom-bottom flask. To this was added 3 N NaOH solution (25 niL) and stirred. (8.5 g) was added to the mixture. After 4 hours, water (100 mL) was added to terminate the reaction. The product resulting from the addition of water was filtered to give a yellow solid product. The product was washed with water and dried under nitrogen gas to give 7.1 g (80%) of the product.
  • 3-iodo-6-nitroindazole (5 g) and DMF (58 ITIL) were placed in the back bottom flask.
  • CuCN (7.5 g) was added to the mixture and heated to 250 ° C.
  • 6-Bromo-l / indazol-3-carboxylic acid 100 g
  • DMF 500 mL
  • HBTU 236 g
  • DIEA 505 mL
  • MeNH 2 — HC1 84 g
  • Methyl— 6 ′ (methyl (2—methyl-5—nitrophenyl) amino) —1— (tetrahydro-2 //-pyran— 2 ilyl indazole-3-carboxamide (352mg, 0.83 ⁇ ol)
  • MeOH MeOH
  • 10% Pd / C 35 mg was added and stirred under a hydrogen gas for 5 hours at room temperature.
  • the mixture was filtered through a pad of diatomaceous earth and the filtrate was removed by distillation under reduced pressure.
  • Dazol-3-carboxamide (6.8 nig) which was ⁇ -methyl-6- (methyl (4— (33 (3— (trifluoromethyl) phenyl) ureido) phenyl) amino shock, was obtained.
  • Example 42 A compound was synthesized in the same manner as in Example 40. MS m / z [M + H] 463. Example 42.
  • 6-Bromo-1— (tetrahydro-2 //-pyran-2—yl intazole-3-carboxylate (200 nig, 0.57 wk ol) and ethyl 3-amino—4-methylbenzoate (102 mg , 0.57 mmol), ⁇ -phos (24.5mg, 0.05 ⁇ ol), 3 ⁇ 4C (394mg, 2.85 ⁇ ol) in 2—butanol (2mL), degassed, and then Pd 2 (dba) 3 (31.3 nig, 0.03 ⁇ ol ) And heated at 90 ° C.
  • Example 43 waves were carried out in the same manner to obtain the title compound.
  • the solvent is removed by distillation under reduced pressure
  • Example 139 Example 139.
  • Example 140 Example 140.
  • Example 141 Example 141.
  • Example 142 Example 142.
  • Example 143 The title compound was obtained in the same manner as the Example 134.
  • Example 143 Example 143.

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Abstract

La présente invention concerne un nouveau dérivé d'indazole 3,6-disubstitué ou un sel pharmaceutiquement acceptable de celui-ci, un procédé pour le produire, et une composition pharmaceutique le comprenant comme ingrédient actif. La composition pharmaceutique selon la présente invention présente un remarquable effet de suppression contre les protéine kinases qui induisent le cancer, comme la kinase B-Raf, et peut par conséquent être utilisée avantageusement dans la prévention ou le traitement du cancer.
PCT/KR2012/011655 2011-12-29 2012-12-28 Dérivé d'indazole 3,6-disubstitué ayant une activité d'inhibition de protéine kinase WO2013100672A1 (fr)

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KR10-2011-0146071 2011-12-29

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JP2017512794A (ja) * 2014-03-26 2017-05-25 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＴｒｋＡキナーゼ阻害薬、その組成物および方法
IL267247A (en) * 2016-12-15 2019-08-29 Univ California Compositions and methods for treating cancer
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JP2022501334A (ja) * 2018-09-13 2022-01-06 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company キナーゼ阻害剤としてのインダゾールカルボキサミド
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US9062051B2 (en) 2013-08-23 2015-06-23 Galapagos Nv Compounds and pharmaceutical compositions thereof for the treatment of proliferative disorders
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