TWI567068B - Trk抑制化合物 - Google Patents
Trk抑制化合物 Download PDFInfo
- Publication number
- TWI567068B TWI567068B TW105107897A TW105107897A TWI567068B TW I567068 B TWI567068 B TW I567068B TW 105107897 A TW105107897 A TW 105107897A TW 105107897 A TW105107897 A TW 105107897A TW I567068 B TWI567068 B TW I567068B
- Authority
- TW
- Taiwan
- Prior art keywords
- phenoxy
- trifluoromethyl
- nmr
- dmso
- amino
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title description 232
- 239000003112 inhibitor Substances 0.000 title description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 464
- 239000004202 carbamide Substances 0.000 claims description 242
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 190
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 135
- 150000003839 salts Chemical class 0.000 claims description 52
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- GYPOVJZOMXEUDO-UHFFFAOYSA-N 1-[2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl]-3-[2-methylsulfonyl-5-(trifluoromethyl)phenyl]urea Chemical compound CS(=O)(=O)C1=CC=C(C(F)(F)F)C=C1NC(=O)NC(C=N1)=CN=C1OC1=CC=C(C=2C(=NC=C(Cl)C=2)N)C=C1 GYPOVJZOMXEUDO-UHFFFAOYSA-N 0.000 claims 1
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 398
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- -1 C 1 -C 3 alkoxy Chemical group 0.000 description 127
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- 125000001424 substituent group Chemical group 0.000 description 11
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- 239000008107 starch Substances 0.000 description 1
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- 125000003107 substituted aryl group Chemical group 0.000 description 1
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- 229940120904 succinylcholine chloride Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
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- 230000002459 sustained effect Effects 0.000 description 1
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- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
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- 150000003522 tetracyclines Chemical class 0.000 description 1
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- ZYXWYDDFNXBTFO-UHFFFAOYSA-N tetrazolidine Chemical compound C1NNNN1 ZYXWYDDFNXBTFO-UHFFFAOYSA-N 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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- GUHPRPJDBZHYCJ-UHFFFAOYSA-N tiaprofenic acid Chemical compound S1C(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-UHFFFAOYSA-N 0.000 description 1
- HTJXMOGUGMSZOG-UHFFFAOYSA-N tiaramide Chemical compound C1CN(CCO)CCN1C(=O)CN1C(=O)SC2=CC=C(Cl)C=C21 HTJXMOGUGMSZOG-UHFFFAOYSA-N 0.000 description 1
- 229950010302 tiaramide Drugs 0.000 description 1
- 239000012974 tin catalyst Substances 0.000 description 1
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- PFENFDGYVLAFBR-UHFFFAOYSA-N tinoridine Chemical compound C1CC=2C(C(=O)OCC)=C(N)SC=2CN1CC1=CC=CC=C1 PFENFDGYVLAFBR-UHFFFAOYSA-N 0.000 description 1
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- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- 229960002044 tolmetin sodium Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229940126307 triamcinolone acetate Drugs 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 229960002835 trimipramine maleate Drugs 0.000 description 1
- YDGHCKHAXOUQOS-BTJKTKAUSA-N trimipramine maleate Chemical compound [O-]C(=O)\C=C/C([O-])=O.C1CC2=CC=CC=C2[NH+](CC(C[NH+](C)C)C)C2=CC=CC=C21 YDGHCKHAXOUQOS-BTJKTKAUSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 229950010121 ufenamate Drugs 0.000 description 1
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- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 229960004298 vecuronium bromide Drugs 0.000 description 1
- VEPSYABRBFXYIB-PWXDFCLTSA-M vecuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 VEPSYABRBFXYIB-PWXDFCLTSA-M 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229950004227 zaltoprofen Drugs 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本發明係有關Trk抑制化合物或其鹽及含有該等作為有效成分之醫藥。詳言之,係有關通式(I)表示之Trk抑制化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥(以下,稱為本發明化合物):
(式中,所有符號與與後述者同意義)及含有該等作為有效成分之醫藥。
原肌球蛋白受體激酶(Tropomyosin receptor kinase)(以下,簡稱為Trk)家族屬於受體型酪胺酸激酶,分類為神經成長因子(以下,簡稱為NGF)的高親和性受體之TrkA、腦衍生營養因子(BDNF)及神經營養素(以下,簡稱為NT)-4/5的高親和性受體之TrkB及NT-3的高親和性受體之TrkC。任何一種Trk受體都於神經組織中高表現,且參予神經細胞分化或機能維持(參照非專利文獻1)。另一方面,已知若藉由NGF將末梢神經之TrkA活化,則
會誘發痛覺過敏(參照非專利文獻2),有根據使用抗NGF抗體之臨床及非臨床試驗結果或使用低分子Trk抑制劑之非臨床試驗結果,TrkA參予變形性關節炎、慢性腰痛症、類風濕性關節炎、骨折、間質性膀胱炎及慢性胰臟炎等所伴隨之痛覺接受性疼痛、神經病變性疼痛及合併具有雙方疼痛之癌症性疼痛等疼痛之報告(參照非專利文獻3至10)。另,有Trk受體於神經胚細胞瘤、前列腺癌及胰臟癌等癌細胞、肥大細胞或嗜酸性球等炎症細胞、T細胞或B細胞等擔任免疫之細胞及角質細胞等中亦有表現,有可能參予癌細胞之增殖、遊走及轉移、潰瘍性大腸炎及克隆氏症(Crohn's disease)等炎症性疾病、氣喘、鼻炎及異位性皮膚炎等過敏性疾病以及乾癬等疾病之報告(參照非專利文獻11至15)。因此,具有Trk抑制活性之化合物有可能可應用於痛覺接受性疼痛、神經病變性疼痛及合併具有雙方疼痛之疼痛、癌症、炎症性疾病、過敏性疾病及乾癬等之治療。
由此等,若可創製抑制Trk之藥劑,則期待Trk抑制劑可能成為至今未曾有之新型疼痛等之預防劑及/或治療劑。
另一方面,於專利文獻1中記載一種藉由酪胺酸激酶調節,用於處置或預防人類或其他哺乳類疾病之方法,係包含對需要之人類或其他哺乳類投予下述式(Ia)之化合物、其鹽、其異構體或其前驅藥之方法。
通式(Ia)為:
(式中,Aa為選自下述(i)至(iii)等群;(i)可經1至3個任意獨立選自Ra1、ORa1、鹵素原子等群之取代基取代之苯基;(ii)可經1至3個任意獨立選自Ra1、ORa1、鹵素原子等群之取代基取代之萘基;(iii)可經1至3個任意獨立選自Ra1、ORa1、鹵素原子等群之取代基取代,且具有1至3個獨立選自氧原子、氮原子及硫原子所成群組之雜原子之5及6員單環雜芳基;Ba為選自下述(i)至(iii)等群;(i)可經1至3個任意獨立選自-La-Ma、C1-C5直鏈或支鏈烷基、鹵素原子等群之取代基取代之苯基;(ii)可經1至3個任意獨立選自-La-Ma、C1-C5直鏈或支鏈烷基、鹵素原子等群之取代基取代之萘基;(iii)可經1至3個任意獨立選自-La-Ma、C1-C5直鎖或支鏈烷基、鹵素原子等群之取代基取代,且具有1至3個獨立選自由氧原子、氮原子及硫原子所成群組之雜原子之5及6員單環雜芳基;La為選自-(CH2)ma-O-(CH2)la-、-(CH2)ma-C(O)-(CH2)la-等群,此處,變數ma及la為獨立選自0至4之整數;Ma為選自下述(i)至(iii)等群;(i)可經1至3個任意獨立選自Ra1、ORa1、鹵素原子等群之取代基取代之苯基;(ii)可經1至3個任意獨立選自Ra1、ORa1、鹵素原子等群之取代基取代之萘基;
(iii)可經1至3個任意獨立選自Ra1、ORa1、鹵素原子等群之取代基取代,且具有1至3個獨立選自由氧原子、氮原子及硫原子所成群組之雜原子之5及6員單環雜芳基;此處,Ra1為獨立選自由(a)氫原子、(b)C1-C6烷基、(c)苯基、(d)具有1至4個選自由氧原子、氮原子及硫原子所成群組之雜原子之5至6員單環雜芳基或8至10員二環雜芳基、(e)C1-C3烷基-苯基及(f)具有1至4個選自由氧原子、氮原子及硫原子所成群組之雜原子之烷基-雜芳基所成群組;Ra1不為氫原子時,可經1至3個任意獨立選自由C1-C5直鏈、支鏈或環狀烷基、C1-C3烷氧基、羥基、胺基、C1-C3烷基胺基、C2-C6二烷基胺基、鹵素原子、氰基及硝基所成群組之取代基取代;摘錄一部分基之定義)。
專利文獻1雖然記載該專利文獻1之化合物使用在抑制KDR,而處置藉由VEGF誘發訊息傳遞路徑仲介之人類或其他哺乳類之疾病,尤其是視網膜症或早產兒視網膜症之方法中,惟,未記載或暗示該專利中記載之化合物具有Trk抑制活性,該專利亦未具體記載本發明化合物。
又,專利文獻2雖記載通式(Ib)表示之化合物、或互變異構體、對映異構體、藥學上容許之鹽、水合物、溶劑化物、錯合物或該等之前驅藥為內因性肌營養不良相關蛋白(utrophin)正調節器,惟,未記載亦未暗示具有Trk阻礙活性。又,該專利未具體記載本發明化合物。
(式中,Yb為N或CH;Lb1為鍵結、-O-、-S-、-SO-、-SO2-等;Lb2為鍵結、-NHC(O)NH-、-NHC(O)-等;Rb1為(i)Rb5或(ii)可經1個以上之鹵素原子、Rb5等取代之C1-C6烷基;Rb2為(i)C1-C6烷基或(ii)芳基或雜芳基,各個基可經1個以上之鹵素原子、Rb9、ORb9、SRb9、N(Rb9)2、C(O)Rb9等取代;Rb3為氫原子、鹵素原子、C1-C6烷基等;Rb5為環烷基、雜環、芳基、雜芳基,各個基可經1個以上之鹵素原子、ORb6、N(Rb6)2、Rb7、ORb7等取代;Rb7為環烷基、雜環、芳基、雜芳基,各個基可經1個以上之鹵素原子、羥基、N(Rb6)2等取代;各個Rb6獨立地為氫原子或C1-C4烷基;摘錄一部分基之定義)。
另,專利文獻3雖記載通式(Ic)表示之化合物或鹽、酯或該等之前驅藥為B-Raf阻礙活性,惟,未記載亦未暗示具有Trk阻礙活性。又,該專利文獻3完全未記載本發明化合物。
(式中,Ac及Cc各自獨立地為選自由可經取代之芳基及雜芳基所成之群組;Bc為選自由-N(H)C(O)N(H)-及-N(H)C(O)N(H)CH2-所成之群組;Xc1至Xc4為選自由C(Rc2)及N所成之群組,Xc1至Xc4中至少有1個為N;Xc5為C(Rc3)(Rc4)、N(Rc3)、O及S(O)mc;Rc1為選自由可經取代之雜芳基及雜環烷基所成之群組;摘錄一部分基之定義)。
又,於至今所知之Trk抑制劑中,對於如本發明化合物之具有以『脲基-ring-O-ring-ring』為特徵之化學構造之化合物完全不知。
專利文獻1:國際公開第2003/068228號冊子
專利文獻2:國際公開第2010/057833號冊子
專利文獻3:國際公開第2007/076473號冊子
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非專利文獻2:Trends in Pharmacological Sciences、第27卷、85-91頁、2006年
非專利文獻3:New England Journal of Medicine、第363卷、1521-1531頁、2010年
非專利文獻4:Pain、第152卷、2248-2258頁、2011年
非專利文獻5:Journal of Urology、第185卷、1716-1721頁、2011年
非專利文獻6:Pain、第116卷、8-16頁、2005年
非專利文獻7:Bone、第48卷、389-398頁、2011年
非專利文獻8:Molecular Pain、第6卷、87頁、2010年
非專利文獻9:Journal of Pharmacological and Experimental Therapeutics、第322卷、282-287頁、2007年
非專利文獻10:Gastroenterology、第141卷、370-377頁、2011年
非專利文獻11:Expert Opinion Therapeutic Patents、第19卷、305-319頁、2009年
非專利文獻12:Gut、第46卷、670-679頁、2000年
非專利文獻13:Current Opinion in Allergy and Clinical Immunology、第10卷、8-13頁、2010年
非專利文獻14:Inflammation and Allergy Drug Targets、第9
卷、173-180頁、2010年
非專利文獻15:Journal of Investigative Dermatology、第126卷、1719-1727頁、2006年
本發明之課題為創製對於Trk具有選擇性抑制活性之化合物,發現有用於作為以疼痛為代表之種種疾病之預防及/或治療藥之化合物。
本發明人等為了發現對於Trk具有選擇性抑制活性,可成為以疼痛為代表之種種疾病之預防及/或治療藥之化合物而進行深入研究之結果發現,後述通式(I)表示之化合物具有Trk抑制作用,具有優越之激酶選擇性及持續抑制NGF血管滲透性亢進,因而完成本發明。
亦即,本發明係有關:[1]一種通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥;
(式中,環Cy1表示C3至10之單環式碳環或二環式碳環、或者4至
10員單環式雜環或二環式雜環,環Cy2表示將1,3-噻唑-5-基之雜環除外之4至10員單環式雜環或二環式雜環,R1表示(1)鹵素原子、(2)可經選自由(i)鹵素原子及(ii)羥基所成群組之取代基取代之C1至6烷基、C2至6烯基或C2至6炔基、(3)可經1至2個R5取代之C5至6單環式碳環、(4)可經1至2個R5取代之5至6員單環式雜環、(5)-S(O)m1-R6、(6)-SO2NR7R8、(7)-C(O)OR9、(8)-NR10C(O)R11、(9)-C(O)NR12R13、(10)-OR14、(11)-NR15R16、(12)氰基或(13)硝基,R5表示(1)鹵素原子、(2)-S(O)m2-R17、(3)-SO2NR18R19、(4)-C(O)OR20、(5)-NR21C(O)R22、
(6)-C(O)NR23R24、(7)-OR25、(8)-NR26R27、(9)氰基、(10)硝基或(11)可經選自由(i)鹵素原子、(ii)羥基及(iii)側氧基所成群組之取代基取代之C1至3烷基,R5為2個時,R5各自獨立,可相同亦可不同,另,2個R5各自獨立地為C1至3烷基或羥基,R5位於C5至6單環式碳環或5至6員單環式雜環上之鄰接碳原子時,該等基可一同形成環,R6至R27各自獨立地表示(1)氫原子或者(2)可經(i)鹵素原子或(ii)羥基取代之C1至6烷基,R18及R19各自獨立地為C1至6烷基時,該等基可一同形成環,R2表示(1)鹵素原子、(2)可經(i)鹵素原子或(ii)羥基取代之C1至6烷基、(3)可經(i)鹵素原子或(ii)羥基取代之C3至6環烷基、(4)可經鹵素原子取代之C1至6烷氧基、(5)-NR28R29、(6)3至7員單環式雜環或(7)-O-(3至7員單環式雜環),R28及R29各自獨立地表示(1)氫原子或者(2)可經(i)鹵素原子或(ii)羥基取代之C1至6烷基,
A1及A2各自獨立地表示=CR3-或=N-,A3、A4、A5及A6各自獨立地表示=CR4-或=N-,R3及R4各自獨立地表示氫原子或鹵素原子,m1表示0至2之整數,m2表示0至2之整數,p表示0至7之整數,q表示0至7之整數,r表示 0至2之整數。
惟,p、q及r各個表示2以上之整數時,R1、R2及R3各自獨立,可相同亦可不同);[2]如上述[1]記載之化合物,其中,該環Cy2為將1,3-噻唑-5-基之雜環除外之5至10員單環式芳族雜環或二環式芳族雜環;[3]如上述[1]或[2]記載之化合物,其中,該環Cy2為吡啶環、嘧啶環、吡唑并嘧啶環、咪唑并嗒環、咪唑并吡啶環、吡咯并吡啶環、咪唑并吡環或吡唑并吡啶環;[4]如上述[1]至[3]中任何一項記載之化合物,其中,A1及A2之任何一方為=N-,另一方為=CH-或是雙方都為=N-,A3、A4、A5及A6為=CH-;[5]如上述[1]記載之化合物,其中,通式(I)為通式(I-i)或通式(I-ii)表示者:
(式中,R2-a與R2同意義,q-a表示0至3之整數,t表示0至4之整數,其他符號與上述[1]記載之符號同意義。惟,q-a及t表示2以上之整數時,R2-a及R4各自獨立,可相同亦可不同);[6]如上述[5]記載之化合物,其中,R2-a為3至7員單環式雜環;[7]如上述[1]記載之化合物,其中,通式(I)為通式(I-iii)或通式(I-iv)表示者:
(式中,R2-b與R2同意義,q-b表示0至4之整數,其他符號與上述[1]及[5]記載之符號同意義。惟,q-b表示2以上之整數時,R2-b各自獨立,可相同亦可不同);[8]如上述[7]記載之化合物,其中,該R2-b為3至7員單環式雜環;[9]如上述[1]至[8}中任何一項記載之化合物,其中,該環Cy1為苯環或5至6員單環式芳族雜環;[10]如上述[9]記載之化合物,其中,該環Cy1為苯環、吡啶環或吡唑環;[11]一種醫藥組成物,由含有上述[1]記載之通式(1)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥作為有效成分而成;[12]如上述[11]記載之組成物,其中,該組成物為Trk抑制劑;
[13]如上述[11]記載之組成物,其中,該組成物為Trk關連疾病之預防及/或治療劑;[14]如上述[13]記載之組成物,其中,該Trk關連疾病為疼痛、搔癢症、下泌尿道障礙、氣喘、過敏性鼻炎、炎症性腸疾病或查加斯病(Chaga’s disease);[15]如上述[14]記載之組成物,其中,該疼痛為變形性關節炎所伴隨之疼痛、癌性疼痛、慢性腰痛症、骨質疏鬆症所伴隨之腰痛、骨折痛、類風濕性關節炎所伴隨之疼痛、神經病變性疼痛、帶狀疱疹後疼痛、糖尿病性神經病變所伴隨之疼痛、纖維肌痛症、胰臟炎所伴隨之疼痛、間質性膀胱炎所伴隨之疼痛、子宮內膜異位症所伴隨之疼痛、過敏性腸症候群所伴隨之疼痛、偏頭痛、術後痛或齒髓炎所伴隨之疼痛;[16]一種醫藥,為由上述[1]記載之通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥,與至少一種以上選自對乙醯胺基酚(acetaminophen)、非類固醇性抗炎症藥、類鴉片藥、抗憂鬱藥、抗癲癇藥、N-甲基-D-天冬胺酸拮抗藥、肌肉鬆弛藥、抗心律不整藥、類固醇藥及雙膦酸酯藥組合形成;[17]一種Trk關連疾病之預防及/或治療方法,其特徵為對病患投予有效量之上述[1]記載之通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥;[18]用於預防及/或治療Trk關連疾病之上述[1]記載之通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥;[19]一種Trk抑制方法,為對病患投予有效量之上述[1]記載之通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前
驅藥;[20]一種上述[1]記載之通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥之用途,係用以製造Trk關連疾病之預防及/或治療劑;[21]如上述[1]至[5]中任何一項記載之化合物,其為(1)1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)脲、(2)1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(4-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)脲、(3)1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(5-(三氟甲基)-2-(3-(三氟甲基)-1H-吡唑-1-基)苯基)脲、(4)1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氯-5-(三氟甲基)苯基)脲、(5)1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基-3-(6-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)吡啶-3-基)脲、(6)1-(2-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基-3-(6-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)吡啶-3-基)脲、(7)1-(6-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)吡啶-3-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲、(8)1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基)脲、(9)1-(2-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)脲、(10)1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶
-3-基)-5-(三氟甲基)苯基)脲、(11)1-(2-(1H-吡唑-1-基)-4-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)脲、(12)1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氟-4-(三氟甲基)苯基)脲、(13)1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氯-4-(三氟甲基)苯基)脲、(14)1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲、(15)1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-(三氟甲基)-2-聯苯基]脲、(16)1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-(三氟甲基)-2-聯苯基]脲、(17)1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(4-氯-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲、(18)1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-{5-氯-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲、(19)1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2,4-雙(三氟甲基)苯基]脲、(20)1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(4-氯-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲、(21)1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲、(22)1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)
-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲、(23)1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲或(24)2-{[(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-N,N-二甲基-4-(三氟甲基)苯磺醯胺;[22]如上述[1]至[4]或上述[7]中任何一項記載之化合物,其為(1)1-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲、(2)1-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基)脲、(3)1-(2-(4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲、(4)1-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲、(5)1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲、(6)1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基]脲、(7)1-{2-[4-(5-甲基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲、(8)1-(2-{4-[5-(乙胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-甲基-4-(三氟甲基)-2-聯苯基]脲、(9)1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[4-(三氟甲基)-2-聯苯基]脲、
(10)1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-甲基-4-(三氟甲基)-2-聯苯基]脲或(11)1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2’-甲基-4-(三氟甲基)-2-聯苯基]脲;[23]一種製品,包含(1)由含有上述[1]記載之通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥所成之醫藥組成物、(2)容器、(3)指示上述組成物可用於預防及/或治療Trk關連疾病之宗旨之指示書、說明書、附加文件或製品標籤;[24]如上述[23]記載之製品,其中,該Trk關連疾病為疼痛;[25]一種製品,包含(1)由含有上述[1]記載之通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥所成之醫藥組成物、(2)容器、(3)指示可將上述組成物與對乙醯胺基酚、非類固醇性抗炎症藥、類鴉片藥、抗憂鬱藥、抗癲癇藥、N-甲基-D-天冬胺酸拮抗藥、肌肉鬆弛藥、抗心律不整藥、類固醇藥及/或雙膦酸酯藥組合使用於預防及/或治療Trk關連疾病之宗旨之指示書、說明書、附加文件或製品標籤;[26]如上述[25]記載之製品,其中,該Trk關連疾病為疼痛;[27]一種製品,包含(1)含有上述[1]記載之通式(I)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥,與對乙醯胺基酚、非類固醇性抗炎症藥、類鴉片藥、抗憂鬱藥、抗癲癇藥、N-甲基-D-天冬胺酸拮抗藥、肌肉鬆弛藥、抗心律不整藥、類固醇藥及/或雙膦酸酯藥組成形成複合劑形態之醫藥組成物、(2)容器、(3)指示上述組成物可用於預防及/或治療Trk關連疾病之宗旨之指示書、說明書、附加文件或製品標籤;
[28]如上述[27]記載之製品,其中,該Trk關連疾病為疼痛等。
本發明化合物具有Trk抑制活性及優越之激酶選擇性,另,由於持續抑制NGF血管滲透性亢進,而成為對於Trk關連疾病,例如疼痛、搔癢症、下泌尿道障礙、氣喘、過敏性鼻炎、炎症性腸疾病或查加斯病等疾病之預防及/或治療藥。
以下,將本發明作詳細說明。
於本發明中,「C3至10之單環式碳環或二環式碳環」為例如環丙烷,、環丁烷、環戊烷、環己烷、環庚烷、環辛烷、環壬烷、環癸烷、環戊烯、環己烯、環庚烯、環辛烯、環戊二烯、環己二烯、環庚二烯、環辛二烯、苯、戊搭烯(pentalene)、全氫戊搭烯、薁、全氫薁、茚、全氫茚、茚烷(indane)、萘、二氫萘、四氫萘及全氫萘環等。
於本發明中,環Cy1中之「4至10員單環式雜環或二環式雜環」為例如氧雜環丁烷、氮雜環丁烷、吡咯啶、吡咯、咪唑、三唑、四唑、吡唑、吡啶、哌啶、六氫吡、吡、嘧啶、嗒、吖呯(azepine)、二吖呯、呋喃、吡喃、呯(oxepine)、噻吩、噻喃、噻呯(thiepine)、唑、異唑、噻唑、異噻唑、呋咱(furazan)、二唑、、二、吖呯、二吖呯、噻二唑、噻、噻二、噻吖呯、噻二吖呯、吲哚、異吲哚、吲哚、苯并呋喃、異苯并呋喃、苯并噻吩、異苯并噻吩、吲唑、喹啉、異喹啉、喹
(quinolizine)、嘌呤、酞(phthalazine)、蝶啶(pteridine)、萘啶(naphthyridine)、喹啉、喹唑啉、噌啉、苯并唑、苯并噻唑、苯并咪唑、苯并二氧雜環戊烯(benzodioxole)、苯并氧硫雜環戊烷(benzoxathiole)、苯并哌喃(chromene)、苯并呋咱、苯并噻二唑、苯并三唑、吡咯啉、吡咯啶、咪唑啉、咪唑啶、三唑啉、三唑啶、四唑啉、四唑啶、吡唑啉、吡唑啶、二氫吡啶、四氫吡啶、二氫吡、四氫吡、二氫嘧啶、四氫嘧啶、全氫嘧啶、二氫嗒、四氫嗒、全氫嗒、二氫吖呯、四氫吖呯、全氫吖呯、二氫二吖呯、四氫二吖呯、全氫二吖呯、二氫呋喃、四氫呋喃、二氫吡喃、四氫吡喃、二氫呯、四氫呯、全氫呯、二氫噻吩、四氫噻吩、二氫噻喃、四氫噻喃、二氫噻呯、四氫噻呯、全氫噻呯、二氫唑、四氫唑(唑啶)、二氫異唑、四氫異唑(異唑啶)、二氫噻唑、四氫噻唑(噻唑啶)、二氫異噻唑、四氫異噻唑(異噻唑啶)、二氫呋咱、四氫呋咱、二氫二唑、四氫二唑(二唑啶)、二氫、四氫、二氫二、四氫二、二氫吖呯、四氫吖呯、全氫吖呯、二氫二吖呯、四氫二吖呯、全氫二吖呯、二氫噻二唑、四氫噻二唑(噻二唑啶)、二氫噻、四氫噻、二氫噻二、四氫噻二、二氫噻吖呯、四氫噻吖呯、全氫噻吖呯、二氫噻二吖呯、四氫噻二吖呯、全氫噻二吖呯、嗎啉、硫代嗎啉、氧硫雜環己烷(oxathiane)、吲哚啉、異吲哚啉、二氫苯并呋喃、全氫苯并呋喃、二氫異苯并呋喃、全氫異苯并呋喃、二氫苯并噻吩、全氫苯并噻吩、二氫異苯并噻吩、全氫異苯并噻吩、二氫吲唑、全氫吲唑、二氫喹啉、四氫喹啉、全氫喹啉、二氫異喹啉、四氫異喹啉、全氫異喹啉、二氫酞、四氫酞、全
氫酞、二氫萘啶、四氫萘啶、全氫萘啶、二氫喹啉、四氫喹啉、全氫喹啉、二氫喹唑啉、四氫喹唑啉、全氫喹唑啉、二氫噌啉、四氫噌啉、全氫噌啉、苯并氧硫雜環己烷、二氫苯并 、二氫苯并噻、吡并嗎啉、二氫苯并唑、全氫苯并唑、二氫苯并噻唑、全氫苯并噻唑、二氫苯并咪唑、全氫苯并咪唑、二戊烷(dioxolane)、二烷、二茚烷、苯并二烷、硫代二氫苯并哌喃(thiochroman)、二氫苯并二英(dioxin)、二氫苯并氧硫雜環己二烯(benzoxathiin)、二氫苯并哌喃、吡唑并嘧啶、咪唑并嗒、咪唑并吡啶、吡咯并吡啶、咪唑并吡、吡唑并吡啶、吡唑并嘧啶、咪唑并吡啶及三唑并吡啶環等。
於本發明中,環Cy2中之「將1,3-噻唑-5-基之雜環除外之4至10員單環式雜環或二環式雜環」表示與將1,3-噻唑-5-基之雜環除外之上述環Cy1中之「4至10員單環式雜環或二環式雜環」同意義。
於本發明中,環Cy2為「將1,3-噻唑-5-基之雜環除外之4至10員單環式雜環或二環式雜環」之化合物為從通式(I)除去下述通式(I’)之化合物。
(式中,q’表示0至2之整數,其他符號與上述[1]記載之符號同意義。惟,q’表示2時,R2各自獨立,可相同亦可不同)
於本發明中,「鹵素原子」為氟原子、氯原子、溴原子及碘原子。
於本發明中,「C1至6烷基」為例如甲基、乙基、正丙基、異丙基、正丁基、第二丁基、第三丁基、異丁基、戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、1-甲基-1-乙基丙基、2-甲基-2-乙基丙基、1-乙基丁基、2-乙基丁基及1,1-二甲基戊基等。
於本發明中,「C2至6烯基」為例如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、3-甲基-1-丁烯基、3-甲基-2-丁烯基、3-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基及5-己烯基等。
於本發明中,「C2至6炔基」為例如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、3-甲基-1-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基及5-己炔基等。
於本發明中,「C5至6單環式碳環」為例如環戊烷、環己烷、環戊烯、環己烯、環戊二烯、環己二烯及苯環。
於本發明中,「5至6員單環式雜環」為例如吡咯、咪唑、三唑、四唑、吡唑、吡啶、哌啶、六氫吡、吡、嘧啶、嗒、呋喃、吡喃、噻吩、噻喃、唑、異唑、噻唑、異噻唑、呋咱、二唑、、二、噻二唑、噻、噻二、吡咯啉、
吡咯啶、咪唑啉、咪唑啶、三唑啉、三唑啶、四唑啉、四唑啶、吡唑啉、吡唑啶、二氫吡啶、四氫吡啶、二氫吡、四氫吡、二氫嘧啶、四氫嘧啶、全氫嘧啶、二氫嗒、四氫嗒、全氫嗒、二氫呋喃、四氫呋喃、二氫吡喃、四氫吡喃、二氫噻吩、四氫噻吩、二氫噻喃、四氫噻喃、二氫唑、四氫唑(唑啶)、二氫異唑、四氫異唑(異唑啶)、二氫噻唑、四氫噻唑(噻唑啶)、二氫異噻唑、四氫異噻唑(異噻唑啶)、二氫呋咱、四氫呋咱、二氫二唑、四氫二唑(二唑啶)、二氫、四氫、二氫二、四氫二、二氫噻二唑、四氫噻二唑(噻二唑啶)、二氫噻、四氫噻、二氫噻二、四氫噻二、嗎啉、硫代嗎啉及氧硫雜環己烷環等。
於本發明中,「C1至3烷基」為甲基、乙基、正丙基及異丙基。
於本發明中,「C3至6環烷基」為環丙基、環丁基、環戊基及環己基。
於本發明中,「C1至6之烷氧基」為例如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、1-甲基丙氧基、第三丁氧基、異丁氧基、戊基氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基、1,1-二甲基丙氧基、1,2-二甲基丙氧基、2,2-二甲基丙氧基、己基氧基、1-甲基戊基氧基、2-甲基戊基氧基、3-甲基戊基氧基、4-甲基戊基氧基、1,1-二甲基丁氧基、1,2-二甲基丁氧基、1,3-二甲基丁氧基、1-甲基-1-乙基丙氧基、1-甲基-2-乙基丙氧基、1,2-二甲基丁氧基、2,2-二甲基丁氧基、1-乙基-2-甲基丙氧基、2-乙基-2-甲基丙氧基及1-乙基丁氧基等。
於本發明中,「3至7員單環式雜環」為例如氮雜環丙烷、氧雜環丁烷、氮雜環丁烷、吡咯、咪唑、三唑、四唑、吡唑、吡啶、哌啶、六氫吡、吡、嘧啶、嗒、吖呯、二吖呯、呋喃、吡喃、呯、噻吩、噻喃、噻呯、唑、異唑、噻唑、異噻唑、呋咱、二唑、、二、吖呯、二吖呯、噻二唑、噻、噻二、噻吖呯、噻二吖呯、吡咯啉、吡咯啶、咪唑啉、咪唑啶、三唑啉、三唑啶、四唑啉、四唑啶、吡唑啉、吡唑啶、二氫吡啶、四氫吡啶、二氫吡、四氫吡、二氫嘧啶、四氫嘧啶、全氫嘧啶、二氫嗒、四氫嗒、全氫嗒、二氫吖呯、四氫吖呯、全氫吖呯、二氫二吖呯、四氫二吖呯、全氫二吖呯、二氫呋喃、四氫呋喃、二氫吡喃、四氫吡喃、二氫呯、四氫呯、全氫呯、二氫噻吩、四氫噻吩、二氫噻喃、四氫噻喃、二氫噻呯、四氫噻呯、全氫噻呯、二氫唑、四氫唑(唑啶)、二氫異唑、四氫異唑(異唑啶)、二氫噻唑、四氫噻唑(噻唑啶)、二氫異噻唑、四氫異噻唑(異噻唑啶)、二氫呋咱、四氫呋咱、二氫二唑、四氫二唑(二唑啶)、二氫、四氫、二氫二、四氫二、二氫吖呯、四氫吖呯、全氫吖呯、二氫二吖呯、四氫二吖呯、全氫二吖呯、二氫噻二唑、四氫噻二唑(噻二唑啶)、二氫噻、四氫噻、二氫噻二、四氫噻二、二氫噻吖呯、四氫噻吖呯、全氫噻吖呯、二氫噻二吖呯、四氫噻二吖呯、全氫噻二吖呯、嗎啉、硫代嗎啉及氧硫雜環己烷環等。
於本發明中,「將1,3-噻唑-5-基之雜環除外之5至10員單環式芳族雜環或二環式芳族雜環」為例如吡咯、咪唑、三
唑、四唑、吡唑、吡啶、吡、嘧啶、嗒、吖呯、二吖呯、呋喃、呯、噻吩、噻呯、唑、異唑、異噻唑、呋咱、二唑、吖呯、二吖呯、噻二唑、吲哚、異吲哚、吲哚、苯并呋喃、異苯并呋喃、苯并噻吩、異苯并噻吩、吲唑、喹啉、異喹啉、喹、嘌呤、酞、蝶啶、萘啶、喹啉、喹唑啉、噌啉、苯并唑、苯并噻唑、苯并咪唑、苯并呋咱、苯并噻二唑、苯并三唑、吡唑并嘧啶、咪唑并嗒、咪唑并吡啶、吡咯并吡啶、咪唑并吡、吡唑并吡啶、吡唑并嘧啶、咪唑并吡啶及三唑并吡啶環等。
於本發明中,「5至6員單環式芳族雜環」為例如吡咯、咪唑、三唑、四唑、吡唑、吡啶、吡、嘧啶、嗒、呋喃、噻吩、唑、異唑、噻唑、異噻唑、呋咱、二唑及噻二唑環等。
於本發明中,「2個R5各自獨立地為C1至3烷基或羥基,R5位於C5至6單環式碳環或5至6員單環式雜環上之鄰接碳原子時,該等基可一同形成環」為例如下述之基等。
(式中,環Cy3表示C5至6單環式碳環或5至6員單環
式雜環,箭頭為對於環Cy1之鍵結)
於本發明中,「R5為-SO2NR18R19,R18及R19各自獨立地為C1至6烷基時,該等基可一同形成環」為例如下述之基等。
於本發明中,環Cy1較好為C5至6單環式碳環或5至6員單環式雜環。
於本發明中,環Cy1更好為環戊烷、環己烷、苯、吡喃、噻喃、吡咯啶、哌啶、六氫吡、咪唑啉、咪唑啶、嗎啉、硫代嗎啉及5至6員單環式芳族雜環。
於本發明中,環Cy1再好為苯及5至6員單環式芳族雜環。
於本發明中,環Cy1再更好為苯、吡咯、咪唑、吡唑、吡啶、吡、嘧啶、嗒、呋喃、噻吩、唑、異唑、噻唑及異噻唑環。
於本發明中,環Cy1還要更好為苯、咪唑、吡唑、吡啶、吡、嘧啶及嗒環。
於本發明中,環Cy1另更好為苯、吡唑及吡啶環。
於本發明中,環Cy1最好為苯及吡啶環。
於本發明中,環Cy2較好為將1,3-噻唑-5-基之雜環除外之5至10員單環式芳族雜環或二環式芳族雜環。
於本發明中,環Cy2更好為吡啶、吡、嘧啶、嗒
、吲哚、異吲哚、吲哚、苯并呋喃、異苯并呋喃、苯并噻吩、異苯并噻吩、吲唑、喹啉、異喹啉、喹、嘌呤、酞、蝶啶、萘啶、喹啉、喹唑啉、噌啉、苯并唑、苯并噻唑、苯并咪唑、苯并呋咱、苯并噻二唑、苯并三唑、吡唑并嘧啶、咪唑并嗒、咪唑并吡啶、吡咯并吡啶、咪唑并吡、吡唑并吡啶、吡唑并嘧啶、咪唑并吡啶及三唑并吡啶環。
於本發明中,環Cy2再好為吡啶、吡、嘧啶、嗒、吲哚、異吲哚、吲哚、吲唑、喹啉、異喹啉、喹、嘌呤、酞、蝶啶、萘啶、喹啉、喹唑啉、噌啉、苯并唑、苯并噻唑、苯并咪唑、苯并呋咱、苯并噻二唑、苯并三唑、吡唑并嘧啶、咪唑并嗒、咪唑并吡啶、吡咯并吡啶、咪唑并吡、吡唑并吡啶、吡唑并嘧啶、咪唑并吡啶及三唑并吡啶環。
於本發明中,環Cy2再更好為吡啶、吡、嘧啶、嗒、吡唑并嘧啶、咪唑并嗒、咪唑并吡啶、吡咯并吡啶、咪唑并吡、吡唑并吡啶、吡唑并嘧啶、咪唑并吡啶及三唑并吡啶環。
於本發明中,環Cy2另更好為吡啶、嘧啶、吡唑并嘧啶、咪唑并嗒、咪唑并吡啶、吡咯并吡啶、咪唑并吡及吡唑并吡啶環。
於本發明中,環Cy2最好為吡啶及吡唑并嘧啶環。
於本發明中,R1較好為(1)鹵素原子、(2)可經鹵素原子取代之C1至3烷基、(3)可經1至2個R5取代之苯環、(4)可經1至2個R5取代之5至6員單環式芳族雜環、(5)甲磺醯基及(6)N,N-二甲磺醯胺。
於本發明中,R1更好為(1)鹵素原子、(2)甲基、(3)三氟甲基、(4)二氟甲基、(5)單氟甲基、(6)三氯甲基、(7)二氯甲基、(8)單氯甲基、(9)可經1至2個R5取代之苯環、(10)可經1至2個R5取代之吡咯、咪唑、三唑、四唑、吡唑、吡啶、吡、嘧啶、嗒、呋喃、噻吩、唑、異唑、噻唑、異噻唑、呋咱、二唑及噻二唑環、(11)甲磺醯基及(12)N,N-二甲磺醯胺。
於本發明中,R1另較好為(1)鹵素原子、(2)甲基、(3)三氟甲基、(4)二氟甲基、(5)單氟甲基、(6)苯環、(7)茚烷環、(8)甲苯基、(9)二甲基苯環、(10)可經1至2個R5取代之咪唑、三唑、吡唑及吡啶環及(11)甲磺醯基。
於本發明中,R1再更好為(1)鹵素原子、(2)三氟甲基、(3)二氟甲基、(4)苯環、(5)茚烷環、(6)甲苯基、(7)二甲基苯環、(8)可經1至2個甲基、二氟甲基或三氟甲基取代之咪唑、三唑、吡唑及吡啶環及(9)甲磺醯基。
於本發明中,R1另更好為(1)三氟甲基、(2)二氟甲基、(3)苯環及(4)可經1至2個甲基、二氟甲基或三氟甲基取代之三唑、吡唑及吡啶環及(5)甲磺醯基。
於本發明中,R1最好為(1)三氟甲基及(2)可經1至2個甲基、二氟甲基或三氟甲基取代之三唑、吡唑及吡啶環。
於本發明中,R5較好為(1)鹵素原子、(2)可經鹵素原子取代之甲基及(3)可經羥基或側氧基取代之C1至3烷基。
於本發明中,R5更好為甲基、三氟甲基、二氟甲基、乙醯基及羥基乙基。
於本發明中,R5最好為甲基、三氟甲基及二氟甲基。
於本發明中,R2較好為(1)鹵素原子、(2)可經鹵素原子或羥基取代之C1至3烷基、(3)C3至6環烷基、(4)C1至3烷氧基、(5)胺基、(6)可經羥基取代之甲胺基、乙胺基、正丙胺基、異丙胺基、正丁胺基、第二丁胺基、第三丁胺基、異丁胺基及二甲胺基、(7)3至7員單環式雜環及(8)-O-(3至7員單環式雜環)。
於本發明中,R2更好為鹵素原子、甲基、三氟甲基、二氟甲基、單氟甲基、羥基甲基、羥基乙基、2-甲基-羥基乙基、環丙基、甲氧基、乙氧基、胺基、甲胺基、乙胺基、二甲胺基、2-甲基-2-羥基丙胺基、氧雜環丁烷基氧基、氮雜環丁烷環、吡咯啶環及哌啶環。
於本發明中,R2另較好為鹵素原子、甲基、環丙基、甲氧基、胺基、二甲胺基、氧雜環丁烷基氧基、氮雜環丁烷環、吡咯啶環及哌啶環。
於本發明中,R2再更好為鹵素原子、甲基、胺基、氮雜環丁烷環及吡咯啶環。
於本發明中,R2最好為氟原子、氯原子、甲基、胺基及氮雜環丁烷環。
於本發明中,R3較好為氫原子及氟原子,最好為氫原子。
於本發明中,R4較好為氫原子及氟原子,最好為氫原子。
於本發明中,R6較好為可經鹵素原子取代之C1至3烷基。
於本發明中,R6更好為甲基、乙基及正丙基。
於本發明中,R7及R8較好各自獨立地為氫原子及可經羥基取代之C1至3烷基。
於本發明中,R7及R8更好各自獨立地為氫原子、甲基、乙基、正丙基、異丙基及2-羥基丙基。
於本發明中,R7及R8另較好各自獨立地為氫原子、甲基、乙基及正丙基。
於本發明中,R9較好為氫原子、甲基及乙基。
於本發明中,R10至R16較好各自獨立地為氫原子、甲基、乙基及正丙基。
於本發明中,R17較好為可經鹵素原子取代之C1至3烷基。
於本發明中,R17更好為甲基、乙基及正丙基。
於本發明中,R18及R19較好各自獨立地為氫原子及可經羥基取代之C1至3烷基。
於本發明中,R18及R19更好各自獨立地為氫原子、甲基、乙基、正丙基、異丙基及2-羥基丙基。
於本發明中,R18及R19另更好各自獨立地為氫原子、甲基、乙基及正丙基。
於本發明中,R20較好為氫原子、甲基及乙基。
於本發明中,R21至R29較好各自獨立地為氫原子、甲基、乙基及正丙基。
於本發明中,m1較好為2之整數。
於本發明中,m2較好為2之整數。
於本發明中,p較好為0至3之整數。
於本發明中,q較好為0至3之整數。
於本發明中,r較好為0至1之整數。
於本發明中,R2-a及R2-b各自獨立地為與R2同意義,較佳之基亦與R2相同。
於本發明中,q-a較好為0至1之整數。
於本發明中,q-b較好為0至1之整數。
於本發明中,通式(I)較好為上述之環Cy1、環Cy2、R1、R2、R3、R4、R5、R2-a、R2-b、m1、m2、p、q、r、t、q-a及q-b之各個較佳定義之組合。
於本發明中,通式(I)更好為通式(I-a)或通式(I-b)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy2-a及環Cy2-b表示將1,3-噻唑-5-基之雜環除外之5至10員單環式芳族雜環或二環式芳族雜環,其他符號表示與上述[1]及[5]記載之符號同意義)
於本發明中,通式(I)另較好為通式(I-c)或通式(I-d)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy2-c及環Cy2-d表示吡啶環、嘧啶環、吡唑并嘧啶環、咪唑并嗒環、咪唑并吡啶環、吡咯并吡啶環、咪唑并吡環或吡唑并吡啶環,其他符號與上述[1]及[5]記載之符號同意義)
於本發明中,通式(I)更好為通式(I-e)或通式(I-f)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy1-e及環Cy1-f表示苯環或5至6員單環式芳族雜環,其他符號與上述[1]及[5]記載之符號同意義)。
於本發明中,通式(I)另較好為通式(I-g)或通式(I-h)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy1-g及環Cy1-h表示苯環、吡啶環或吡唑環,其他符號與上述[1]及[5]記載之符號同意義)
於本發明中,通式(I)更好為通式(I-j)或通式(I-k)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy2-j及環Cy2-k表示將1,3-噻唑-5-基之雜環除外之5至10員單環式芳族雜環或二環式芳族雜環,環Cy1-j及環Cy1-k表示苯環或5至6員單環式芳族雜環,其他符號與上述[1]及[5]記載之符號同意義)
於本發明中,通式(I)更好為通式(I-m)或通式(I-n)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy2-m及環Cy2-n表示吡啶環、嘧啶環、吡唑并嘧啶環、咪唑并嗒環、咪唑并吡啶環、吡咯并吡啶環、咪唑并吡環或吡唑并吡啶環,環Cy1-m及環Cy1-n表示苯環、吡啶環或吡唑環,其他符號與上述[1]及[5]記載之符號同意義)
於本發明中,通式(I-n)表示之Cy2-n為嘧啶環之化合物較好為後述實施例16-1至實施例16-8之本發明化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
於本發明中,通式(I-m)或通式(I-n)表示之環Cy2-m或Cy2-n為咪唑并嗒環之化合物較好為後述實施例22-1至實施例22-67之本發明化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
於本發明中,通式(I-m)或通式(I-n)較好為後述實施例23-1至實施例23-12之本發明化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
於本發明中,通式(I)更好為通式(I-i)或通式(I-ii)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,所有符號與上述[1]及[5]記載之符號同意義)
於本發明中,通式(I-i)或通式(I-ii)較好為通式(I-i-a)或通式(I-ii-b)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy1-i-a及環Cy1-ii-b表示苯環或5至6員單
環式芳族雜環,其他符號與上述[1]及[5]記載之符號同意義)
於本發明中,通式(I-i)或通式(I-ii)更好為通式(I-i-c)或通式(I-ii-d)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy1-i-c及環Cy1-ii-d表示苯環、吡啶環或吡唑環,其他符號與上述[1]及[5]記載之符號同意義)
於本發明中,通式(I-i)或通式(I-ii)最好為後述實施例7、實施例8-1至實施例8-22、實施例9-1至實施例9-3、實施例11、實施例12、實施例13-1至實施例13-4、實施例14-1至實施例14-20或實施例15-1至實施例15-251之本發明化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
於本發明中,通式(I)另較好為通式(I-iii)或通式(I-iv)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,所有符號表示與上述[1]、[5]及[7]記載之符號同意義)
於本發明中,通式(I-iii)或通式(I-iv)較好為通式(I-iii-a)或通式(I-iv-b)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy1-iii-a及環Cy1-iv-b表示苯環或5至6員單環式芳族雜環,其他符號表示與上述[1]、[5]及[7]記載之符號同意義)
於本發明中,通式(I-iii)或通式(I-iv)更好為通式(I-iii-c)或通式(I-iv-d)表示之化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
(式中,環Cy1-iii-c及環Cy1-iv-d表示苯環或吡啶環,其他符號表示與上述[1]、[5]及[7]記載之符號同意義)
於本發明中,通式(I-iii)或通式(I-iv)最好為後述實施例20或實施例21-1至實施例21-134之本發明化合物、其鹽、其N-氧化物、其溶劑化物或該等之前驅藥。
於本發明中,若無特別指示,包含所有之異構體。例如於烷基、烯基、炔基及烷氧基等包含直鏈者及支鏈者。另,環、稠環中之異構體(E、Z、順式、反式體)、因不對稱碳原子存
在等而產生之異構體(R、S體,α、β體,對映異構體、非對映異構體)、具有旋光性之光學活性體(D、L、d、l體)、藉由層析儀分離之極性體(高極性體、低極性體)、平衡化合物、旋轉異構體、該等之任意比例之混合物、消旋混合物均包含於本發明中。又,於本發明中,包含所有因互變異構性而產生之異構體。
於本發明中,若無特別說明,則以業者都明瞭之符號:
表示鍵結於紙面之另一側(亦即α-配置),符號
表示鍵結於靠近紙面側(亦即β配置),符號
表示為α-配置或β-配置,符號
表示α-配置與β-配置之任意比例之混合物。
通式(I)表示之化合物係以公知之方法轉換為鹽。
鹽較好為藥學上容許之鹽。
鹽較好為水溶性鹽。
鹽可列舉例如酸加成鹽、鹼金屬鹽、鹼土金屬鹽、銨鹽或胺鹽等。
酸加成鹽可列舉例如:如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、磷酸鹽、硝酸鹽之無機酸鹽,或如乙酸鹽、乳酸鹽、酒石酸鹽、苯甲酸鹽、檸檬酸鹽、甲磺酸鹽、乙磺酸鹽、三氟乙酸鹽、苯磺酸鹽、甲苯磺酸鹽、羥乙磺酸鹽、葡糖醛酸鹽或葡糖酸鹽之有機酸鹽。
鹼金屬鹽可列舉例如鉀及鈉等。
鹼土金屬鹽可列舉例如鈣及鎂等。
銨鹽可列舉例如四甲基銨等。
胺鹽可列舉例如三乙胺、甲胺、二甲胺、環戊胺、苯甲胺、苯乙胺、哌啶、單乙醇胺、二乙醇胺、三(羥基甲基)胺基甲烷、離胺酸、精胺酸及N-甲基-D-還原葡糖胺等。
又,本發明化合物可以任意方法作成N-氧化物。N-氧化物表示通式(I)表示之化合物之氮原子經氧化者,具體而言,在通式(I)表示之化合物中之A1、A2、A3、A4、A5或A6為=N-時,表示該氮原子經氧化者。或者,在Cy1或Cy2為含氮雜環時,表示該氮原子經氧化者。另,表示胺基經氧化者。
通式(I)表示之化合物及其鹽可轉換為溶劑化物。
溶劑化物較好為無毒性且為水溶性。適當之溶劑化物可列舉例如水或如醇系溶劑(例如乙醇等)之溶劑化物。
通式(I)表示之化合物之前驅藥為於生體內藉由酵素或胃酸等之反應,轉換為通式(I)表示之化合物之化合物。通式(I)表示之化
合物之前驅藥可列舉例如通式(I)表示之化合物具有胺基時,為該胺基經醯基化、烷基化、磷酸化之化合物(例如通式(I)表示之化合物之胺基經二十烷醯基化、丙胺醯基化、戊胺基羰基化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲氧基羰基化、四氫呋喃基化、吡咯啶基甲基化、三甲基乙醯氧基甲基化、乙醯氧基甲基化、第三丁基化之化合物等);通式(I)表示之化合物具有羥基時,為該羥基經醯基化、烷基化、磷酸化、硼酸化之化合物(例如通式(I)表示之化合物之羥基經乙醯基化、棕櫚醯基化、丙醯基化、三甲基乙醯基化、琥珀醯基化、富馬醯基化、丙胺醯基化、二甲胺基甲基羰基化之化合物等);通式(I)表示之化合物具有羧基時,為該羧基經酯化、醯胺化之化合物(例如通式(I)表示之化合物之羧基經乙基酯化、苯基酯化、羧基甲基酯化、二甲胺基甲基酯化、三甲基乙醯氧基甲基酯化、1-{(乙氧基羰基)氧基}乙基酯化、酞基酯(phthalidyl ester)化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲基酯化、1-{[(環己基氧基)羰基]氧基}乙基酯化、甲基醯胺化之化合物等)等。該等化合物可藉由其本身公知之方法製造。又,通式(I)表示之化合物之前驅藥可為水合物及非水合物中之任何一種。又,通式(I)表示之化合物之前驅藥亦可為以如廣川書店1990年刊「醫藥品之開發」第7卷「分子設計」163至198頁中記載之生理條件轉換為通式(I)表示之化合物者。
另,構成通式(I)表示之化合物之各原子亦可經其同位素(例如2H、3H、13C、14C、15N、16N、17O、18O、35S、36Cl、77Br、125I等)等取代。
通式(I)表示之本發明化合物可以公知之方法,例如根據以下表示之方法、以該等方法為基準之方法或實施例中表示之方法製造。又,於以下之各製造方法中,原料化合物可作為鹽使用。該等鹽可使用作為通式(I)之藥學上容許之鹽所記載之鹽。
通式(I)之本發明化合物可藉例如以下之反應步驟式所表示之方法製造。
(式中,X1表示硼酸基(-B(OH)2)或硼酸酯基(-B(ORi)(ORii)(式中,Ri及Rii表示C1至3烷基,Ri及Rii可一同形成環),例如4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基等),X2表示鹵素原子,X3表示鹵素原子,其他符號與上述[1]記載之符號同意義)
又,具有胺基、酯基或羥基之本發明化合物可依需要使用以對於該等基廣泛使用之保護基,例如「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」中記載之
保護基保護之化合物,進行至上述反應步驟式中記載之脲化反應為止之反應後進行公知之去保護反應或進行例如「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」中記載之去保護反應而製造。
於反應步驟式中,從通式(Ⅱ)表示之化合物製造通式(Ⅲ)表示之化合物之反應步驟(胺基甲酸酯化反應)為公知之方法。藉由該反應獲得之通式(Ⅲ)表示之化合物係藉由例如使用通式(Ⅱ)表示之化合物及2,2,2-三氯乙氧基碳醯氯,於有機溶劑(例如吡啶、乙酸乙酯、二氯甲烷、二烷、二乙醚或將該等有機溶劑適當混合之溶劑等)或該等有機溶劑與水之混合溶劑中,在鹼(例如4-二甲胺基吡啶、吡啶、三乙胺、碳酸氫鈉等)存在或不存在下,於約-20℃至80℃之溫度進行反應而製造。
於反應步驟式中,從通式(Ⅳ)表示之化合物製造通式(Ⅵ)表示之化合物之反應步驟(醚化反應、還原反應)為公知之方法。藉由該反應獲得之通式(Ⅵ)表示之化合物係藉由例如使用通式(Ⅳ)表示之化合物及通式(V)表示之化合物,於有機溶劑(例如二甲亞碸、二甲基甲醯胺、甲醇、乙腈、四氫呋喃或將該等有機溶劑適當混合之溶劑等)或該等有機溶劑與水之混合溶劑中,在鹼(例如氟化鉀、碳酸鉀、磷酸三鉀、氫氧化鈉、氫化鈉、三乙胺等)存在下,於約0℃至120℃之溫度進行反應所獲得之化合物於氫氣環境下,於有機溶劑(例如甲醇、乙醇、乙酸乙酯、四氫呋喃、乙酸、1,2-二甲氧基乙烷或將該等有機溶劑適當混合之溶劑等)或該等有機溶劑與水之混合溶劑中,於觸媒(例如銀觸媒(例如乙酸銀
等)、鉑觸媒(例如鉑-碳、氧化鉑等)、銠觸媒(例如銠-碳等)、鐵觸媒(例如乙酸鐵等)、釕觸媒(例如釕-碳等)、鈀觸媒(例如鈀-碳、氫氧化鈀等)、鋅觸媒(溴化鋅、碘化鋅、乙酸鋅等)、雷氏鎳(Raney nickel)或將該等觸媒適當混合之觸媒等)存在下,於室溫至約80℃之溫度進行反應,或者於有機溶劑(例如乙酸、鹽酸、乙醇、甲醇、二甲基甲醯胺、甲苯或將該等有機溶劑適當混合之溶劑等)或該等有機溶劑與水之混合溶劑中,於觸媒(例如鐵觸媒(例如鐵、氯化鐵、鐵-氯化銨等)、鋅觸媒(例如鋅等)、鎳觸媒(例如氯化鎳等)、銦觸媒(例如銦等)、錫觸媒(例如錫、氯化錫等)或將該等觸媒適當混合之觸媒等)存在下,於室溫至約80℃之溫度進行反應而製造。
於反應步驟式中,從通式(Ⅵ)表示之化合物製造通式(Ⅷ)表示之化合物之反應步驟(芳基化反應)為公知之方法。藉由該反應獲得之通式(Ⅷ)表示之化合物係藉由例如使用通式(Ⅵ)表示之化合物及通式(Ⅶ)表示之化合物,於有機溶劑(例如二甲基乙醯胺、二甲基甲醯胺、醇(例如甲醇、乙醇、異丙醇等)、碳酸二乙酯、二烷、1,2-二甲氧基乙烷、甲苯或將該等有機溶劑適當混合之溶劑等)或該等有機溶劑與水之混合溶劑中,於鹼(例如碳酸銫、乙酸鉀、碳酸鉀、碳酸鈉、第三丁醇鋰、碳酸銀、磷酸三鉀、三乙胺或將該等鹼適當混合之鹼等)存在下或不存在下,於觸媒(例如鈀觸媒(例如氫氧化鈀、乙酸鈀、雙(三-第三丁基膦)鈀、鈀(O)四(三苯基膦)、雙(三苯基膦)二氯鈀(Ⅱ)或將該等觸媒適當混合之觸媒等))中,於室溫至約120℃之溫度進行反應而製造。
於反應步驟式中,從通式(Ⅷ)表示之化合物製造通式(I)表示之本發明化合物之反應步驟(脲化反應)為使用通式(Ⅷ)
表示之化合物及通式(Ⅲ)或通式(IX)表示之化合物進行之反應,可在本說明書中記載之實施例之條件或公知之條件下進行。
於反應步驟式中,作為起始原料所使用之通式(Ⅱ)、(Ⅳ)、(V)、(VⅡ)及(IX)表示之化合物為公知者或可藉由使用公知之方法,例如「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」中記載之方法而容易的製造。
又,通式(I)之本發明化合物亦可藉由例如作為另一方法之使用上述反應步驟式中通式(Ⅷ)表示之化合物及2,2,2-三氯乙氧基碳醯氯製造之胺基甲酸2,2,2-三氯乙酯衍生物,與通式(Ⅱ)表示之化合物進行脲化反應而製造。
於通式(I)表示之本發明化合物中,對於上述表示之化合物以外之化合物可藉由將本說明書中記載之實施例或公知之方法,例如「Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)」中記載之方法組合使用而製造。
於本說明書中之各反應中,伴隨加熱之反應為如業者所明瞭的,可使用水浴、油浴、砂浴或微波進行。
於本說明書中之各反應中,可適當使用附載於高分子聚合物(例如聚苯乙烯、聚丙烯醯胺、聚丙烯、聚乙二醇等)之固體載體試藥。
於本說明書中之各反應中,反應生成物可藉由通常之精製方法,例如於常壓下或減壓下蒸餾、使用矽膠或矽酸鎂之高速液相層析、薄層層析、離子交換樹脂、清除劑樹脂(scavenger
resin)或管柱層析或者洗淨、再結晶等方法精製。精製可於每個反應進行,亦可於數個反應完成後進行。
本發明化合物之毒性夠低。本發明化合物為未呈現例如肝毒性及消化道障礙等,且腦轉移性低之化合物。因此,本發明化合物作為醫藥品,可安全的使用。
本發明化合物由於顯示Trk抑制活性,故有用於作為Trk關連疾病,例如疼痛、搔癢症、下泌尿道障礙、氣喘、過敏性鼻炎、炎症性腸疾病或查加斯病等之預防及/或治療劑。
更具體而言,疼痛可列舉例如變形性關節炎所伴隨之疼痛、癌性疼痛、慢性腰痛症、骨質粗鬆症所伴隨之腰痛、骨折痛、類風濕性關節炎所伴隨之疼痛、神經病變性疼痛、帶狀疱疹後疼痛、糖尿病性神經病變所伴隨之疼痛、纖維肌痛症、胰臟炎所伴隨之疼痛、間質性膀胱炎伴所隨之疼痛、子宮內膜異位症所伴隨之疼痛、過敏性腸症候群所伴隨之疼痛、偏頭痛、術後痛、齒髓炎所伴隨之疼痛等。搔癢症可列舉全身性皮膚搔癢症、局部性皮膚搔癢症、老人性皮膚搔癢症、妊娠搔癢症、肛門搔癢症、外陰部搔癢症等。炎症性腸疾病可列舉例如潰瘍性大腸炎、克隆氏症等。
本發明化合物作為疼痛之預防及/或治療劑特別有用。
本發明化合物可為了下列因素而與其他藥劑組合,並作成併用劑投予:
1)補齊及/或增強該化合物的預防及/或治療效果;2)改善該化合物的動態/吸收、減低投予量;及/或3)減輕該化合物的副作用。
本發明化合物與其他藥劑的併用劑可以在1個製劑中調配兩個成分之複合劑形態投予,亦可採取製作成個別的製劑並投予的形態。製作成個別的製劑並投予時,包含同時投予及時間差投予。以時間差投予可先投予本發明化合物,再投予其他藥劑,亦可先投予其他藥劑再投予本發明化合物。各個的投予方法可相同亦可不同。
藉由上述併用劑達成預防及/或治療效果的藥劑並無特別限制,只要是將本發明化合物之預防及/或治療效果補齊及/或增強的藥劑即可。
作為用以補齊及/或增強本發明化合物對於疼痛之預防及/或治療效果之其他藥劑可列舉例如對乙醯胺基酚、非類固醇性抗炎症藥、類鴉片藥、抗憂鬱藥、抗癲癇藥、N-甲基-D-天冬胺酸拮抗藥、肌肉鬆弛藥、抗心律不整藥、類固醇藥及雙膦酸酯藥等。
非類固醇系抗炎症藥可列舉例如雙水楊酸酯(sasapyrine)、水楊酸鈉、阿斯匹林(aspirin)、阿斯匹林‧二鋁酸酯調和等阿斯匹林製劑、二氟苯水楊酸(diflunisal)、吲哚美辛(indomethacin)、舒洛芬(suprofen)、烏芬那酯(ufenamate)、二甲基異丙基薁、丁苯羥酸(bufexamac)、聯苯乙酸(felbinac)、待克菲那(diclofenac)、托美汀鈉(tolmetin sodium)、奇諾力(clinoril)、芬布芬(fenbufen)、萘丁美酮(nabumetone)、丙谷美辛(proglumetacin)、吲
哚美辛法呢酯(indomethacin farnesil)、阿西美辛(acemetacin)、馬來酸丙谷美辛、胺芬酸鈉(amfenac sodium)、莫苯唑酸(mofezolac)、依托度酸(etodolac)、布洛芬(ibuprofen)、布洛芬吡啶甲醇(ibuprofen piconol)、那普洛仙(naproxen)、氟比洛芬(flurbiprofen)、氟比洛芬酯(flurbiprofen axetil)、酮洛芬(ketoprofen)、菲諾洛芬鈣(fenoprofen calcium)、噻洛芬(tiaprofen)、奧沙普秦(oxaprozin)、普拉洛芬(pranoprofen)、洛索洛芬鈉(loxoprofen sodium)、阿明洛芬(alminoprofen)、扎托洛芬(zaltoprofen)、甲芬那酸(mefenamic acid)、甲芬那酸鋁(mefenamic acid aluminum)、托芬那酸(tolfenamic acid)、夫洛非寧(floctafenine)、酮基保泰松(ketophenylbutazone)、羥基保泰松(oxyphenbutazone)、吡羅昔康(piroxicam)、替諾昔康(tenoxicam)、安吡昔康(ampiroxicam)、聯苯乙酸(napageln)軟膏、依匹唑(epirizole)、鹽酸噻拉米特(tiaramide hydrochloride)、鹽酸替諾立定(tinoridine hydrochloride)、依莫法宗(emorfazone)、舒爾必寧(sulpyrin)、米格來寧(migrenin)、散利痛(saridon)、協德斯G(Sedes G)、阿米匹羅-N(amipylo-N)、索魯朋(sorbon)、比林(pyrine)系感冒藥、對乙醯胺基酚(acetaminophen)、非那西丁(phenacetin)、甲磺酸二甲替(dimetotiazine mesilate)、美洛昔康(meloxicam)、塞來昔布(celecoxib)、羅菲昔布(rofecoxib)、伐迪昔布(valdecoxib)、西美曲特(simetride)複合劑及非比林系感冒藥等。
類鴉片藥可列舉例如可待因(codeine)、吩坦尼(fentanyl)、氫嗎啡酮(hydromorphone)、左啡諾(levorphanol)、哌替啶(meperidine)、美沙酮(methadone)、嗎啡(morphine)、羥考酮(oxycodone)、羥嗎啡酮(oxymorphone)及丙氧芬(propoxyphene)等。
抗憂鬱藥可列舉例如三環系抗憂鬱藥(例如鹽酸阿米替林(amitriptyline HCl)、鹽酸米帕明(imipramine HCl)、鹽酸氯米帕明(clomipramine HCl)、鹽酸度硫平(dosulepin HCl)、鹽酸去甲替林(nortriptyline HCl)、鹽酸洛非帕明(lofepramine HCl)、馬來酸曲米帕明(trimipramine maleate)、阿莫沙平(amoxapine))、四環系抗憂鬱藥(例如鹽酸馬普替林(maprotiline HCl)、鹽酸米安色林(mianserin HCl)、馬來酸司普替林(setiptiline maleate))、單胺氧化酶(MAO)抑制劑(鹽酸沙夫(safrazine HCl)、血清素(serotonin)及正腎上腺素(noradrenaline)再回收抑制劑(SNRI)(例如鹽酸米那普侖(milnacipran HCl)、鹽酸文拉法辛(venlafaxine HCl)等)、選擇性血清素再回收抑制劑(SSRI)(例如馬來酸氟伏沙明(fluvoxamine maleate)、鹽酸帕羅西汀(paroxetine HCl)、鹽酸氟西汀(fluoxetine HCl)、鹽酸西酞普蘭(citalopram HCl)及血清素再回收抑制劑(例如鹽酸曲唑酮(trazodone HCl)等。
抗癲癇藥可列舉例如苯巴比妥(phenobarbital)、普利德敏(puridomin)、苯妥英(phenytoin)、乙琥胺(ethosuximide)、唑尼沙胺(zonisamide)、硝西泮(nitrazepam)、氯硝西泮(clonazepam)、卡馬西平(carbamazepine)、丙戊酸鈉(sodium valproate)、乙醯偶氮胺(acetazolamide)及磺斯安(sulthiame)等。
N-甲基-D-天冬胺酸拮抗藥可列舉例如鹽酸K他命(ketamine HCl)、鹽酸金剛烷胺(amantadine HCl)、鹽酸美金剛(memantine HCl)、右旋美沙酚(dextromethorphan)及美沙酮(methadone)等。
肌肉鬆弛藥可列舉例如琥珀醯膽鹼(succinylcholine)、
琥珀醯膽鹼鎓(suxamethonium)、維庫溴銨(vecuronium bromide)、潘庫溴銨(pancuronium bromide)及丹曲林鈉(dantrolene sodium)等。
抗心律不整藥可列舉例如普魯卡因胺(procainamide)、雙異丙吡胺(disopyramide)、西苯唑啉(cibenzoline)、吡哌醇(pirmenol)、利多卡因(lidocaine)、美西律(mexiletine)、安搏律定(aprindine)、吡西卡尼(pilsicainide)、氟卡尼(flecainide)、普羅帕酮(propafenone)、普萘洛爾(propranolol)、阿替洛爾(atenolol)、比索洛爾(bisoprolol)、胺碘酮(amiodarone)、索他洛爾(sotalol)、維拉帕米(verapamil)、迪太贊(diltiazem)及苄普地爾(bepridil)等。
類固醇藥作為外用藥可列舉例如氯倍他松丙酸酯(clobetasol propionate)、雙氟拉松乙酸酯(diflorasone acetate)、氟欣諾能(fluocinonide)、莫美他松糠酸酯(mometasone furoate)、倍他米松二丙酸酯(betamethasone dipropionate)、倍他米松丁酸丙酸酯(betamethasone butyrate propionate)、倍他米松戊酸酯(betamethasone valerate)、二氟潑尼酯(difluprednate)、布地奈德(budesonide)、二氟可托龍戊酸酯(diflucortolone valerate)、安席奈德(amcinonide)、哈西奈德(halcinonide)、地塞米松(dexamethasone)、地塞米松丙酸酯(dexamethasone propionate)、地塞米松戊酸酯(dexamethasone valerate)、地塞米松乙酸酯(dexamethasone acetate)、氫化可的松乙酸酯(hydrocortisone acetate)、氫化可的松丁酸酯(hydrocortisone butyrate)、氫化可的松丁酸丙酸酯(hydrocortisone butyrate propionate)、德普羅酮丙酸酯(deprodone propionate)、氫化潑尼松戊酸乙酸酯(prednisolone valerate acetate)、丙酮化氟席奈德(fluocinolone acetonide)、貝可米松丙酸酯(beclomethasone propionate)、
去炎松縮丙酮(triamcinolone acetonide)、氟米松三甲基乙酸酯(flumethasone pivalate)、阿氯米松丙酸酯(alclomethasone propionate)、氯倍他松丁酸酯(clobetasone butyrate)、氫化潑尼松(prednisolone)、倍氯米松丙酸酯(peclomethasone propionate)及氟氫縮松(fludroxycortide)等。
作為內服藥或注射藥可列舉可的松乙酸酯(cortisone acetate)、氫化可的松(hydrocortisone)、氫化可的松磷酸鈉(hydrocortisone sodium phosphate)、氫化可的松琥珀酸鈉(hydrocortisone sodium succinate)、氟氫可的松乙酸酯(fludrocortisone acetate)、氫化潑尼松(prednisolone)、氫化潑尼松乙酸酯(prednisolone acetate)、氫化潑尼松琥珀酸鈉(prednisolone sodium succinate)、氫化潑尼松丁基乙酸酯(prednisolone butyl acetate)、氫化潑尼松磷酸鈉(prednisolone sodium phosphate)、鹵潑尼松乙酸酯(halopredone acetate)、甲基氫化潑尼松(methylprednisolone)、甲基氫化潑尼松乙酸酯(methylprednisolone acetate)、甲基氫化潑尼松琥珀酸鈉(methylprednisolone sodium succinate)、去炎松(triamcinolone)、去炎松乙酸酯(triamcinolone acetate)、去炎松縮丙酮(triamcinolone acetonide)、地塞米松(dexamethasone)、地塞米松乙酸酯(dexamethasone acetate)、地塞米松磷酸鈉(dexamethasone sodium phosphate)、地塞米松棕櫚酸酯(dexamethasone palmitate)、對氟米松乙酸酯(paramethasone acetate)及倍他米松(betamethasone)等。
作為吸入藥可列舉倍氯米松丙酸酯(beclomethasone propionate)、氟替卡松丙酸酯(fluticasone propionate)、布地奈德(budesonide)、氟尼縮松(flunisolide)、去炎松(triamcinolone)、
ST-126P、環索奈德(ciclesonide)、地塞米松棕櫚酸酯(dexamethasone palmitate)、莫美他松糠酸酯(mometasone furoate)、磺酸普拉睪酮(prasterone sulfonate)、地夫可特(deflazacort)、磺庚甲基氫化潑尼松(methylprednisolone suleptanate)及甲基氫化潑尼松琥珀酸鈉等。
雙膦酸酯藥可列舉例如依替膦酸酯(etidronate)、帕米磷酸酯(pamidronate)、阿侖膦酸酯(alendronate)、利塞膦酸酯(risedronate)、唑來磷酸酯(zoledronate)及米諾磷酸酯(minodronate)等。
本發明化合物與其他藥劑之質量比並無特別限制。
亦可將任意2種以上之其他藥劑組合投予。
又,補齊及/或增強本發明化合物的預防及/或治療效果之其他藥劑係根據上述機制為基礎,不僅包含至今所發現者,亦包含今後發現者。
以上述之目的使用本發明化合物或本發明化合物與其他藥劑之併用劑,通常與藥學上容許之擔體一同作成適當之醫藥組成物製劑化,以全身性或局部性、經口或非經口之形態投予。
投予量依年齡、體重、症狀、治療效果、投予方法、處理時間等而異,通常係成人每人每次以1mg至1000mg之範圍,且一日一次至數次經口投予,或者成人每人每次以0.1mg至100mg之範圍,且一日一次至數次非經口投予,或一日以1小時至24小時之範圍靜脈內持續投予。
當然,如上所述,由於投予量依種種條件而改變,有比上述投予量少之量即足夠的情況,亦有需要投予超過範圍量的情況。
投予本發明之化合物或本發明化合物與其他藥劑的併用劑時,可作為經口投予用之內服用固形劑、內服用液劑及非經口投予用之注射劑、外用劑、栓劑、點眼劑、吸入劑等使用。
經口投予用之內服用固形劑包含錠劑、丸劑、膠囊劑、散劑、顆粒劑等。膠囊劑包含硬膠囊及軟膠囊。又,錠劑包含舌下錠、口腔內貼附錠、口腔內速崩解錠等。
於該等內服用固形劑中,一種或一種以上之活性物質可維持原狀,或可與賦形劑(乳糖、甘露糖醇、葡萄糖、微結晶纖維素、澱粉等)、黏合劑(羥丙基纖維素、聚乙烯吡咯啶酮、矽酸鋁酸鎂等)、崩解劑(纖維素乙醇酸鈣等)、潤滑劑(硬脂酸鎂等)、安定劑、溶解輔助劑(谷胺酸、天冬胺酸等)等混合,根據常法製劑化並使用。又,可依需要以包覆劑(白糖、明膠、羥丙基纖維素、羥丙基甲基纖維素鄰苯二甲酸酯等)包覆,亦可包覆2層以上。另,亦包含如明膠之可被吸收物質之膠囊。
經口投予用的內服用液劑包含藥劑上容許的水劑、懸浮劑、乳劑、糖漿劑、酏劑等。於該等液劑中,一種或一種以上之活性物質係溶解、懸浮或乳化於通常使用之稀釋劑(精製水、乙醇或該等之混合液等)。另,該液劑亦可含有濕潤劑、懸浮化劑、乳化劑、甜味劑、風味劑、芳香劑、保存劑、緩衝劑等。
非經口投予用之外用劑之劑型包含例如軟膏劑、凝膠劑、乳膏劑、濕布劑、貼布劑、塗敷劑、噴霧劑、吸入劑、噴劑(spray)、霧劑(aerosol)、點眼劑及點鼻劑等。該等含有一種或一種以上之活性物質,且根據公知之方法或通常使用之處方調製。
噴霧劑、吸入劑及噴劑除了通常使用之稀釋劑以
外,亦可含有如亞硫酸氫鈉之安定劑及賦予等張性之緩衝劑,例如如氯化鈉、檸檬酸鈉或檸檬酸之等張劑。噴劑之製造方法詳細記載於例如美國專利第2,868,691號及美國專利第3,095,355號中。
作為非經口投予用之注射劑係包含溶解或懸浮於溶液、懸浮液、乳濁液及用時溶劑中使用之固體注射劑。注射劑為將一種或一種以上之活性物質溶解、懸浮或乳化於溶劑中使用。溶劑可使用例如注射用蒸餾水、生理食鹽水、植物油;如丙二醇、聚乙二醇、乙醇之醇類等及該等之組合。另,該注射劑亦可含有安定劑、溶解輔助劑(谷膠酸、天冬胺酸、聚山梨醇酯80(註冊商標)等)、懸浮化劑、乳化劑、無痛化劑、緩衝劑、保存劑等。該等係於最後步驟進行滅菌或藉由無菌操作法製造。又,可製造無菌之固體劑,例如凍結乾燥品,並在使用前溶解於無菌化或無菌之注射用蒸餾水或其他溶劑使用。
作為非經口投予用之其他組成物包含含有一種或一種以上之活性物質,藉由常法處方之直腸投予用之栓劑及陰道內投予用之子宮帽托等。
於本發明中,「製品」至少包含一種(1)含有本發明化合物而成之醫藥組成物或含有本發明化合物與其他藥劑之併用劑而成之複合劑形態之醫藥組成物、(2)含有上述組成物之容器、(3)揭示上述之組成物可依需要與適當之併用劑(較好為對乙醯胺基酚、非類固醇性抗炎症藥、類鴉片藥、抗憂鬱藥、抗癲癇藥、N-甲基-D-天冬胺酸拮抗藥、肌肉鬆弛藥、抗心律不整藥、類固醇藥及/或雙膦酸酯藥等)組合,用於預防及/或治療Trk關連疾病之主旨之指示書、說明書、附加文件或製品標籤(包含於美國之標籤
或相當於貼標籤者)等。
此處,附加文件相當於日本藥事法之「附加文件」(亦稱為說明書)、於歐洲聯盟(EU)稱為指令之「製品情報概要(Summary of Product Characteristics:SPC or SmPC)」、於美國稱為聯邦規則之「美國附加文件(US Package Insert:USPI)」或於其他國家相當於該等文件之記載醫藥品正當使用必需事項且附加於醫藥品之公文文件。
對於該等文件中記載之事項,例如只要是日本之附加文件,於藥事法第52條、第54條及第68條之4等(依需要參照平成9年4月25日之藥發第606號、607號及/或相關通知等)、只要是歐洲聯盟之製品情報概要,於Directive 2001/83/EC Article 11等(依需要參照A guideline on SmPC及/或相關之指南等)、只要是美國之美國附加文件,於21 CFR 201.100等(依需要參照21 CFR 201.57及/或相關之聯邦規則等)中有詳細之規定,通常,包含適應症、用法、用量、投予方法、警告及/或禁忌等之情報。
又,於美國中,除了上述美國附加文件之外,作為標籤(Label)或貼標籤(Labeling or Labelling),依21 CFR 201 Subpart B中之規定而記載美國附加文件中所記載之內容之一部分或全部。此處,標籤為直接表示於容器上者,貼標籤為除了標籤之外還包含在包裝上之印刷或隨著製品附隨之印刷物等之概念。
於本發明中,「容器」為直接內包含有本發明化合物而成之醫藥組成物或含有本發明化合物與其他藥劑之併用劑而成之複合劑形態之醫藥組成物者,亦有稱為「直接容器(immediate container)」、「直接包膜(immediate wrapper)」或「內封袋(inner seals)」
等。容器包含例如罐、瓶、箱、安瓿、小瓶(vial)、管、點眼劑用單劑量容器、紙、布、乙烯樹脂袋、塑膠袋、SP片、PTP片、塑膠容器等。
內包醫藥組成物之容器係如上所述,以組合指示書、說明書、附加文件或製品標籤(包含相當於美國之標籤或貼標籤)等之至少一種之狀態,通常藉由外部之容器(outer container)或外部之包膜(outer wrapper)包裝,於市場流通。
又,本發明亦揭示一種含有本發明化合物而成之醫藥組成物或含有本發明化合物與其他藥劑之併用劑而成之複合劑形態之醫藥組成物之廣告方法,其係包含促使作為對象之視聽者使用上述組成物來預防及/或治療Trk關連疾病之方法。
於上述方法中,將敍述在預防及/或治療Trk關連疾病時,使用含有本發明化合物而成之醫藥組成物或含有本發明化合物與其他藥劑之併用劑而成之複合劑型態之醫藥組成物之有用性,尤其在健康方面之優點之情報公開發行(public distribution)。相關情報之發布除了藉由言語通訊之外,亦藉由適當之廣告媒體進行。此處,廣告媒體可任意使用報紙、雜誌、電視、收音機、錄影帶、小冊子、傳單、海報、社交網站、工作系統、電子郵件、電子看板、數位電子看板、網站廣告(網站首頁/網站、橫幅廣告等)、屋外廣告(廣告板、霓虹燈、大型映象裝置等)、交通廣告(電車/巴士/計程車等之掛式海報、窗上廣告、額面廣告、車站廣告等)、影片/幻燈片廣告(電影院之銀幕廣告等)、POP廣告(店頭廣告、店內廣告等)、直接廣告(直接郵寄(DM)、夾報傳單、傳單廣告等)、特殊廣告(日曆或原子筆等之新奇廣告等)、其他之廣告(空
中文字、板凳廣告等)等。只要是該業者,可容易地製造該等廣告媒體。
除非特別定義,本說明書中使用之所有技術、科學用語及簡稱與在本發明領域之業者通常理解者同意義。
本專利申請以於2013年2月19日提出專利申請之日本出願第2013-029563號及於2013年7月5日提出專利申請之日本出願第2013-141246號為基礎,主張優先權,援用該日本專利申請中記載之所有記載內容。
又,於本說明書中,明白指示引用之所有專利文獻及非專利文獻或參考文獻之內容可作為本說明書之一部分於此引用。
以下,根據實施例對本發明作詳細的敍述,惟,本發明不只限於該等例。
在經由層析分離之部份及TLC中所表示之括弧內的溶劑表示使用之溶出溶劑或展開溶劑,比率表示體積比。
在NMR的部份所表示之括弧內之溶劑表示測定時使用之溶劑。
LC-MS/ELSD係以下述條件實施:(管柱:Waters ACQUITY C18(粒徑:1.7 x 10-6m;管柱長:30 x 2.1mm I.D.);流速:1.0mL/分鐘;管柱溫度:40℃;移動相(A):0.1%三氟乙酸水溶液;移動相(B):0.1%三氟乙酸-乙腈溶液;梯度(記載移動相(A):移動相(B)之比率):[0分鐘]95:5;[0.1分鐘]95:5;[1.2分鐘]5:95;[1.4分鐘]5:95;[1.41分鐘]95:5;[1.5分鐘]95:
5;檢測器:UV(PDA)、ELSD、MS。
本說明書中使用之化合物名稱通常使用以IUPAC之規則為基準進行命名之電腦程式ACD/Name(註冊商標)、或Chemdraw Ultra(版本12.0、Cambridge Soft公司製造)或是以IUPAC命名法為基準命名者。
實施例1:1-(2-硝基-4-(三氟甲基)苯基)-1H-吡唑
於1H-吡唑(0.39g)之二甲亞碸(以下,簡稱為DMSO)(5.2mL)溶液中加入第三丁醇鉀(0.7g)。將反應混合物於室溫攪拌40分鐘。逐次少量加入1-氟-2-硝基-4-(三氟甲基)苯(1.1g),另將反應混合物攪拌90分鐘。於反應混合物中注入飽和氯化銨水溶液,以乙酸乙酯萃取。獲得之有機層以水、飽和食鹽水洗淨,以硫酸鎂乾燥後減壓濃縮。將獲得之殘渣以矽膠管柱層析(己烷:乙酸乙酯=10:1→2:1)精製,獲得具有以下物性值之標題化合物(0.43g)。
TLC:Rf 0.43(己烷:乙酸乙酯=3:1);1H-NMR(DMSO-d6):δ 6.61-6.64(m,1H),7.82(d,1H),8.07(d,1H),8.20(dd,1H),8.45-8.49(m,2H)。
實施例2:2-(1H-吡唑-1-基)-5-(三氟甲基)苯胺
於實施例1製造之化合物(430mg)之甲醇(16mL)溶液中加入鈀-碳(5%wet,380mg)。將該反應混合物作成在氫氣環境下,於室溫攪拌6小時。反應混合物以矽藻土(商品名)過濾後將濾液濃縮,獲得具有以下物性值之標題化合物(357mg)。
TLC:Rf 0.56(己烷:乙酸乙酯=3:1);1H-NMR(DMSO-d6):δ 6.10(s,2H),6.52-6.56(m,1H),6.92(dd,1H),7.19(d,1H),7.45(d,1H),7.79(d,1H),8.21(d,1H)。
實施例3:(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)胺基甲酸2,2,2-三氯乙酯
於實施例2製造之化合物(356mg)之乙酸乙酯(8mL)溶液中加入碳酸氫鈉(400mg)及氯甲酸2,2,2-三氯乙酯(430mg)。將反應混合物於室溫攪拌150分鐘。於反應混合物中加入水,以乙酸乙酯萃取。獲得之有機層以硫酸鎂乾燥後減壓濃縮。將獲得之殘渣經由矽膠管柱層析(己烷:乙酸乙酯=10:1→2:1)精製,獲得具有以下物性值之標題化合物(610mg)。
TLC:Rf 0.60(己烷:乙酸乙酯=3:1);1H-NMR(DMSO-d6):δ 4.93(s,2H),6.63-6.66(m,1H),7.66(dd,1H),7.88(d,1H),7.94(d,1H),8.29(s,1H),8.42(d,1H),10.6(s,1H)。
實施例4:5-硝基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)嘧啶
於4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(10g)之四氫呋喃(以下,簡稱為THF)(91mL)溶液中加入三乙
胺(7mL)及2-氯-5-硝基嘧啶(7.6g)。將反應混合物於0℃攪拌1小時。將反應混合物以乙酸乙酯稀釋,將反應混合物以飽和碳酸氫鈉水溶液、水及飽和食鹽水洗淨。獲得之有機層以硫酸鈉乾燥後減壓濃縮,獲得具有以下物性值之標題化合物(17g)。
TLC:Rf 0.45(己烷:乙酸乙酯=4:1);1H-NMR(CDCL3):δ 1.35(s,12H),7.20(d,2H),7.93(d,2H),9.31(s,2H)。
實施例5:2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)嘧啶-5-胺
於實施例4製造之化合物(17g)之乙醇(187mL)及乙酸乙酯(94mL)混合溶液中加入氫氧化鈀(20%wet、1.56g)。將反應混合物於氫氣環境下,於35℃攪拌4小時。於反應混合物中加入甲醇(90mL)及活性碳(0.32g),於室溫攪拌5分鐘。將反應混合物以矽藻土(商品名)過濾後將濾液濃縮。於獲得之殘渣中加入第三丁基甲醚/己烷之1:1混合溶劑,濾取析出之固體,獲得具有以下物性值之標題化合物(12.8g)。
TLC:Rf 0.29(己烷:乙酸乙酯=1:1);1H-NMR(CDCL3):δ 1.33(s,12H),3.51(br s,2H),7.14(d,2H),7.85(d,2H),8.06(s,2H)。
實施例6:2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-
胺
於實施例5製造之化合物(1g)之2-丙醇(6.4mL)及1,2-二甲氧基乙烷(1.6mL)之混合溶液中加入3-溴-5-氯吡啶-2-胺(662mg)、磷酸鉀水溶液(2M、3.2mL)及雙(三苯基膦)二氯化鈀(112mg)。將反應混合物於氬氣環境下,於85℃攪拌2小時。將反應混合物冷卻至室溫後以乙酸乙酯稀釋,以水洗淨。將獲得之有機層以鹽酸(0.5M、120mL)逆萃取。將獲得之水層以飽和碳酸鈉水溶液中和,以乙酸乙酯萃取。將獲得之有機層以飽和食鹽水洗淨,以硫酸鈉乾燥後過濾。將獲得之有機層濃縮至約100mL。經濃縮之溶液以管柱層析(富士矽(Fuji Silysia)Chromatorex NH DM1020(商品名)、乙酸乙酯)精製,獲得具有以下物性值之標題化合物(857mg)。
TLC:Rf 0.32(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 5.28(br s,2H),5.82(br s,2H),7.14(d,2H),7.39(d,1H),7.45(d,2H),7.94(d,1H),7.99(s,2H)。
實施例7:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)脲
於實施例6製造之化合物(400mg)及實施例3製造之化合物(513mg)之N,N-二甲基乙醯胺(以下,簡稱為DMA)(2.6mL)溶液中加入三乙胺(0.018mL)。於氬氣環境下將反應混合物於65℃攪拌21小時。將反應混合物冷卻至室溫後以乙酸乙酯稀釋。將獲得之有機層以水洗淨3次及以飽和食鹽水洗淨1次。將獲得之有機層以硫酸鈉乾燥,過濾後濃縮。獲得之殘渣以矽膠管柱層析(二氯甲烷:乙酸乙酯=2:1)精製,獲得具有以下物性值之本發明化合物(465mg)。
TLC:Rf 0.29(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 5.86(br s,2H),6.68(dd,1H),7.27(d,2H),7.42(d,1H),7.46-7.56(m,3H),7.75(d,1H),7.92-7.99(m,2H),8.41(d,1H),8.58(d,1H),8.70(s,2H),9.71(br s,1H),9.97(br s,1H)。
實施例8
使用相當之胺基甲酸酯化合物或異氰酸酯化合物替代實施例3製造之化合物,進行與實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例8-1:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(4-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.21(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 2.38(s,3H),5.85(s,2H),7.26(d,2H),7,41(d,1H),7.50(d,2H),7.58(dd,1H),7.69(d,1H),7.94(d,1H),8.39(s,1H),8.58-8.61(m,1H),8.68(s,2H),8.76(s,1H),9.69(s,1H)。
實施例8-2:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(5-(三氟甲基)-2-(3-(三氟甲基)-1H-吡唑-1-基)苯基)脲
TLC:Rf 0.80(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.12(d,1H),7.26(s,2H),7.42(s,1H),7.51(d,2H),7.58(dd,1H),7.71(d,1H),7.95(d,1H),8.47(s,2H),8.59(s,1H),8.67(s,2H),9.48(s,1H)。
實施例8-3:1-(2-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.69(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.84(s,2H),7.26(d,2H),7.41(d,1H),7.51(d,2H),7.61(dd,1H),7.74(d,1H),7.95(d,1H),8.09(d,1H),8.57(s,1H),8.67(s,3H),8.71(s,1H),9.65(s,1H)。
實施例8-4:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶
-5-基)-3-(2-氯-5-(三氟甲基)苯基)脲
TLC:Rf 0.52(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.26(d,2H),7.41(d,1H),7.51(d,2H),7.68(dd,1H),7.86-7.89(m,1H),7.94(d,1H),8.42(s,1H),8.74(s,2H),8.79(s,1H),9.76(s,1H)。
實施例8-5:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(5-(三氟甲基)-2-(4-三氟甲基)-1H-吡唑-1-基)苯基)脲
TLC:Rf 0.36(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.26(d,2H),7.42(d,1H),7.50(d,2H),7.56(dd,1H),7.76(d,1H),7.95(d,1H),8.38(s,1H),8.54-8.59(m,1H),8.69(s,2H),8.98(d,2H),9.75(s,1H)。
實施例8-6:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(3-(二氟甲基)-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.27(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),6.90-6.96(m,1H),7.14(t,1H),7.26(d,2H),7.41(d,1H),7.50(d,2H),7.53-7.59(m,1H),7.72(d,1H),7.95(d,1H),8.41-8.46(m,1H),8.53(s,1H),8.68(s,2H),8.95(s,1H),9.66(s,1H)。
實施例8-7:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(5-(三氟甲基)-2-(3-(三氟甲基)-1H-1,2,4-三唑-1-基)苯基)
脲
TLC:Rf 0.62(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.26(d,2H),7.42(d,1H),7.50(d,2H),7.63(dd,1H),7.81(d,1H),7.95(d,1H),8.47-8.50(m,1H),8.65(s,1H),8.66(s,2H),9.24(s,1H),9.33(s,1H)。
實施例8-8:1-(2-(3-乙醯基-1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.34(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 2.58(s,3H),5.85(s,2H),7.05(d,1H),7.26(d,2H),7.42(d,1H),7.50(d,2H),7.57(dd,1H),7.74(d,1H),7.95(d,1H),8.39(d,1H),8.63(s,1H),8.68(s,2H),8.74(s,1H),9.63(s,1H)。
實施例8-9:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(3-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.50(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 2.37(s,3H),5.85(s,2H),6.45(d,1H),7.27(d,2H),7.43(d,1H),7.47-7.54(m,3H),7.70(d,1H),7.95(d,1H),8.28(d,1H),8.57(s,1H),8.70(s,2H),9.81(s,1H),9.92(s,1H)。
實施例8-10:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.47(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 7.27-7.34(m,3H),7.42-7.53(m,4H),7.61-7.66(m,1H),7.88-7.92(m,2H),8.73(s,2H)。
實施例8-11:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氟-5-(三氟甲基)苯基)脲
TLC:Rf 0.50(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.26(d,2H),7.38-7.55(m,5H),7.95(d,1H),8.51-8.55(m,1H),8.74(s,2H),9.09(s,1H),9.30(s,1H)。
實施例8-12:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(4-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.55(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 2.15(s,3H),5.85(s,2H),7.26(d,2H),7.42(d,1H),7.49-7.52(m,3H),7.69(d,1H),7.78(s,1H),7.95(d,1H),8.18(d,1H),8.57(d,1H),8.70(d,2H),9.83(s,1H),9.97(s,1H)。
實施例8-13:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(5-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.63(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.19(s,3H),5.84(d,2H),7.26(d,2H),7.42(d,2H),7.50(d,2H),7.61(d,1H),7.84(s,1H),7.94(d,1H),8.29(s,1H),8.64(s,1H),8.66(s,2H),9.45(s,1H)。
實施例8-14:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-甲基-5-(三氟甲基)苯基)脲
TLC:Rf 0.30(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 2.32(s,3H),5.85(s,2H),7.28(d,2H),7.31(d,1H),7.39-7.44(m,2H),7.51(d,2H),7.95(d,1H),8.27(s,1H),8.38(s,1H),8.75(s,2H),9.34(s,1H)。
實施例8-15:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(3-(1-羥乙基)-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.19(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 1.44(d,3H),4.92(quint.,1H),5.23(d,1H),5.85(s,2H),6.58(d,1H),7.26(d,2H),7.42(d,1H),7.47-7.54(m,3H),7.72(d,1H),7.95(d,1H),8.28-8.31(m,1H),8.50(d,1H),8.69(s,2H),9.69(s,1H),9.85(s,1H)。
實施例8-16:1-(2-(1H-1,2,4-三唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.46(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.26(d,2H),7.42(d,1H),7.50(d,2H),7.59(d,1H),7.77(d,1H),7.95(d,1H),8.42(s,1H),8.56(s,1H),8.68(s,2H),8.79(s,1H),9.09(s,1H),9.66(s,1H)。
實施例8-17:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(4-甲基-3-(三氟甲基)苯基)脲
TLC:Rf 0.80(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.36(d,3H),5.85(s,2H),7.26(dd,2H),7.34(d,1H),7.42(d,1H),7.51(dd,2H),7.57(d,1H),7.89(d,1H),7.96
(d,1H),8.72(s,2H),8.92(s,1H),9.18(s,1H)。
實施例8-18:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-氟-5-(三氟甲基)苯基)脲
TLC:Rf 0.26(乙酸乙酯:己烷=1:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.26(d,1H),7.27(dd,2H),7.43(d,1H),7.51(dd,2H),7.53-7.65(m,2H),7.70(s,1H),7.95(d,1H),8.73(s,2H),9.11(s,1H),9.52(s,1H)。
實施例8-19:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(4-氯-3-(三氟甲基)苯基)脲
TLC:Rf 0.53(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.25(dd,2H),7.42(dd,1H),7.51(d,2H),7.61(d,1H),7.70(d,1H),7.95(dd,1H),8.06(s,1H),8.72(s,2H),9.04(s,1H),9.44(s,1H)。
實施例8-20:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(5-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.39(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 2.20(s,3H),5.84(s,2H),6.40(s,1H),7.26(d,2H),7.41(d,1H),7.52(d,2H),7.53(d,1H),7.55(d,1H),7.75(d,1H),7.94(d,1H),8.40(s,1H),8.61(s,1H),8.67(s,2H),9.73(s,1H)。
實施例8-21:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.28(己烷:乙酸乙酯=1:2);
1H-NMR(DMSO-d6):δ 2.19(s,3H),5.85(s,2H),6.88(s,1H),7.26(d,2H),7.38-7.43(m,1H),7.46-7.63(m,4H),7.92-7.97(m,1H),8.31(s,1H),8.61(s,1H),8.67(s,2H),9.38(s,1H)。
實施例8-22:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-氯-5-(三氟甲基)苯基)脲
TLC:Rf 0.80(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.86(s,2H),7.27(d,2H),7.43(s,2H),7.51(d,2H),7.84(s,2H),7.95(d,1H),8.73(s,2H),9.15(s,1H),9.51(s,1H)。
實施例9
使用3-溴-5-氯吡啶-2-胺,或者使用3-溴-5-氟吡啶-2-胺替代3-溴-5-氯吡啶-2-胺,使用2-氯-5-硝基吡啶替代2-氯-5-硝基嘧啶,使用實施例3製造之化合物,或者使用相當之胺基甲酸酯化合物替代實施例3製造之化合物,進行與實施例4→實施例5→實施例6→實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例9-1:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基-3-(6-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)吡啶-3-基)脲
TLC:Rf 0.62(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 5.85(s,2H),6.67(t,1H),7.04(d,1H),7.15(d,2H),7.39(d,1H),7.45-7.51(m,3H),7.72(d,1H),7.93-7.94(m,
2H),8.00(dd,1H),8.19(d,1H),8.39(d,1H),8.58(d,1H),9.56(s,1H),9.82(s,1H)。
實施例9-2:1-(2-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基-3-(6-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)吡啶-3-基)脲
TLC:Rf 0.69(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.84(s,2H),7.04(d,1H),7.16(d,2H),7.39(d,1H),7.47(d,2H),7.59(d,1H),7.72(d,1H),7.94(d,1H),7.99(dd,1H),8.10(d,1H),8.15(d,1H),8.59-8.61(m,2H),8.68(s,1H),9.57(s,1H)。
實施例9-3:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基-3-(6-(4-(2-胺基-5-氟H啶-3-基)苯氧基)吡啶-3-基)脲
TLC:Rf 0.27(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 5.55(s,2H),6.67(t,1H),7.04(d,1H),7.16(d,2H),7.34(dd,1H),7.47-7.50(m,3H),7.72(d,1H),7.91-7.94(m,2H),8.01(dd,1H),8.19(d,1H),8.39(d,1H),8.59(d,1H),9.55(s,1H),9.82(s,1H)。
實施例10:2-(吡啶-3-基)-5-(三氟甲基)苯胺
於2-溴-5-(三氟甲基)苯胺(10g)與吡啶-3-基硼酸(5.63g)之乙腈(20mL)溶液中加入水(10mL)、碳酸鈉(14.57g)及雙(三苯基膦)二氯化鈀(II)(1.46g)。在氬氣環境下將反應混合物於100℃攪拌14小時。將反應混合物冷卻至室溫後以乙酸乙酯萃取。將有機層以硫酸鎂乾燥後減壓濃縮。獲得之殘渣以矽膠管柱層析(己烷:乙酸乙酯=1:0→0:1)精製,以己烷洗淨後乾燥,獲得具有以下物性值之標題化合物(7.62g)。
TLC:Rf 0.56(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 5.40(s,2H),6.90(d,1H),7.08(s,1H),7.18(d,1H),7.48(dd,1H),7.85(d,1H),8.57(d,1H),8.60(d,1H)。
實施例11:1-(6-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)吡啶-3-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
使用2-氯-5-硝基吡啶替代2-氯-5-硝基嘧啶,使用實施例10製造之化合物替代實施例2製造之化合物,進行與實施例3→實施例4→實施例5→實施例6→實施例7相同之操作,獲得具有以下物性值之本發明化合物。
TLC:Rf 0.43(乙酸乙酯);
1H-NMR(DMSO-d6):δ 5.80(s,2H),7.04(d,1H),7.16(s,2H),7.41(d,1H),7.47(s,1H),7.50(s,2H),7.54-7.61(m,2H),7.90(dt,1H),7.91(d,1H),7.99(s,1H),8.11-8.15(m,2H),8.43(s,1H),8.64-8.71(m,2H),9.20(s,1H)。
實施例12:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
使用實施例10製造之化合物替代實施例2製造之化合物,進行與實施例3→實施例7相同之操作,獲得具有以下物性值之本發明化合物。
TLC:Rf 0.60(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 5.84(s,2H),7.25(d,2H),7.41(d,1H),7.48-7.58(m,5H),7.89(dd,1H),7.94(d,1H),8.23(s,1H),8.38(s,1H),8.65-8.68(m,4H),9.23(s,1H)。
實施例13
使用相當之硼酸化合物或硼酸酯化合物替代3-吡啶硼酸,進行與實施例10→實施例3→實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例13-1:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.60(乙酸乙酯);1H-NMR(DMSO-d6):δ 3.65(s,3H),5.85(s,2H),6.46(s,1H),7.27(d,2H),7.42(d,1H),7.50-7.52(m,4H),7.62(s,1H),7.95(d,1H),8.09(s,1H),8.56(s,1H),8.68(s,2H),9.49(s,1H)。
實施例13-2:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(1-甲基-1H-吡唑-4-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.40(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 3.92(s,3H),5.85(s,2H),7.25-7.27(m,2H),7.39-7.42(m,2H),7.49-7.51(m,3H),7.76(s,1H),7.95(d,1H),8.10(s,1H),8.24-8.27(m,2H),8.71(s,2H),9.41(s,1H)。
實施例13-3:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.78(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 3.73(s,3H),5.85(s,2H),6.96(s,1H),7.26(d,2H),7.42(d,1H),7.51(d,2H),7.53(d,1H),7.58(d,1H),7.95(d,1H),8.28(s,1H),8.53(s,1H),8.68(s,2H),9.32(s,1H)。
實施例13-4:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(1-甲基-1H-吡唑-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.48(乙酸乙酯);1H-NMR(DMSO-d6):δ 4.03(s,3H),8.57(s,2H),6.92(d,1H),7.28(d,2H),7.39(d,1H),7.43(d,1H),7.52(d,2H),7.94(dd,3H),8.65(s,1H),8.74(s,2H),9.93(s,1H),10.77(s,1H)。
實施例14
使用3-溴-5-氟吡啶-2-胺替代3-溴-5-氯吡啶-2-胺,使用實施例3,或者使用相當之胺基甲酸酯化合物或異氰酸酯化合物替代實施例3,進行與實施例6→實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例14-1:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氟-5-(三氟甲基)苯基)脲
TLC:Rf 0.65(己烷:乙酸乙酯=1:9);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.28(d,2H),7.35-7.54(m,5H),7.93(d,1H),8.51-8.53(m,1H),8.74(s,2H),9.09(s,1H),9.29(s,1H)。
實施例14-2:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.16(乙酸乙酯:己烷=1:1);
1H-NMR(DMSO-d6):δ 5.56(s,2H),7.27(d,2H),7.33(d,1H),7.38(dd,1H),7.51(d,1H),7.53(dd,2H),7.60(d,1H),7.94(d,1H),7.97(s,1H),8.73(s,2H),8.98(s,1H),9.431(s,1H)。
實施例14-3:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(5-(三氟甲基)-2-(3-(三氟甲基)-1H-吡唑-1-基)苯基)脲
TLC:Rf 0.74(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.12(d,1H),7.27(d,2H),7.37(dd,1H),7.53(d,2H),7.59(dd,1H),7.71(d,1H),7.94(d,1H),8.47(s,2H),8.58(s,1H),8.67(s,2H),9.48(s,1H)。
實施例14-4:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.49(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),6.68(s,1H),7.27(d,2H),7.38(dd,1H),7.53(d,3H),7.75(d,1H),7.92-7.98(m,2H),8.41(s,1H),8.58(s,1H),8.70(s,2H),9.70(s,1H),9.96(s,1H)。
實施例14-5:1-(2-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.69(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.55(s,2H),7.27(d,2H),7.37(dd,1H),7.52(d,2H),7.61(d,1H),7.74(d,1H),7.93(d,1H),8.09(s,1H),8.57(s,1H),8.67(s,3H),8.71(s,1H),9.65(s,1H)。
實施例14-6:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.62(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 5.55(s,2H),7.25(d,2H),7.36(dd,1H),7.48-7.58(m,5H),7.89(dd,1H),7.93(d,1H),8.24(s,1H),8.38(s,1H),8.64-8.68(m,4H),9.23(s,1H)。
實施例14-7:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(4-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.33(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 2.38(s,3H),5.56(s,2H),7.26(d,2H),7.36(dd,1H),7.52(dd,2H),7.60(d,1H),7.69(d,1H),7.94(d,1H),8.34(s,1H),8.59(d,1H),8.68(d,2H),8.76(s,1H),9.69(s,1H)。
實施例14-8:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶
-5-基)-3-(2-(1-甲基-1H-吡唑-4-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.31(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 3.92(s,3H),5.56(s,2H),7.27(d,2H),7.35-7.42(m,2H),7.51-7.55(m,3H),7.76(s,1H),7.93(d,1H),8.10(s,1H),8.24(s,1H),8.28(s,1H),8.71(s,2H),9.42(s,1H)。
實施例14-9:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.50(乙酸乙酯);1H-NMR(DMSO-d6):δ 3.65(s,3H),5.56(s,2H),6.45(s,1H),7.27(d,2H),7.37(dd,1H),7.49-7.54(m,4H),7.62(s,1H),7.94(d,1H),8.09(s,1H),8.56(s,1H),8.68(s,2H),9.49(s,1H)。
實施例14-10:1-(2-(1H-1,2,4-三唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.44(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.27(d,2H),7.36(dd,1H),7.51(d,2H),7.57(d,1H),7.77(d,1H),7.93(d,1H),8.41(s,1H),8.56(d,1H),8.68(s,2H),8.78(s,1H),9.09(s,1H),9.66(s,1H)。
實施例14-11:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-甲基-5-(三氟甲基)苯基)脲
TLC:Rf 0.38(乙酸乙酯:己烷=2:1);
1H-NMR(DMSO-d6):δ 2.32(s,3H),5.56(s,2H),7.25-7.46(m,5H),7.54(d,2H),7.94(d,1H),8.27(s,1H),8.38(s,1H),8.75(s,2H),9.33(s,1H)。
實施例14-12:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氯-5-(三氟甲基)苯基)脲
TLC:Rf 0.71(己烷:乙酸乙酯=1:9);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.28(d,2H),7.36-7.41(m,2H),7.53(d,2H),7.72(d,1H),7.93(d,1H),8.56(s,1H),8.74(s,2H),8.78(s,1H),9.71(s,1H)。
實施例14-13:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(4-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.50(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 2.15(s,3H),5.56(s,2H),7.26(d,2H),7.36(dd,1H),7.47-7.55(m,3H),7.70(d,1H),7.78(s,1H),7.93(d,1H),8.18(s,1H),8.57(d,1H),8.70(s,2H),9.83(s,1H),9.96(s,1H)。
實施例14-14:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(5-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.63(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.20(s,3H),5.55(s,2H),7.27(d,2H),7.37(dd,1H),7.53(d,2H),7.62(d,2H),7.84(s,1H),7.94(d,1H),8.30(s,1H),8.65(s,1H),8.67(s,2H),9.46(s,1H)。
實施例14-15:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(4-甲基-3-(三氟甲基)苯基)脲
TLC:Rf 0.43(己烷:乙酸乙酯=1:4);
1H-NMR(DMSO-d6):δ 2.36(s,3H),5.57(s,2H),7.27(d,2H),7.30-7.42(m,2H),7.50-7.60(m,3H),7.89(s,1H),7.94(d,1H),8.72(s,2H),8.92(s,1H),9.18(s,1H)。
實施例14-16:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(3-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.45(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 2.37(s,3H),5.56(s,2H),6.45(s,1H),7.28(d,2H),7.38(dd,1H),7.48-7.60(m,1H),7.53(d,2H),7.70(d,1H),7.94(d,1H),8.28(d,1H),8.57(s,1H),8.70(s,2H),9.81(s,1H),9.92(s,1H)。
實施例14-17:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-氟-5-(三氟甲基)苯基)脲
TLC:Rf 0.20(乙酸乙酯:己烷=1:1);1H-NMR(DMSO-d6):δ 5.57(s,2H),7.22-7.33(m,3H),7.38(dd,1H),7.53(d,2H),7.62(d,1H),7.72(s,1H),7.94(d,1H),8.73(s,2H),9.11(s,1H),9.52(s,1H)。
實施例14-18:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(4-氯-3-(三氟甲基)苯基)脲
TLC:Rf 0.46(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.26(d,2H),7.38(dd,1H),7.52(d,2H),7.61(d,1H),7.68(d,1H),7.93(dd,1H),8.07(s,1H),8.72(d,2H),9.05(s,1H),9.44(s,1H)。
實施例14-19:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-氯-5-(三氟甲基)苯基)脲
TLC:Rf 0.80(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.57(s,2H),7.27(dd,2H),7.36(dd,1H),7.43(s,1H),7.53(dd,2H),7.83(d,2H),7.93(s,1H),8.73(s,2H),9.13(s,1H),9.49(s,1H)。
實施例14-20:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(5-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.39(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 2.20(s,3H),5.50(s,2H),6.40(s,1H),7.27(d,2H),7.37(dd,1H),7.51-7.55(m,4H),7.75(s,1H),7.93(d,1H),8.40(s,1H),8.61(s,1H),8.67(s,2H),9.73(s,1H)。
實施例15
使用3-溴-5-氯吡啶-2-胺,或者使用相當之胺化合物替代3-溴-5-氯吡啶-2-胺,使用2-氯-5-硝基嘧啶,或者使用2-氯-5-硝基吡啶替代2-氯-5-硝基嘧啶,使用相當之胺基甲酸酯化合物或異氰酸酯化合物替代實施例3製造之化合物,進行與實施例4→實施例5→實施例6→實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例15-1:1-(2-(4-(2-胺基-5-甲基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.22(乙酸乙酯:甲醇=9:1);
1H-NMR(DMSO-d6):δ 2.16(s,3H),5.47(s,2H),7.21-7.27(m,3H),7.33(d,1H),7.47-7.54(m,3H),7.62(d,1H),7.79(s,1H),7.97(s,1H),8.73(s,2H),8.99(s,1H),9.32(s,1H)。
實施例15-2:1-(2-(1H-吡唑-1-基)-4-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.54(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),6.66(d,1H),7.27(d,2H),7.36(dd,1H),7.52(dd,2H),7.75(d,1H),7.83(s,1H),7.94(d,2H),8.42-8.44(m,2H),8.70(s,2H),9.57(s,1H),9.97(s,1H)。
實施例15-3:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氯-4-(三氟甲基)苯基)脲
TLC:Rf 0.37(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.29(d,2H),7.38(dd,1H),7.50-7.55(m,2H),7.69(dd,1H),7.89(d,1H),7.94(d,1H),8.43(d,1H),8.75(s,2H),8.80(s,1H),9.77(s,1H)。
實施例15-4:1-(2-(1H-吡唑-1-基)-4-(三氟甲基)苯基)-3-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.40(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.83(s,2H),6.67(t,1H),7.28(d,2H),7.43(d,1H),7.52(d,2H),7.74-7.77(m,1H),7.84(s,1H),7.94-7.97(m,2H),8.43-8.45(m,2H),8.72(s,2H),9.57(s,1H),9.96(s,1H)。
實施例15-5:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氟-4-(三氟甲基)苯基)脲
TLC:Rf 0.45(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.84(s,2H),7.27(d,2H),7.43(d,1H),7.46-7.55(m,3H),7.67(d,1H),7.96(d,1H),8.38(t,1H),8.75(s,2H),9.24(br,2H)。
實施例15-6:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氯-4-(三氟甲基)苯基)脲
TLC:Rf 0.45(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.28(d,2H),7.43(d,1H),7.52
(d,2H),7.69(dd,1H),7.89(d,1H),7.96(d,1H),8.42(d,1H),8.75(s,2H),8.80(s,1H),9.77(s,1H)。
實施例15-7:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,4-二氯苯基)脲
TLC:Rf 0.59(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.27(d,2H),7.41(dd,1H),7.42(d,1H),7.50(d,2H),7.63(d,1H),7.95(d,1H),8.14(d,1H),8.57(s,1H),8.72(s,2H),9.59(s,1H)。
實施例15-8:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,4-二氯苯基)脲
TLC:Rf 0.50(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.27(d,2H),7.35-7.43(m,2H),7.51(d,2H),7.63(d,1H),7.93(d,1H),8.14(d,1H),8.57(s,1H),8.72(s,2H),9.59(s,1H)。
實施例15-9:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,4,5-三氟苯基)脲
TLC:Rf 0.40(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.28(d,2H),7.38(dd,1H),7.53(d,2H),7.62-7.66(m,1H),7.94(d,1H),8.08-8.15(m,1H),8.73(s,2H),8.93(s,1H),9.21(s,1H)。
實施例15-10:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,4-二氟苯基)脲
TLC:Rf 0.45(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.04(t,1H),7.26(d,2H),7.31
(dd,1H),7.42(d,1H),7.51(d,2H),7.94-8.04(m,2H),8.71-8.72(m,3H),9.16(s,1H)。
實施例15-11:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,5二氯苯基)脲
TLC:Rf 0.56(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.12(dd,1H),7.26(d,2H),7.42(d,1H),7.49-7.55(m,3H),7.95-7.97(m,1H),8.26(d,1H),8.64(s,1H),8.74(d,2H),9.68(s,1H)。
實施例15-12:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,5-二氟苯基)脲
TLC:Rf 0.54(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),6.84(m,1H),7.26-7.32(m,3H),7.42(d,1H),7.51(dd,2H),7.93-8.01(m,2H),8.73(s,2H),8.96(s,1H),9.27(s,1H)。
實施例15-13:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(二氟甲基)苯基)脲
TLC:Rf 0.34(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.00(t,1H),7.17(d,1H),7.25-7.29(m,2H),7.39-7.45(m,2H),7.49-7.53(m,3H),7.78(s,1H),7.95(d,1H),8.73(s,2H),8.91(s,1H),9.17(s,1H)。
實施例15-14:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(4-氟苯基)脲
TLC:Rf 0.50(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 5.84(s,2H),7.06-7.13(m,2H),7.25(d,2H),
7.42(d,1H),7.46-7.51(m,4H),7.94(d,1H),8.71(d,2H),9.40(br,2H)。
實施例15-15:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,5二氯苯基)脲
TLC:Rf 0.50(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.12(dd,1H),7.28(d,2H),7.37(dd,1H),7.49(d,1H),7.53(d,2H),7.94(d,1H),8.25(d,1H),8.64(s,1H),8.73(s,2H),9.68(s,1H)。
實施例15-16:1-(2-(4-(2-胺基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.47(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 5.57(s,2H),6.66(t,1H),7.24(d,2H),7.34(d,1H),7.46-7.58(m,6H),7.89(d,1H),7.94(d,1H),8.24(s,1H),8.38(s,1H),8.65-8.68(m,3H),9.24(s,1H)。
實施例15-17:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3,4-二氟苯基)脲
TLC:Rf 0.79(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.13-7.16(m,1H),7.26(d,2H),7.30-7.40(m,1H),7.42(d,1H),7.51(d,2H),7.59-7.67(m,1H),7.95(d,1H),8.71(s,2H),8.93(s,1H),9.16(s,1H)。
實施例15-18:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(3-甲基-1H-吡唑-1-基)-4-(三氟甲基)苯基)脲
TLC:Rf 0.23(己烷:乙酸乙酯=1:1);1H-NMR(DMSO-d6):δ 2.36(s,3H),5.85(s,2H),6.43(d,1H),7.27(d,2H),7.42(d,1H),7.50(d,2H),7.70(d,1H),7.76(s,1H),7.95(d,1H),8.29(d,1H),8.40(d,1H),8.70(s,2H),9.63(s,1H),9.92(s,1H)。
實施例15-19:1-(2-(4-(2-胺基-5-環丙基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.54(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 0.59-0.64(m,2H),0.81-0.87(m,2H),1.77-1.86(m,1H),5.36(s,2H),7.01(d,1H),7.25(d,2H),7.32(d,1H),7.47-7.54(m,3H),7.62(d,1H),7.80(d,1H),7.97(s,1H),8.72(s,2H),8.99(s,1H),9.32(s,1H)。
實施例15-20:1-(2-(4-(2-胺基-5-甲基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.53(乙酸乙酯:甲醇:氨水=9:1:0.5);1H-NMR(DMSO-d6):δ 2.15(s,3H),5.34(s,2H),7.20-7.24(m,3H),7.46-7.58(m,5H),7.78(s,1H),7.87-7.90(m,1H),8.24(s,1H),8.38(s,1H),8.64-8.68(m,4H),9.24(s,1H)。
實施例15-21:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-4-(三氟甲基)苯基)脲
TLC:Rf 0.51(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.84(s,2H),7.26(d,2H),7.42(d,1H),7.51-7.56(m,5H),7.76(d,1H),7.90(d,1H),7.95(d,1H),8.24(s,1H),8.27(d,1H),8.66-8.68(m,2H),9.28(s,1H)。
實施例15-22:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(二氟甲基)苯基)脲
TLC:Rf 0.33(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 5.57(s,2H),7.00(t,1H),7.17(d,1H),7.26-7.29(m,2H),7.36-7.45(m,2H),7.51-7.55(m,3H),7.78(s,1H),7.94(d,1H),8.73(s,2H),8.91(s,1H),9.17(s,1H)。
實施例15-23:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(4-(三氟甲基)苯基)脲
TLC:Rf 0.82(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.27(d,2H),7.42(d,1H),7.51(d,2H),7.64(d,4H),7.95(d,1H),8.73(s,2H),8.98(s,1H),9.37(s,1H)。
實施例15-24:1-(2-(4-(2-胺基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.20(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 5.58(s,2H),6.60(dd,1H),7.25-7.37(m,4H),7.47-7.63(m,4H),7.94-7.97(m,2H),8.73(s,2H),9.00(s,1H),9.33(s,1H)。
實施例15-25:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(4-(三氟甲基)-2-(3-(三氟甲基)-1H-吡唑-1-基)-苯基)脲
TLC:Rf 0.39(己烷:乙酸乙酯=1:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.11(d,1H),7.26(d,2H),7.42(d,1H),7.50(d,2H),7.81(s,1H),7.85-7.88(m,1H),7.95(d,1H),8.36(d,1H),8.47(s,1H),8.53(s,1H),8.67(s,2H),9.50(s,1H)。
實施例15-26:1-(2-(4-(2-胺基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(3,4-二甲基苯基)-5-(三氟甲基)吡啶-3-基)脲
TLC:Rf 0.29(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 2.31(s,6H),5.57(s,2H),6.66(dd,1H),7.25(d,2H),7.31-7.42(m,4H),7.48(d,2H),7.95(dd,1H),8.35(s,1H),8.68-8.72(m,3H),8.78(s,1H),9.51(s,1H)。
實施例15-27:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,4-二氟苯基)脲
TLC:Rf 0.40(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.55(s,2H),7.00-7.09(m,1H),7.27(d,2H),7.28-7.39(m,2H),7.52(d,2H),7.93(d,1H),7.96-8.02(m,1H),8.70(s,1H),8.71(s,2H),9.15(s,1H)。
實施例15-28:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧
啶-5-基)-3-(2-氟苯基)脲
TLC:Rf 0.50(乙酸乙酯:己烷=3:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.03-7.06(m,1H),7.12(t,1H),7.20-7.24(m,1H),7.28(d,2H),7.42(d,1H),7.50(dd,2H),7.95(d,1H),8.04(t,1H),8.73(s,2H),9.15(br,2H)。
實施例15-29:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,4,6-三氟苯基)脲
TLC:Rf 0.60(己烷:乙酸乙酯=1:9);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.24-7.30(m,4H),7.42(d,1H),7.49(d,2H),7.94(d,1H),8.34(s,1H),8.70(s,2H),9.22(s,1H)。
實施例15-30:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-4-(三氟甲基)苯基)脲
TLC:Rf 0.50(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.56(d,2H),7.27(d,2H),7.36(dd,1H),7.52(d,2H),7.53-7.55(m,2H),7.70(d,1H),7.89-7.94(m,2H),8.24(s,1H),8.28(d,1H),8.66(s,2H),8.67-8.69(m,2H),9.29(s,1H)。
實施例15-31:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-氯-4-(三氟甲基)苯基)脲
TLC:Rf 0.40(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.27(d,2H),7.42(d,1H),7.46-7.55(m,3H),7.74(d,1H),7.89(d,1H),7.95(d,1H),8.72(s,2H),9.09(s,1H),9.55(s,1H)。
實施例15-32:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3,4-二氟苯基)脲
TLC:Rf 0.73(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.13-7.17(m,1H),7.26(d,2H),7.29(d,1H),7.38(dd,1H),7.52(d,2H),7.59-7.67(m,1H),7.93(d,1H),8.70(s,2H),8.93(s,1H),9.16(s,1H)。
實施例15-33:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氟-4-(三氟甲基)苯基)脲
TLC:Rf 0.45(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.29(d,2H),7.38(dd,1H),7.52-7.56(m,3H),7.69-7.76(m,1H),7.94(d,1H),8.32-8.42(m,1H),8.75(s,2H),9.12(d,1H),9.33(s,1H)。
實施例15-34:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,5-二氟苯基)脲
TLC:Rf 0.80(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.57(s,2H),6.81-6.87(m,1H),7.25-7.58(m,2H),7.29(d,1H),7.38(dd,1H),7.53(d,2H),7.92-8.00(m,2H),8.73(s,2H),8.96(s,1H),9.26(s,1H)。
實施例15-35:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-氯-4-(三氟甲基)苯基)脲
TLC:Rf 0.40(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.57(s,2H),7.28(d,2H),7.39(dd,1H),7.53(d,3H),7.75(d,1H),7.94(dd,2H),8.73(s,2H),9.11(s,1H),9.57(s,1H)。
實施例15-36:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(4-(三氟甲基)苯基)脲
TLC:Rf 0.80(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.58(s,2H),7.27(d,2H),7.38(dd,1H),7.54(d,2H),7.61-7.68(m,4H),7.93(d,1H),8.73(s,2H),8.99(s,1H),9.37(s,1H)。
實施例15-37:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(5-甲基-1H-吡唑-1-基)-4-(三氟甲基)苯基)脲
TLC:Rf 0.54(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 2.18(s,3H),5.85(s,2H),6.40(s,1H),7.26(d,2H),7.41(d,1H),7.50(d,2H),7.65(d,1H),7.74(d,1H),7.82(d,1H),7.95(d,1H),8.31(s,1H),8.47(d,1H),8.67(s,2H),9.75(s,1H)。
實施例15-38:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3,5-二氟苯基)脲
TLC:Rf 0.68(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.85(s,2H),6.81-6.87(m,1H),7.19(dd,2H),7.27(d,2H),7.42(d,1H),7.50(d,1H),7.52(d,2H),7.96(d,1H),8.71(s,2H),9.03(s,1H),9.36(s,1H)。
實施例15-39:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,4,6-三氟苯基)脲
TLC:Rf 0.59(己烷:乙酸乙酯=1:9);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.25-7.30(m,4H),7.37(dd,1H),7.52(d,2H),7.93(d,1H),8.35(s,1H),8.70(s,2H),9.24(s,1H)。
實施例15-40:1-(6-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)吡啶-3-基)-3-(2-氯-4-(三氟甲基)苯基)脲
TLC:Rf 0.64(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 5.84(s,2H),7.08(d,1H),7.16-7.20(m,2H),7.20(d,1H),7.39-7.41(m,1H),7.47-7.51(m,2H),7.68(dd,1H),7.87(d,1H),7.95(d,1H),8.03(dd,1H),8.24(d,1H),8.45(d,1H),8.68(s,1H),9.70(s,1H)。
實施例15-41:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3,5-二氟苯基)脲
TLC:Rf 0.68(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.56(s,2H),6.81(t,1H),7.20(dd,2H),7.28(d,2H),7.38(dd,1H),7.53(d,2H),7.94(d,1H),8.72(s,2H),9.02(s,1H),9.35(s,1H)。
實施例15-42:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,3,4-三氟苯基)脲
TLC:Rf 0.50(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.28(d,3H),7.38(dd,1H),7.53(d,2H),7.76-7.80(m,1H),7.94(s,1H),8.72(s,2H),8.91(s,1H),9.20(s,1H)。
實施例15-43:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,3-二氟苯基)脲
TLC:Rf 0.49(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.05-7.16(m,2H),7.29(d,2H),
7.38(dd,1H),7.53(d,2H),7.63-7.66(m,1H),7.87(t,1H),7.94(d,1H),8.73(s,1H),8.96(s,1H),9.26(s,1H)。
實施例15-44:1-(6-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)吡啶-3-基)-3-(2-氯-4-(三氟甲基)苯基)脲
TLC:Rf 0.52(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 5.55(s,2H),7.08(d,1H),7.18(d,2H),7.34(dd,1H),7.50(d,2H),7.68(d,1H),7.87(s,1H),7.93(d,1H),8.04(dd,1H),8.24(d,1H),8.45(d,1H),8.68(s,1H),9.70(s,1H)。
實施例15-45:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,6-二氟苯基)脲
TLC:Rf 0.75(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.55(s,2H),7.12-7.28(m,2H),7.27(d,2H),7.36(dd,2H),7.53(d,2H),7.93(d,1H),8.42(s,1H),8.71(s,2H),9.18(s,1H)。
實施例15-46:1-(2-(4-(2-胺基-5-氟吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2,3,5,6-四氟苯基)脲
TLC:Rf 0.50(乙酸乙酯:己烷=2:1);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.28(d,2H),7.38(dd,1H),7.53(d,2H),7.74-7.88(m,1H),7.94(d,1H),8.72(s,2H),8.89(s,1H),9.33(s,1H)。
實施例15-47:1-(2-(4-(2-胺基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(第三丁基)-1-(鄰-甲苯基)-1H-吡唑-5-基)脲
TLC:Rf 0.35(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.26(s,9H),1.99(s,3H),5.57(s,2H),6.34(s,1H),6.66(dd,1H),7.20-7.50(m,9H),7.94(dd,1H),8.39(s,1H),8.64(s,2H),9.07(s,1H)。
實施例15-48:1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(第三丁基)-1-(鄰-甲苯基)-1H-吡唑-5-基)脲
TLC:Rf 0.71(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.26(s,9H),1.99(s,3H),5.84(s,2H),6.34(s,1H),7.25(d,2H),7.31-7.43(m,5H),7.50(d,2H),7.95(d,1H),8.39(s,1H),8.64(s,2H),9.07(s,1H)。
實施例15-49:1-(2-(4-(2-胺基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(第三丁基)-1-(2,3-二氫-1H-茚-5-基)-1H-吡唑-5-基)脲
TLC:Rf 0.68(乙酸乙酯:甲醇=10:1);1H-NMR(DMSO-d6):δ 1.25(s,9H),2.06(quint.,2H),2.85-2.94(m,4H),5.56(s,2H),6.33(s,1H),6.62-6.69(m,1H),7.19-7.27(m,3H),7.30-7.37(m,3H),7.47(d,2H),7.92-7.96(m,1H),8.56(s,1H),8.66
(s,2H),9.18(s,1H)。
實施例15-50:1-(2-(4-(2-胺基-5-甲基吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(第三丁基)-1-(鄰-甲苯基)-1H-吡唑-5-基)脲
TLC:Rf 0.67(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.26(s,9H),1.99(s,3H),2.15(s,3H),5.33(s,2H),6.34(s,1H),7.20-7.24(m,3H),7.31-7.48(m,6H),7.78(s,1H),8.39(s,1H),8.64(s,2H),9.06(s,1H)。
實施例15-51:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):601(M+H)+;1H-NMR(DMSO-d6):δ 6.49(s,2H),6.67-6.69(m,1H),7.26-7.30(m,2H),7.50-7.56(m,4H),7.76(d,1H),7.95(d,1H),8.26(d,1H),8.41(d,1H),8.58(d,1H),8.70(s,2H),9.71(s,1H),9.97(s,1H)。
實施例15-52:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.07分);MASS(ESI,Pos.):669(M+H)+;1H-NMR(DMSO-d6):δ 6.48(s,2H),7.12(d,1H),7.28(d,2H),
7.50-7.60(m,4H),7.71(d,1H),8.27(s,1H),8.48(s,2H),8.59(s,1H),8.67(s,2H),9.48(s,1H)。
實施例15-53:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):568(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.25-7.30(m,2H),7.43(d,1H),7.49-7.53(m,2H),7.59(dd,1H),7.95(d,1H),8.07(d,1H),8.33(s,2H),8.65(d,1H),8.72(s,2H),9.67(s,1H),10.03(s,1H)。
實施例15-54:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(2H-1,2,3-三唑-2-基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.97分);MASS(ESI,Pos.):534(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.25-7.31(m,3H),7.43(d,1H),7.49-7.53(m,2H),7.80(d,1H),7.95(d,1H),8.26(s,2H),8.32(d,1H),8.70(s,2H),9.37(s,1H),9.93(s,1H)。
實施例15-55:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.61(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.26(d,2H),7.40-7.60(m,10H),
7.95(d,1H),8.09(s,1H),8.04(s,1H),8.66(s,2H),9.39(s,1H)。
實施例15-56:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(2-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.58(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.25(s,3H),5.85(s,2H),7.23-7.31(m,2H),7.35-7.56(m,6H),7.60-7.68(m,1H),7.88(s,1H),7.94-7.98(m,1H),8.52-8.56(m,1H),8.58-8.62(m,1H),8.65(s,2H),9.29(s,1H)。
實施例15-57:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-苯基-2-(三氟甲基)-4-吡啶基]脲
TLC:Rf 0.38(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 5.86(s,2H),7.25-7.31(m,2H),7.42(d,1H),7.50-7.66(m,7H),7.95(d,1H),8.43-8.46(m,2H),8.69(s,2H),8.75(s,1H),9.74(s,1H)。
實施例15-58:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.60(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 5.57(s,2H),7.23-7.29(m,2H),7.34-7.58(m,10H),7.92-7.96(m,1H),8.09(s,1H),8.41(s,1H),8.66(s,2H),9.39(s,1H)。
實施例15-59:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-
嘧啶基}-3-[2-(4-氟-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.56(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 5.86(s,2H),7.24-7.32(m,2H),7.42(d,1H),7.48-7.58(m,3H),7.67-7.73(m,1H),7.95(d,1H),8.03-8.07(m,1H),8.56-8.60(m,2H),8.70(s,2H),9.27(s,1H),9.85(s,1H)。
實施例15-60:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(4-氟-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.50(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 5.57(s,2H),7.26-7.32(m,2H),7.38(dd,1H),7.51-7.59(m,3H),7.66-7.73(m,1H),7.94(d,1H),8.03-8.07(m,1H),8.55-8.60(m,2H),8.70(s,2H),9.27(s,1H),9.85(s,1H)。
實施例15-61:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-苯基-5-(三氟甲基)-3-吡啶基]脲
TLC:Rf 0.43(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 5.86(s,2H),7.26(d,2H),7.42(d,1H),7.49-7.70(m,7H),7.95(d,1H),8.43(s,1H),8.68(s,2H),8.73(s,1H),8.76(s,1H),9.47(s,1H)。
實施例15-62:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’,4’-二甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.72(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 2.29(s,6H),5.85(s,2H),7.12-7.55(m,10H),7.95(d,1H),8.01(s,1H),8.44(s,1H),8.66(s,2H),9.44(s,1H)。
實施例15-63:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(4-氯-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.43(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 5.86(s,2H),7.24-7.30(m,2H),7.42(d,1H),7.47-7.57(m,3H),7.70(d,1H),7.95(d,1H),8.07(s,1H),8.57(d,1H),8.63(s,1H),8.70(s,2H),9.11(s,1H),9.81(s,1H)。
實施例15-64:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.63(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 2.39(s,3H),5.86(brs,2H),7.26(d,2H),7.29-7.49(m,7H),7.50(d,2H),7.95(d,1H),8.05(s,1H),8.43(s,1H),8.67(s,2H),9.42(s,1H)。
實施例15-65:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.55(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 2.39(s,3H),5.56(brs,2H),7.26(d,2H),7.29-7.48(m,7H),7.52(d,2H),7.94(d,1H),8.05(s,1H),8.43(s,1H),8.67(s,2H),9.42(s,1H)。
實施例15-66:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.58(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 2.39(s,3H),5.86(brs,2H),7.19-7.55(m,
11H),7.95(d,1H),8.04(s,1H),8.43(s,1H),8.66(s,2H),9.43(s,1H)。
實施例15-67:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.53(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 2.38(s,3H),5.57(brs,2H),7.19-7.48(m,9H),7.52(d,2H),7.94(d,1H),8.04(s,1H),8.44(s,1H),8.66(s,2H),9.43(s,1H)。
實施例15-68:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-{2-[4-(二氟甲基)-1H-吡唑-1-基]-5-(三氟甲基)苯基}脲
TLC:Rf 0.20(己烷:乙酸乙酯:甲醇=6:4:0.4);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.16(t,1H),7.26(d,2H),7.41(d,1H),7.48-7.57(m,3H),7.74(d,1H),7.94(d,1H),8.17(s,1H),8.55(d,1H),8.69(s,2H),8.70(s,1H),9.19(s,1H),9.85(s,1H)。
實施例15-69:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-{2-[4-(二氟甲基)-1H-吡唑-1-基]-5-(三氟甲基)苯基}脲
TLC:Rf 0.16(己烷:乙酸乙酯:甲醇=6:4:0.4);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.16(t,1H),7.26(d,2H),7.36(dd,1H),7.49-7.57(m,3H),7.74(d,1H),7.92(d,1H),8.18(s,1H),8.55(d,1H),8.69(s,2H),8.70(s,1H),9.19(s,1H),9.85(s,1H)。
實施例15-70:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-{5-氯-2-[4-(二氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.17(己烷:乙酸乙酯:甲醇=6:4:0.4);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.14(t,1H),7.22-7.29(m,3H),
7.41(d,1H),7.47-7.53(m,3H),7.94(d,1H),8.12(s,1H),8.24(d,1H),8.58(s,1H),8.68(s,2H),8.91(s,1H),9.78(s,1H)。
實施例15-71:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-{5-氯-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.21(己烷:乙酸乙酯:甲醇=6:4:0.4);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.07(s,1H),7.22-7.31(m,3H),7.39-7.53(m,4H),7.94(d,1H),8.18(s,1H),8.37(d,2H),8.65(s,2H),9.43(s,1H)。
實施例15-72:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-{5-氯-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.29(己烷:乙酸乙酯=2:3);1H-NMR(DMSO-d6):δ 1.25(t,3H),2.69(q,2H),5.86(s,2H),7.20-7.55(m,11H),7.95(d,1H),8.09(s,1H),8.40(s,1H),8.66(s,2H),9.40(s,1H)。
實施例15-73:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’-乙基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.32(己烷:乙酸乙酯=2:3);1H-NMR(DMSO-d6):δ 1.22(t,3H),2.68(q,2H),5.85(s,2H),7.24-7.55(m,11H),7.94(d,1H),8.06(s,1H),7.38-7.42(m,1H),8.65(s,2H),9.41(s,1H)。
實施例15-74:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’-乙基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.33(己烷:乙酸乙酯=2:3);1H-NMR(DMSO-d6):δ 1.22(t,3H),2.68(q,2H),5.57(s,2H),7.24-7.56(m,11H),7.94(d,1H),8.07(s,1H),8.39(s,1H),8.66(s,2H),9.41(s,1H)。
實施例15-75:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-甲氧基-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.94分);MASS(ESI,Pos.):531(M+H)+;1H-NMR(DMSO-d6):δ 3.97(s,3H),5.86(s,2H),7.25-7.33(m,4H),7.43(d,1H),7.49-7.56(m,2H),7.96(d,1H),8.32(d,1H),8.70(s,1H),8.73(s,2H),9.66(s,1H)。
實施例15-76:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.90分);MASS(ESI,Pos.):579(M+H)+;1H-NMR(DMSO-d6):δ 3.42(s,3H),5.87(s,2H),7.26-7.33(m,2H),7.43(d,1H),7.47-7.57(m,2H),7.96(dd,1H),8.04-8.12(m,2H),8.50(d,1H),8.76(s,2H),9.04(s,1H),10.36(s,1H)。
實施例15-77:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基1-5-嘧啶基}-3-[2,4-雙(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):569(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.26-7.34(m,2H),7.42-7.44(m,1H),7.49-7.56(m,2H),7.95-7.99(m,2H),8.04(d,1H),8.33(d,1H),8.56(s,1H),8.75(s,2H),9.80(s,1H)。
實施例15-78:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(5-氯-2-甲基苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.88分);MASS(ESI,Pos.):481(M+H)+;1H-NMR(DMSO-d6):δ 2.22(s,3H),5.86(s,2H),7.01(dd,1H),7.20(d,1H),7.25-7.32(m,2H),7.43(d,1H),7.48-7.55(m,2H),7.95-7.99(m,2H),8.26(s,1H),8.74(s,2H),9.30(s,1H)。
實施例15-79:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(5-氯-2-甲基苯基)脲
TLC:Rf 0.32(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 5.86(s,2H),7.23-7.30(m,2H),7.42(d,1H),7.46-7.56(m,3H),7.70(d,1H),7.95(d,1H),8.06(s,1H),8.56(d,1H),8.62(s,1H),8.69(s,2H),9.11(s,1H),9.81(s,1H)。
實施例15-80:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-{5-(二氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.47(己烷:乙酸乙酯=1:2);
1H-NMR(DMSO-d6):δ 5.85(s,2H),7.08(d,1H),7.13(t,1H),7.25(d,2H),7.39-7.44(m,2H),7.50(d,2H),7.60(d,1H),7.94(d,1H),8.28(s,1H),8.40-8.43(d,1H),8.46(s,1H),8.66(s,2H),9.42(s,1H)。
實施例15-81:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-{4-氯-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.51(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.84(s,2H),7.05(d,1H),7.24(d,2H),7.40(d,1H),7.52(d,2H),7.53-7.61(m,2H),7.94(d,1H),8.01(d,1H),8.35(s,1H),8.37-8.42(m,1H),8.63(s,2H),9.35(s,1H)。
實施例15-82:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-{2-[3-(二氟甲基)-1H-吡唑-1-基]-5-(三氟甲基)苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.04分);MASS(ESI,Pos.):651(M+H)+;1H-NMR(DMSO-d6):δ 6.48(s,2H),6.93(d,1H),7.14(t,1H),7.26-7.33(m,2H),7.49-7.60(m,4H),7.73(d,1H),8.27(d,1H),8.45(d,1H),8.54(d,1H),8.69(s,2H),8.95(s,1H),9.66(s,1H)。
實施例15-83:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-1,2,4-三唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);MASS(ESI,Pos.):670(M+H)+;1H-NMR(DMSO-d6):δ 6.48(s,2H),7.25-7.32(m,2H),7.48-7.58(m,
3H),7.72(dd,1H),7.82(d,1H),8.27(d,1H),8.49(d,1H),8.66-8.69(m,3H),9.24(s,1H),9.33(s,1H)。
實施例15-84:1-[2-(3-乙醯基-1H-吡唑-1-基)-5-(三氟甲基)苯基]-3-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):643(M+H)+;1H-NMR(DMSO-d6):δ 2.59(s,3H),6.48(s,2H),7.04-7.07(m,1H),7.24-7.32(m,2H),7.48-7.62(m,4H),7.75(d,1H),8.25-8.29(m,1H),8.40(d,1H),8.63(d,1H),8.68(s,2H),8.75(s,1H),9.64(s,1H)。
實施例15-85:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(2-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.84分);MASS(ESI,Pos.):626(M+H)+;1H-NMR(DMSO-d6):δ 2.25(s,3H),6.48(s,2H),7.23-7.57(m,8H),7.63(dd,1H),7.88(s,1H),8.27(d,1H),8.53(s,1H),8.59(dd,1H),8.65(s,2H),9.29(s,1H)。
實施例15-86:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(4-氟-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);MASS(ESI,Pos.):619(M+H)+;1H-NMR(DMSO-d6):δ 6.49(s,2H),7.26-7.33(m,2H),7.48-7.58(m,4H),7.68(d,1H),8.03-8.07(m,1H),8.26-8.30(m,1H),8.56-8,63(m,2H),8.70(s,2H),9.27(s,1H),9.85(s,1H)。
實施例15-87:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(4-氯-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):635(M+H)+;1H-NMR(DMSO-d6):δ 6.49(s,2H),7.26-7.32(m,2H),7.50-7.59(m,4H),7.70(d,1H),8.07-8.09(m,1H),8.26-8.30(m,1H),8.57(d,1H),8.63-8.64(m,1H),8.69(s,2H),9.11(s,1H),9.81(s,1H)。
實施例15-88:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-氯-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.04分);MASS(ESI,Pos.):569(M+H)+;1H-NMR(DMSO-d6):δ 6.49(s,2H),7.27-7.34(m,2H),7.50-7.60(m,3H),7.70(dd,1H),7.89-7.93(m,1H),8.26-8.31(m,1H),8.43(d,1H),8.75(s,2H),8.81(s,1H),9.78(s,1H)。
實施例15-89:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]
苯氧基}-5-嘧啶基)-3-[2-氯-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);MASS(ESI,Pos.):569(M+H)+;1H-NMR(DMSO-d6):δ 6.49(s,2H),7.26-7.34(m,2H),7.40(dd,1H),7.50-7.59(m,3H),7.73(d,1H),8.26-8.30(m,1H),8.56(d,1H),8.75(s,2H),8.79(s,1H),9.72(s,1H)。
實施例15-90:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-氟-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):553(M+H)+;1H-NMR(DMSO-d6):δ 6.49(s,2H),7.26-7.33(m,2H),7.38-7.59(m,5H),8.26-8.30(m,1H),8.52(dd,1H),8.75(s,2H),9.11(s,1H),9.31(s,1H)。
實施例15-91:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-(2,5-二氯苯基)脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):535(M+H)+;1H-NMR(DMSO-d6):δ 6.49(s,2H),7.12(dd,1H),7.27-7.34(m,2H),7.50-7.59(m,4H),8.26-8.30(m,2H),8.65(s,1H),8.74(s,2H),9.68(s,1H)。
實施例15-92:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-(2,4-二氯苯基)脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):535(M+H)+;
1H-NMR(DMSO-d6):δ 6.49(s,2H),7.27-7.33(m,2H),7.39(dd,1H),7.50-7.59(m,3H),7.64(d,1H),8.14(d,1H),8.27-8.30(m,1H),8.59(s,1H),8.73(s,2H),9.60(s,1H)。
實施例15-93:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-甲基-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):549(M+H)+;1H-NMR(DMSO-d6):δ 2.32(s,3H),6.49(s,2H),7.27-7.34(m,3H),7.42(d,1H),7.50-7.59(m,3H),8.26-8.30(m,2H),8.39(s,1H),8.75(s,2H),9.34(s,1H)。
實施例15-94:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-異丙基-5-(三氟甲基)苯基]脲
TLC:Rf 0.67(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.22(d,6H),3.21(m,1H),5.86(s,2H),7.25-7.31(m,2H),7.39-7.56(m,5H),7.95(d,1H),8.12-8.15(m,1H),8.43(s,1H),8.74(s,2H),9.28(s,1H)。
實施例15-95:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-乙基-5-(三氟甲基)苯基]脲
TLC:Rf 0.35(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.20(t,3H),2.69(q,2H),5.86(s,2H),7.25-7.31(m,2H),7.33-7.46(m,3H),7.48-7.56(m,2H),7.95(d,1H),8.24-8.27(m,1H),8.38(m,1H),8.75(s,2H),9.34(s,1H)。
實施例15-96:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.44(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 3.38(s,3H),5.57(s,2H),7.25-7.31(m,2H),7.37(dd,1H),7.48-7.56(m,2H),7.61-7.67(m,1H),7.93(d,1H),8.04-8.09(m,1H),8.61-8.65(m,1H),8.75(s,2H),8.97(s,1H),10.30(s,1H)。
實施例15-97:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)-4-(三氟甲基)苯基]脲
TLC:Rf 0.31(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 3.42(s,3H),6.49(s,2H),7.27-7.33(m,2H),7.49-7.58(m,3H),8.03-8.11(m,2H),8.25-8.30(m,1H),8.50(d,1H),8.76(s,2H),9.04(s,1H),10.36(s,1H)。
實施例15-98:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.32(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 3.38(s,3H),6.49(s,2H),7.24-7.32(m,2H),7.48-7.58(m,3H),7.64(d,1H),8.06(d,1H),8.24-8.29(m,1H),
8.61-8.64(m,1H),8.75(s,2H),8.97(s,1H),10.30(s,1H)。
實施例15-99:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(4-氯-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.28(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.27(d,2H),7.36(dd,1H),7.51-7.57(m,3 H),7.68-7.74(m,1 H),7.93(d,1H),8.06(s,1H),8.56(s,1H),8.62(s,1H),8.69(s,2H),9.10(s,1H),9.80(s,1H)。
實施例15-100:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-甲基-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.94分);MASS(ESI,Pos.):515(M+H)+;1H-NMR(DMSO-d6):δ 2.36(s,3H),5.86(s,2H),7.15(s,1H),7.26(d,2H),7.40-7.45(m,2H),7.50(d,2H),7.76(s,1H),7.95(d,1H),8.73(s,2H),8.98(s,1H),9.23(s,1H)。
實施例15-101:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-甲基-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):515(M+H)+;1H-NMR(DMSO-d6):δ 2.32(s,3H),5.86(s,2H),7.27(d,2H),7.45(d,1H),7.47-7.54(m,3H),7.56(s,1H),7.95(d,1H),8.14(d,1H),8.40(s,1H),8.75(s,2H),9.39(s,1H)。
實施例15-102:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2,5-雙(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.97分);
MASS(ESI,Pos.):569(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.27(d,2H),7.42(d,1H),7.50(d,2H),7.63(d,1H),7.90-7.97(m,2H),8.41(s,1H),8.57(s,1H),8.74(s,2H),9.73(s,1H)。
實施例15-103:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-甲氧基-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):531(M+H)+;1H-NMR(DMSO-d6):δ 3.96(s,3H),5.86(s,2H),7.17-7.37(m,4H),7.42(d,1H),7.50(d,2H),7.95(d,1H),8.48(d,1H),8.66(s,1H),8.72(s,2H),9.60(s,1H)。
實施例15-104:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.91分);MASS(ESI,Pos.):579(M+H)+;1H-NMR(DMSO-d6):δ 3.38(s,3H),5.87(s,2H),7.25-7.31(m,2H),7.43(d,1H),7.48-7.54(m,2H),7.62-7.67(m,1H),7.96(d,1H),8.07(d,1H),8.61-8.65(m,1H),8.75(s,2H),8.97(s,1H),10.31(s,1H)。
實施例15-105:2-{[(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-N,N-二甲基-4-(三氟甲基)苯
磺醯胺
TLC:Rf 0.64(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 2.76(s,6H),6.49(s,2H),7.27-7.35(m,2H),7.50-7.65(m,4H),7.94(d,1H),8.26-8.30(m,1H),8.61(s,1H),8.74(s,2H),8.99(s,1H),10.31(s,1H)。
實施例15-106:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’-(羥甲基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.95分);MASS(ESI,Pos.):607(M+H)+;1H-NMR(DMSO-d6):δ 4.59(d,2H),5.28(t,1H),5.86(s,2H),7.22-7.33(m,3H),7.36(s,1H),7.37-7.53(m,7H),7.93-7.98(m,1H),8.06(s,1H),8.42(s,1H),8.66(s,2H),9.42(s,1H)。
實施例15-107:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’-(羥甲基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):99%(保持時間:0.88分);MASS(ESI,Pos.):591(M+H)+;1H-NMR(DMSO-d6):δ 4.58(d,2H),5.28(t,1H),5.57(s,2H),7.22-7.32(m,3H),7.35-7.56(m,8H),7.94(d,1H),8.06(s,1H),8.42(s,1H),8.66(s,2H),9.42(s,1H)。
實施例15-108:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-
嘧啶基}-3-[3’-(1-羥乙基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):621(M+H)+;1H-NMR(DMSO-d6):δ 1.36(d,3H),4.74-4.93(m,1H),5.21(d,1H),5.86(s,2H),7.22-7.36(m,3H),7.38-7.56(m,8H),7.95(d,1H),8.09(s,1H),8.37(s,1H),8.66(s,2H),9.40(s,1H)。
實施例15-109:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’-(1-羥乙基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.91分);MASS(ESI,Pos.):605(M+H)+;1H-NMR(DMSO-d6):δ 1.36(d,3H),4.74-4.93(m,1H),5.21(d,1H),5.57(s,2H),7.22-7.57(m,11H),7.94(d,1H),8.09(s,1H),8.37(s,1H),8.66(s,2H),9.40(s,1H)。
實施例15-110:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(乙磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.59(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 1.15(t,3H),3.45(q,2H),6.48(s,2H),7.27(d,2H),7.51(d,2H),7.55(d,1H),7.62(d,1H),8.02(d,1H),8.24-8.28(m,1H),8.64(s,1H),8.74(s,2H),9.00(s,1H),10.32(s,1H)。
實施例15-111:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(甲磺醯基)苯基]脲
TLC:Rf 0.38(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 3.33(s,3H),5.86(s,2H),7.25-7.31(m,2H),
7.36(dd,1H),7.43(d,1H),7.48-7.55(m,2H),7.85(d,1H),7.96(dd,1H),8.33(d,1H),8.75(s,2H),8.88(s,1H),10.26(s,1H)。
實施例15-112:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[5-氟-2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.92分);MASS(ESI,Pos.):563(M+H)+;1H-NMR(DMSO-d6):δ 3.31(s,3H),6.49(s,2H),7.09-7.19(m,1H),7.29(d,2H),7.50-7.60(m,3H),7.92(dd,1H),8.11(dd,1H),8.25-8.32(m,1H),8.75(s,2H),8.95(s,1H),10.29(s,1H)。
實施例15-113:2-{[(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-4-氟-N,N-二甲基苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):592(M+H)+;1H-NMR(DMSO-d6):δ 2.70(s,6H),6.49(s,2H),7.09-7.18(m,1H),7.28(d,2H),7.48-7.59(m,3H),7.80(dd,1H),8.11(dd,1H),8.25-8.30(m,1H),8.74(s,2H),8.98(s,1H),10.29(s,1H)。
實施例15-114:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲硫基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.25(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 2.53(s,3H),5.56(s,2H),7.26(d,2H),7.35-7.43(m,2H),7.49-7.56(m,3H),7.92(d,1H),8.18(d,1H),8.44(s,1H),8.73(s,2H),9.64(s,1H)。
實施例15-115:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(甲亞磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.34(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.88(s,3H),6.47(s,2H),7.27(d,2H),7.48-7.57(m,3H),7.65(d,1H),7.90(d,1H),8.26(s,2H),8.73(s,2H),9.25(s,1H),9.68(s,1H)。
實施例15-116:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲亞磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.32(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.88(s,3H),5.56(s,2H),7.27(d,2H),7.36(dd,1H),7.52(d,2H),7.65(d,1H),7.88-7.94(m,2H),8.26(s,1H),8.73(s,2H),9.24(s,1H),9.68(s,1H)。
實施例15-117:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[5-氯-2-(甲亞磺醯基)苯基]脲
TLC:Rf 0.43(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.86(s,3H),6.48(s,2H),7.27(d,2H),7.35(dd,1H),7.51(d,2H),7.55(d,1H),7.67(d,1H),8.00(d,1H),8.25-8.29(m,1H),8.73(s,2H),9.24(s,1H),9.69(s,1H)。
實施例15-118:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’-(2-羥基-2-丙烷基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD);100%(保持時間:1.00分);MASS(ESI,Pos.):635(M+H)+;1H-NMR(DMSO-d6):δ 1.45(s,6H),5.07(s,1H),5.85(s,2H),7.21-7.33(m,3H),7.40-7.60(m,8H),7.95(d,1H),8.10(s,1H),8.34(s,1H),8.65(s,2H),9.38(s,1H)。
實施例15-119:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]
苯氧基}-5-嘧啶基)-3-[3’-(2-羥基-2-丙烷基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):669(M+H)+;1H-NMR(DMSO-d6):δ 1.45(s,6H),5.07(s,1H),6.48(s,2H),7.22-7.34(m,3H),7.41-7.60(m,8H),8.10(s,1H),8.25-8.29(m,1H),8.34(s,1H),8.65(s,2H),9.39(s,1H)。
實施例15-120:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(1H-吡唑-1-基)苯基]脲
TLC:Rf 0.43(己烷:乙酸乙酯=3:7);1H-NMR(DMSO-d6):δ 5.87(s,2H),6.63-6.64(m,1H),7.23(d,1H),7.24-7.28(m,2H),7.40-7.55(m,4H),7.91(d,1H),7.96(d,1H),8.27(d,1H),8.30(d,1H),8.70(s,2H),9.40(s,1H),9.91(s,1H)。
實施例15-121:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-氯-2-(1H-吡唑-1-基)苯基]脲
TLC:Rf 0.52(己烷:乙酸乙酯=3:7);1H-NMR(DMSO-d6):δ 5.86(s,2H),6.61-6.65(m,1H),7.26(d,2H),7.41-7.47(m,2H),7.52(d,2H),7.64(d,1H),7.91(d,1H),7.96(d,1H),8.14(d,1H),8.36(d,1H),8.69(s,2H),9.37(s,1H),9.85(s,1H)。
實施例15-122:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(1H-1,2,3-三唑-1-基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):568(M+H)+;
1H-NMR(DMSO-d6):δ 5.86(s,2H),7.26(d,2H),7.42(d,1H),7.50(d,2H),7.89-7.92(m,2H),7.95(d,1H),8.09(s,1H),8.45(d,1H),8.68-8.70(m,4H),9.69(brs,1H)。
實施例15-123:1-{6-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-3-吡啶基}-3-[2-氟-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.99分);MASS(ESI,Pos.):518(M+H)+;1H-NMR(DMSO-d6):δ 5.85(s,2H),7.07(d,1H),7.17(d,2H),7.39-7.53(m,5H),7.94(d,1H),8.05(dd,1H),8.22(d,1H),8.56(dd,1H),8.96(d,1H),9.25(s,1H)。
實施例15-124:1-{6-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-3-吡啶基}-3-[2-(1H-吡唑-1-基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):566(M+H)+;1H-NMR(DMSO-d6):δ 5.85(s,2H),6.65(t,1H),7.05(d,1H),7.16(d,2H),7.40(d,1H),7.47(d,2H),7.74(d,1H),7.81(d,1H),7.93-8.00(m,3H),8.22(d,1H),8.42-8.44(m,2H),9.42(s,1H),9.84(s,1H)。
實施例15-125:1-{6-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-3-吡啶基}-3-[2-(1H-1,2,3-三唑-1-基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):567(M+H)+;1H-NMR(DMSO-d6):δ 5.85(s,2H),7.04(d,1H),7.16(d,2H),7.40(d,1H),7.47(d,2H),7.59(dd,1H),7.72(d,1H),7.94(d,1H),7.99(dd,1H),8.10(d,1H),8.15(d,1H),8.59-8.61(m,2H),8.69(s,1H),9.57(s,1H)。
實施例15-126:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(3-吡啶基)苯基]脲
純度(LC-MS/ELSD):98%(保持時間:0.79分);MASS(ESI,Pos.):544(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.23-7.30(m,4H),7.42(d,1H),7.49-7.55(m,3H),7.80-7.85(m,1H),7.95(d,1H),8.08(d,1H),8.14(s,1H),8.56-8.65(m,4H),9.21(s,1H)。
實施例15-127:1-{2-[4-(2-胺基-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.76分);MASS(ESI,Pos.):533(M+H)+;1H-NMR(DMSO-d6):δ 5.58(s,2H),6.64-6.68(m,2H),7.26(d,2H),7.35(dd,1H),7.47-7.54(m,3H),7.75(d,1H),7.93-7.95(m,2H),8.42(d,1H),8.59(d,1H),8.70(s,2H),9.60-10.08(br,2H)。
實施例15-128:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.90分);MASS(ESI,Pos.):612(M+H)+;
1H-NMR(DMSO-d6):δ 6.48(s,2H),7.24-7.29(m,2H),7.50-7.58(m,6H),7.86-7.91(m,1H),8.25-8.28(m,2H),8.38(d,1H),8.62-8.71(m,4H),9.25(s,1H)。
實施例15-129:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):602(M+H)+;1H-NMR(DMSO-d6):δ 6.48(s,2H),7.28(d,2H),7.50-7.56(m,3H),7.61(dd,1H),7.74(d,1H),8.10(s,1H),8.27(d,1H),8.58(d,1H),8.69-8.73(m,4H),9.67(s,1H)。
實施例15-130:1-{6-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-3-吡啶基}-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.08分);MASS(ESI,Pos.):634(M+H)+;1H-NMR(DMSO-d6):δ 5.85(s,2H),7.04(d,1H),7.14-7.18(m,3H),7.40(d,1H),7.45-7.49(m,2H),7.56(dd,1H),7,69(d,1H),7.94(d,1H),7.98(dd,1H),8.16(d,1H),8.45(s,1H),8.47(d,1H),8.51(d,1H),9.40(s,1H)。
實施例15-131:1-{6-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-3-吡啶基}-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):618(M+H)+;1H-NMR(DMSO-d6):δ 5.55(s,2H),7.04(d,1H),7.14-7.18(m,3H),7.41(dd,1H),7.46-7.51(m,2H),7.55(dd,1H),7.68(d,1H),7.92(d,
1H),7.97(dd,1H),8.15(d,1H),8.44(s,1H),8.46-8.47(m,1H),8.51(d,1H),9.39(s,1H)。
實施例15-132:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-(1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):567(M+H)+;1H-NMR(DMSO-d6):δ 5.87(s,2H),6.58-6.59(m,1H),7.28(d,2H),7.43(d,1H),7.49-7.54(m,2H),7.80-7.84(m,3H),8.00(d,1H),8.25(s,1H),8.63(d,1H),8.75(s,2H),9.09(s,1H),9.55(s,1H)。
實施例15-133:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.82分);MASS(ESI,Pos.):578(M+H)+;1H-NMR(DMSO-d6):δ 5.87(s,2H),7.28(d,2H),7.43(d,1H),7.50-7.55(m,3H),7.66(s,1H),7.95-7.96(m,2H),8.01(s,1H),8.09-8.13(m,1H),8.62-8.64(m,1H),8.75(s,2H),8.90(d,1H),9.13(s,1H),9.44(s,1H)。
實施例15-134:1-{6-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-3-吡啶基}-3-[2-(4-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.96分);MASS(ESI,Pos.):581(M+H)+;1H-NMR(DMSO-d6):δ 2.39(s,3H),5.84(s,2H),7.04(d,1H),7.14-7.17(m,2H),7.39(d,1H),7.45-7.48(m,2H),7.56(dd,1H),7.67(d,1H),7.93(d,1H),7.99(dd,1H),8.15(d,1H),8.38(d,1H),
8.61-8.62(m,2H),9.59(s,1H)。
實施例15-135:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(1H-1,2,3-三唑-1-基)苯基]脲
純度(LC-MS/ELSD):98%(保持時間:0.85分);MASS(ESI,Pos.):534(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.24-7.29(m,2H),7.32(dd,1H),7.42(d,1H),7.48-7.53(m,3H),7.95(d,1H),8.06(d,1H),8.27(d,1H),8.51(s,1H),8.59(d,1H),8.67(s,2H),9.60(s,1H)。
實施例15-136:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(5-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.58(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.38(s,3H),5.86(s,2H),7.24-7.31(m,2H),7.40-7.54(m,5H),7.70-7.74(m,1H),7.95(d,1H),8.20(s,1H),8.40-8.47(m,2H),8.51-8.55(m,1H),8.66(s,2H),9.28(s,1H)。
實施例15-137:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(5-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.45(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.38(s,3H),5.57(s,2H),7.22-7.31(m,2H),7.37(dd,1H),7.43-7.58(m,4H),7.68-7.75(m,1H),7.93(d,1H),8.20(s,1H),8.40-8.46(m,2H),8.51-8.55(m,1H),8.66(s,2H),9.29(s,1H)。
實施例15-138:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(2-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.18(乙酸乙酯:甲醇=19:1);
1H-NMR(DMSO-d6):δ 2.25(s,3H),5.56(s,2H),7.22-7.30(m,2H),7.33-7.56(m,6H),7.59-7.66(m,1H),7.87(s,1H),7.93(d,1H),8.53(s,1H),8.56-8.61(m,1H),8.65(s,2H),9.28(s,1H)。
實施例15-139:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-苯基-2-(三氟甲基)-4-吡啶基]脲
TLC:Rf 0.44(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 5.57(s,2H),7.25-7.32(m,2H),7.37(dd,1H),7.50-7.65(m,7H),7.94(d,1H),8.42-8.47(m,2H),8.69(s,2H),8.75(s,1H),9.74(s,1H)。
實施例15-140:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(6-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.68(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 2.55(s,3H),5.85(s,2H),7.26(d,2H),7.42-7.53(m,6H),7.76(dd,1H),7.95(d,1H),8.20(s,1H),8.42(s,1H),8.50(d,1H),8.67(s,2H),9.28(s,1H)。
實施例15-141:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-苯基-5-(三氟甲基)-3-吡啶基]脲
TLC:Rf 0.43(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 5.57(s,2H),7.27(d,2H),7.38(dd,1H),7.51-7.69(m,7H),7.94(d,1H),8.43(s,1H),8.68(s,2H),8.73(s,1H),8.76(s,1H),9.47(s,1H)。
實施例15-142:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3’,4’-二甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.79(己烷:乙酸乙酯=1:3);
1H-NMR(DMSO-d6):δ 2.29(s,6H),5.56(s,2H),7.13-7.56(m,10H),7.93(d,1H),8.01(s,1H),8.45(s,1H),8.67(s,1H),9.45(s,1H)。
實施例15-143:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(6-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.69(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 2.55(s,3H),5.56(s,2H),7.26(d,2H),7.35-7.57(m,6H),7.77(dd,1H),7.94(d,1H),8.20(s,1H),8.42(s,1H),8.50(d,1H),8.70(s,2H),9.28(s,1H)。
實施例15-144:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.59(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 2.04(s,3H),5.86(brs,2H),7.16-7.46(m,9H),7.50(d,2H),7.72(s,1H),7.95(d,1H),8.53(s,1H),8.65(s,2H),9.45(s,1H)。
實施例15-145:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.56(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 2.04(s,3H),5.56(brs,2H),7.16-7.48(m,9H),7.52(d,2H),7.72(s,1H),7.93(d,1H),8.53(s,1H),8.65(s,2H),9.45(s,1H)。
實施例15-146:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2’-乙基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.51(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 0.99(t,3H),2.21-2.50(m,2H),5.85(s,2H),
7.16(d,1H),7.15-7.51(m,10H),7.66(s,1H),7.94(d,1H),8.53(s,1H),8.64(s,2H),9.47(s,1H)。
實施例15-147:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2’-乙基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.50(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 0.99(t,3H),2.21-2.50(m,2H),5.56(s,2H),7.16(d,1H),7.22-7.56(m,10H),7.66(s,1H),7.93(d,1H),8.53(s,1H),8.64(s,2H),9.47(s,1H)。
實施例15-148:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-{5-氯-2-[4-(二氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.16(己烷:乙酸乙酯:甲醇=6:4:0.4);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.13(t,1H),7.20-7.29(m,3H),7.36(dd,1H),7.46-7.57(m,3H),7.92(d,1H),8.11(s,1H),8.23(d,1H),8.58(s,1H),8.67(s,2H),8.90(s,1H),9.77(s,1H)。
實施例15-149:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-{5-氯-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.20(己烷:乙酸乙酯:甲醇=6:4:0.4);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.07(s,1H),7.20-7.32(m,3H),7.37(dd,1H),7.43-7.57(m,3H),7.92(d,1H),8.18(s,1H),8.37(s,2H),8.65(s,2H),9.43(s,1H)。
實施例15-150:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(4-氟-1H-吡唑-1-基)苯基]脲
TLC:Rf 0.45(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.19-7.30(m,3H),7.38-7.54(m,
4H),7.91-7.99(m,2H),8.24(d,1H),8.42(d,1H),8.69(s,2H),8.94(s,1H),9.76(s,1H)。
實施例15-151:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(4-氟-1H-吡唑-1-基)苯基]脲
TLC:Rf 0.39(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.19-7.30(m,3H),7.36(dd,1H),7.44(d,1H),7.51(d,2H),7.92(d,1H),7.95(d,1H),8.24(d,1H),8.42(d,1H),8.68(s,2H),8.94(s,1H),9.75(s,1H)。
實施例15-152:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4’-乙基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.31(己烷:乙酸乙酯=2:3);1H-NMR(DMSO-d6):δ 1.24(t,3H),2.69(q,2H),5.57(s,2H),7.24-7.31(m,2H),7.34-7.56(m,9H),7.93(d,1H),8.09(s,1H),8.41(s,1H),8.67(s,2H),9.41(s,1H)。
實施例15-153:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氟-2-(3-吡啶基)苯基]脲
TLC:Rf 0.51(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 5.86(s,2H),7.02(dt,1H),7.24-7.31(m,3H),7.42(d,1H),7.49-7.55(m,3H),7.82(dt,1H),7.88(dd,1H),7.95(d,1H),8.12(s,1H),8.58-8.65(m,4H),9.23(s,1H)。
實施例15-154:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3,4-雙(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.99分);MASS(ESI,Pos.):569(M+H)+;
1H-NMR(DMSO-d6):δ 5.87(s,2 H),7.25-7.31(m,2 H),7.43(d,1 H),7.49-7.55(m,2 H),7.86-7.98(m,3 H),8.20(s,1 H),8.74(s,2 H),9.16(s,1 H),9.77(s,1 H)。
實施例15-155:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-甲基-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.94分);MASS(ESI,Pos.):515(M+H)+;1H-NMR(DMSO-d6):δ 2.39(s,3H),5.87(s,2H),7.25-7.32(m,2H),7.42-7.61(m,6H),7.95(d,1H),8.73(s,2H),8.98(s,1H),9.28(s,1H)。
實施例15-156:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-氟-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):519(M+H)+;1H-NMR(DMSO-d6):δ 5.87(s,2H),7.25-7.32(m,2H),7.33-7.39(m,1H),7.43(d,1H),7.48-7.51(m,2H),7.63-7.74(m,2H),7.96(d,1H),8.73(s,2H),9.10(s,1H),9.62(s,1H)。
實施例15-157:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-氟-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.90分);MASS(ESI,Pos.):531(M+H)+;1H-NMR(DMSO-d6):δ 3.84(s,3H),5.86(s,2H),7.07-7.15(m,1H),7.25-7.32(m,2H),7.41-7.56(m,5H),7.95(d,1H),8.73(s,2H),8.98(s,1H),9.38(s,1H)。
實施例15-158:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2,3-二氟-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.95分);MASS(ESI,Pos.):537(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.25-7.32(m,2H),7.43(d,1H),7.48-7.61(m,3H),7.94-7.98(m,1H),8.13-8.21(m,1H),8.75(s,2H),9.36(s,2H)。
實施例15-159:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-甲氧基-3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):531(M+H)+;1H-NMR(DMSO-d6):δ 3.84(s,3H),5.87(s,2H),7.19-7.31(m,3H),7.43(d,1H),7.49-7.54(m,2H),7.60(dd,1H),7.80(d,1H),7.95(d,1H),8.71(s,2H),8.90(s,1H),9.03(s,1H)。
實施例15-160:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-甲氧基-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.91分);MASS(ESI,Pos.):531(M+H)+;1H-NMR(DMSO-d6):δ 3.80(s,3H),5.87(s,2H),6.83-6.90(m,1H),7.24-7.31(m,3H),7.41-7.45(m,1H),7.46-7.55(m,3H),7.94-7.97(m,1H),8.72(s,2H),8.98(s,1H),9.31(s,1H)。
實施例15-161:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3,4-雙(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.92分);
MASS(ESI,Pos.):553(M+H)+;1H-NMR(DMSO-d6):δ 5.58(s,2H),7.25-7.33(m,2H),7.38(dd,1H),7.51-7.58(m,2H),7.85-7.99(m,3H),8.19-8.23(m,1H),8.74(s,2H),9.17(s,1H),9.78(s,1H)。
實施例15-162:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-甲基-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):499(M+H)+;1H-NMR(DMSO-d6):δ 2.40(s,3H),5.58(s,2H),7.25-7.60(m,8H),7.94-7.96(m,1H),8.73(s,2H),8.98(s,1H),9.28(s,1H)。
實施例15-163:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-氟-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.86分);MASS(ESI,Pos.):503(M+H)+;1H-NMR(DMSO-d6):δ 5.58(s,2H),7.25-7.43(m,4H),7.50-7.58(m,2H),7.63-7.75(m,2H),7.94(d,1H),8.73(s,2H),9.10(s,1H),9.61(s,1H)。
實施例15-164:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-甲氧基-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):515(M+H)+;1H-NMR(DMSO-d6):δ 3.97(s,3H),5.57(s,2H),7.25-7.57(m,7H),7.94(d,1H),8.29-8.36(m,1H),8.69-8.75(m,3H),9.66(s,1H)。
實施例15-165:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-
嘧啶基}-3-[3-甲氧基-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.83分);MASS(ESI,Pos.):515(M+H)+;1H-NMR(DMSO-d6):δ 3.83(s,3H),5.57(s,2H),7.07-7.14(m,1H),7.25-7.32(m,2H),7.35-7.57(m,5H),7.93(d,1H),8.72(s,2H),8.97(s,1H),9.37(s,1H)。
實施例15-166:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-氟-3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):88%(保持時間:0.83分);MASS(ESI,Pos.):503(M+H)+;1H-NMR(DMSO-d6):δ 5.58(s,2H),7.25-7.32(m,2H),7.35-7.58(m,4H),7.65-7.75(m,1H),7.92-8.00(m,2H),8.72(s,2H),9.01(s,1H),9.31(s,1H)。
實施例15-167:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-甲氧基-3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.80分);MASS(ESI,Pos.):515(M+H)+;1H-NMR(DMSO-d6):δ 3.84(s,3H),5.58(s,2H),7.19-7.31(m,3H),7.38(dd,1H),7.50-7.57(m,2H),7.58-7.65(m,1H),7.78-7.83(m,1H),7.93-7.96(m,1H),8.72(s,2H),8.90(s,1H),9.03(s,1H)。
實施例15-168:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3-甲氧基-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.84分);MASS(ESI,Pos.):515(M+H)+;
1H-NMR(DMSO-d6):δ 3.80(s,3H),5.57(s,2H),6.86(s,1H),7.25-7.58(m,7H),7.94(d,1H),8.72(s,2H),8.98(s,1H),9.31(s,1H)。
實施例15-169:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2,6-二氟-3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.84分);MASS(ESI,Pos.):537(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.24-7.30(m,2H),7.37-7.55(m,4H),7.71-7.82(m,1H),7.95(d,1H),8.67(brs,1H),8.72(s,2H),9.38(brs,1H)。
實施例15-170:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2,6-二氟-3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.77分);MASS(ESI,Pos.):521(M+H)+;1H-NMR(DMSO-d6):δ 5.57(s,2H),7.24-7.31(m,2H),7.35-7.56(m,4H),7.71-7.82(m,1H),7.92-7.96(m,1H),8.66(s,1H),8.72(s,2H),9.37(s,1H)。
實施例15-171:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3,5-雙(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):569(M+H)+;1H-NMR(DMSO-d6):δ 5.87(s,2H),7.25-7.31(m,2H),7.42-7.45(m,1H),7.49-7.55(m,2H),7.65-7.70(m,1H),7.95-7.98(m,1H),8.15(s,2H),8.74(s,2H),9.21(s,1H),9.68(s,1H)。
實施例15-172:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3,5-雙(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.89分);MASS(ESI,Pos.):485(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.05-7.13(m,1H),7.25-7.37(m,3H),7.43(d,1H),7.48-7.56(m,2H),7.95(d,1H),8.20(dd,1H),8.74(s,2H),8.97(s,1H),9.28(s,1H)。
實施例15-173:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[3,5-雙(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.96分);MASS(ESI,Pos.):501(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.20(t,1H),7.25-7.31(m,2H),7.43(d,1H),7.49-7.56(m,4H),7.95(d,1H),8.72(s,2H),9.09(s,1H),9.33(s,1H)。
實施例15-174:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(3-氯-5-甲基苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.91分);MASS(ESI,Pos.):481(M+H)+;1H-NMR(DMSO-d6):δ 3.32(s,3H),5.86(s,2H),6.86-6.90(s,1H),7.10-7.15(m,1H),7.24-7.31(m,2H),7.42-7.55(m,4H),7.95(d,1H),8.72(s,2H),8.92(s,1H),9.06(s,1H)。
實施例15-175:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(3-氯-5-氟苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.90分);
MASS(ESI,Pos.):485(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),6.98-7.06(m,1H),7.25-7.55(m,7H),7.95(d,1H),8.72(s,2H),9.06(s,1H),9.36(s,1H)。
實施例15-176:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(5-氯-2-甲氧基苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.90分);MASS(ESI,Pos.):497(M+H)+;1H-NMR(DMSO-d6):δ 3.88(s,3H),5.86(s,2H),6.98-7.08(m,2H),7.25-7.32(m,2H),7.43(d,1H),7.49-7.55(m,2H),7.95(d,1H),8.18(d,1H),8.56(s,1H),8.72(s,2H),9.59(s,1H)。
實施例15-177:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(3-氯-5-甲氧基苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):497(M+H)+;1H-NMR(DMSO-d6):δ 3.74(s,3H),5.86(s,2H),6.60-6.66(m,1H),6.95-7.00(m,1H),7.15-7.20(m,1H),7.24-7.30(m,2H),7.43(d,1H),7.45-7.55(m,2H),7.95(d,1H),8.71(s,2H),8.93(s,1H),9.13(s,1H)。
實施例15-178:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.94分);MASS(ESI,Pos.):535(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.25-7.31(m,2H),7.34-7.40(m,1H),7.43(d,1H),7.49-7.55(m,2H),7.72(d,1H),7.95(d,1H),
8.10-8.14(m,1H),8.42(brs,1H),8.74(s,2H),9.67(brs,1H)。
實施例15-179:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(2,3-二氯苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.91分);MASS(ESI,Pos.):501(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.25-7.55(m,7H),7.96(d,1H),8.08-8.15(m,1H),8.66(s,1H),8.74(s,2H),9.65(s,1H)。
實施例15-180:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(4-氯-2-甲氧基苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.89分);MASS(ESI,Pos.):497(M+H)+;1H-NMR(DMSO-d6):δ 3.90(s,3H),5.86(s,2H),6.96(dd,1H),7.10(d,1 H),725-7.31(m,2H),7.42(d,1H),7.48-7.55(m,2H),7.95(d,1H),8.09(d,1H),8.45(s,1H),8.71(s,2H),9.52(s,1H)。
實施例15-181:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(4-氯-2-甲基苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):481(M+H)+;1H-NMR(DMSO-d6):δ 2.23(s,3H),5.86(s,2H),7.18-7.31(m,4H),7.42(d,1H),7.48-7.55(m,2H),7.80(d,1H),7.95(d,1H),8.22(s,1H),8.72(s,2H),9.21(s,1H)。
實施例15-182:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(4-氯-2-氟苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);
MASS(ESI,Pos.):485(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.20-7.55(m,7H),7.95(d,1H),8.09(t,1H),8.73(s,2H),8.56(s,1H),9.22(s,1H)。
實施例15-183:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-氯-2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.85分);MASS(ESI,Pos.):545(M+H)+;1H-NMR(DMSO-d6):δ 3.36(s,3H),5.86(s,2H),7.25-7.32(m,2H),7.43(d,1H),7.49-7.56(m,2H),7.75-7.84(m,2H),7.96(d,1H),8.21(d,1H),8.74(s,2H),8.79(s,1H),10.18(s,1H)。
實施例15-184:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-氯-3-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.75分);MASS(ESI,Pos.):545(M+H)+;1H-NMR(DMSO-d6):δ 3.35(s,3H),5.87(s,2H),7.25-7.32(m,2H),7.43(d,1H),7.49-7.55(m,2H),7.63(d,1H),7.78(dd,1H),7.95-7.96(m,1H),8.27(d,1H),8.73(s,2H),9.00(s,1H),9.56(s,1H)。
實施例15-185:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-氯-2-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):535(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.25-7.31(m,2H),7.42-7.45(m,1H),7.49-7.55(m,2H),7.71-7.79(m,2H),7.95-8.01(m,2H),8.38(s,1H),8.74(s,2H),9.57(s,1H)。
實施例15-186:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(2,3-二氫-1H-茚-5-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.49(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 2.00-2.10(m,2H),2.93(t,4H),5.85(s,2H),7.17(dd,1H),7.25-7.27(m,3H),7.37-7.44(m,4H),7.50(d,2H),7.95(d,1H),8.04(s,1H),8.45(s,1H),8.67(s,2H),9.45(s,1H)。
實施例15-187:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(2,3-二氫-1H-茚-5-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.44(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 2.00-2.10(m,2H),2.93(t,4H),5.57(s,2H),7.16(dd,1H),7.25-7.28(m,3H),7.35-7.44(m,4H),7.52(d,2H),7.93(d,1H),8.04(s,1H),8.45(s,1H),8.67(s,2H),9.45(s,1H)。
實施例15-188:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(2,3-二氫-1-苯并呋喃-5-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.28(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 3.25(t,2H),4.60(t,2H),5.85(s,2H),6.91(d,1H),7.14(dd,1H),7.24-7.29(m,3H),7.37-7.42(m,3H),7.50(d,2H),7.95(d,1H),8.03(s,1H),8.44(s,1H),8.67(s,2H),9.45(s,1H)。
實施例15-189:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(2,3-二氫-1-苯并呋喃-5-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.24(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 3.25(t,2H),4.60(t,2H),5.57(s,2H),6.91(d,1H),7.14(dd,1H),7.25-7.29(m,3H),7.35-7.42(m,3H),7.53(d,2H),7.94(d,1H),8.03(s,1H),8.45(s,1H),8.68(s,2H),9.45(s,1H)。
實施例15-190:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-{5-(二氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.40(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.08(d,1H),7.13(t,1H),7.26(d,2H),7.32-7.45(m,2H),7.51(d,2H),7.60(d,1H),7.92(d,1H),8.28(s,1H),8.41(s,1H),8.45(s,1H),8.65(s,2H),9.42(s,1H)。
實施例15-191:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-{4-氯-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
TLC:Rf 0.45(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.06(d,1H),7.25(d,2H),7.36(dd,1H),7.49-7.62(m,4H),7.92(d,1H),8.02(d,1H),8.35(s,1H),8.38-8.42(m,1H),8.64(s,2H),9.36(s,1H)。
實施例15-192:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2,3-二氟-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):93%(保持時間:0.89分);MASS(ESI,Pos.):521(M+H)+;1H-NMR(DMSO-d6):δ 5.57(s,2H),7.26-7.33(m,2H),7.38(dd,1H),7.51-7.62(m,3H),7.94(d,1H),8.13-8.22(m,1H),8.75(s,2H),9.36(s,2H)。
實施例15-193:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-
嘧啶基}-3-[3-氯-2-氟-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):553(M+H)+;
實施例15-194:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(5-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.89分);MASS(ESI,Pos.):626(M+H)+;1H-NMR(DMSO-d6):δ 2.38(s,3H),6.48(s,2H),7.24-8.54(m,13H),8.66(s,2H),9.29(s,1H)。
實施例15-195:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.09分);MASS(ESI,Pos.):611(M+H)+;1H-NMR(DMSO-d6):δ 6.48(s,2H),7.25-7.31(m,2H),7.40-7.59(m,10H),8.09(s,1H),8.26-8.30(m,1H),8.40-8.44(m,1H),8.66(s,2H),9.40(s,1H)。
實施例15-196:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[5-苯基-2-(三氟甲基)-4-吡啶基]脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);MASS(ESI,Pos.):612(M+H)+;1H-NMR(DMSO-d6):δ 6.48(s,2H),7.26-7.32(m,2H),7.49-7.66(m,8H),8.27-8.30(m,1H),8.42-8.46(m,2H),8.69(s,2H),8.75(s,1H),9.74(s,1H)。
實施例15-197:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]
苯氧基}-5-嘧啶基)-3-[2-苯基-5-(三氟甲基)-3-吡啶基]脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):612(M+H)+;1H-NMR(DMSO-d6):δ 6.48(s,2H),7.25-7.32(m,2H),7.49-7.70(m,8H),8.26-8.30(m,1H),8.43(s,1H),8.68(s,2H),8.74-8.75(m,1H),8.76-8.78(m,1H),9.47(s,1H)。
實施例15-198:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[3’,4’-二甲基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.17分);MASS(ESI,Pos.):639(M+H)+;1H-NMR(DMSO-d6):δ 2.29(s,6H),6.48(s,2H),7.12-7.58(m,10H),8.01(s,1H),8.26-8.30(m,1H),8.45-8.48(m,1H),8.67(s,2H),9.46(s,1H)。
實施例15-199:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(6-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):98%(保持時間:0.84分);MASS(ESI,Pos.):626(M+H)+;1H-NMR(DMSO-d6):δ 2.55(s,3H),6.48(s,2H),7.25-7.32(m,2H),7.39-7.59(m,6H),7.75-7.80(m,1H),8.19-8.23(m,1H),8.26-8.30(m,1H),8.41-8.44(m,1H),8.49-8.53(m,1H),8.67(s,2H),9.28(s,1H)。
實施例15-200:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.96分);MASS(ESI,Pos.):535(M+H)+;
1H-NMR(DMSO-d6):δ 6.49(s,2H),7.26-7.36(m,3H),7.48-7.66(m,5H),7.96-8.00(m,1H),8.27-8.30(m,1H),8.73(s,2H),8.99(s,1H),9.33(s,1H)。
實施例15-201:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-氟-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):553(M+H)+;1H-NMR(DMSO-d6):δ 6.49(s,2H),7.26-7.34(m,2H),7.49-7.59(m,4H),7.72(dd,1H),8.26-8.31(m,1H),8.37(t,1H),8.75(s,2H),9.14(s,1H),9.34(s,1H)。
實施例15-202:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-氟-4-(三氟甲基)苯基]脲
TLC:Rf 0.28(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.20(t,3H),2.68(q,2H),5.57(s,2H),7.25-7.46(m,5H),7.51-7.58(m,2H),7.94(d,1H),8.25(s,1H),8.38(s,1H),8.75(s,2H),9.34(s,1H)。
實施例15-203:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(6-乙基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.34(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 1.29(t,3H),2.84(q,2H),5.86(brs,2H),7.26(d,2H),7.39-7.54(m,6H),7.80(dd,1H),7.95(d,1H),8.24(s,1H),8.40(s,1H),8.54(d,1H),8.67(s,2H),9.26(s,1H)。
實施例15-204:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(6-乙基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.34(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 1.29(t,3H),2.84(q,2H),5.58(brs,2H),7.26(d,2H),7.37(dd,1H),7.41-7.55(m,5H),7.80(dd,1H),7.94(d,1H),8.24(s,1H),8.40(s,1H),8.54(d,1H),8.67(s,2H),9.26(s,1H)。
實施例15-205:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(5-乙基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.33(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 1.23(t,3H),2.70(q,2H),5.86(brs,2H),7.26(d,2H),7.42(d,1H),7.45-7.55(m,4H),7.73(s,1H),7.95(dd,1H),8.23(s,1H),8.38(s,1H),8.47(d,1H),8.54(d,1H),8.65(s,2H),9.27(s,1H)。
實施例15-206:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(5-乙基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.33(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 1.23(t,3H),2.70(q,2H),5.57(brs,2H),7.26(d,2H),7.37(dd,1H),7.47-7.56(m,4H),7.73(t,1H),7.93(d,1H),8.23(s,1H),8.38(s,1H),8.47(d,1H),8.54(d,1H),8.65(s,2H),9.27(s,1H)。
實施例15-207:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-異丙基-5-(三氟甲基)苯基]脲
TLC:Rf 0.38(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.22(d,6H),3.14-3.27(m,1H),5.57(s,2H),7.26-7.33(m,2H),7.36-7.57(m,5H),7.94(d,1H),8.12-8.15(m,1H),8.43(s,1H),8.74(s,2H),9.28(s,1H)。
實施例15-208:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-4-(三氟甲基)苯基]脲
TLC:Rf 0.62(乙酸乙酯);1H-NMR(DMSO-d6):δ 3.42(s,3H),5.58(s,2H),7.27-7.34(m,2H),7.38(dd,1H),7.52-7.60(m,2H),7.94(d,1H),8.05-8.12(m,2H),8.46-8.56(m,1H),8.76(s,2H),9.04(s,1H),10.36(s,1H)。
實施例15-209:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(4-氰基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.20(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.26(d,2H),7.41(dd,1H),7.50(d,2H),7.58(d,1H),7.73(d,1H),7.94(dd,1H),8.52(s,1H),8.54(s,1H),8.69(s,2H),8.80(s,1H),9.13(s,1H),9.63(s,1H)。
實施例15-210:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(4-氰基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.16(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.56(s,2H),7.26(d,2H),7.37(dd,1H),7.52(d,2H),7.58(d,1H),7.73(d,1H),7.92(d,1H),8.52(s,1H),8.54(s,1H),8.68(s,2H),8.80(s,1H),9.13(s,1H),9.63(s,1H)。
實施例15-211:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-苯基脲
純度(LC-MS/ELSD):100%(保持時間:0.77分);MASS(ESI,Pos.):433(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),6.98(t,1H),7.23-7.32(m,4H),7.41-7.55(m,5H),7.95(dd,1H),8.72(s,2H),8.85(s,1H),8.93(s,1H)。
實施例15-212:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-(三氟甲基)-2-噻吩基]脲
純度(LC-MS/ELSD):100%(保持時間:0.90分);MASS(ESI,Pos.):507(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),6.62-6.66(m,1H),7.25-7.32(m,2H),7.38-7.45(m,2H),7.49-7.55(m,2H),7.95(d,1H),8.72(s,2H),9.23(s,1H),10.60(s,1H)。
實施例15-213:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(4-嗎啉基)-3-吡啶基]脲
純度(LC-MS/ELSD):100%(保持時間:0.71分);MASS(ESI,Pos.):519(M+H)+;1H-NMR(DMSO-d6):δ 2.96-3.03(m,4H),3.80-3.86(m,4H),5.86(s,2H),7.08(dd,1H),7.25-7.32(m,2H),7.43(d,1H),7.48-7.55(m,2H),7.95-8.02(m,2H),8.14(s,1H),8.28(dd,1H),8.74(s,2H),9.71(s,1H)。
實施例15-214:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(2,3-二氫-1-苯并呋喃-7-基)脲
純度(LC-MS/ELSD):100%(保持時間:0.80分);MASS(ESI,Pos.):475(M+H)+;1H-NMR(DMSO-d6):δ 3.22(t,2H),4.60(t,2H),5.86(s,2H),6.76(t,1H),6.89(d,1H),7.24-7.30(m,2H),7.42(d,1H),7.49-7.55(m,2H),7.77(d,1H),7.95-7.98(m,1H),8.35(s,1H),8.71(s,2H),9.24(s,1H)。
實施例15-215:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(2,3-二氫-1-苯并呋喃-5-基)脲
純度(LC-MS/ELSD):100%(保持時間:0.75分);MASS(ESI,Pos.):475(M+H)+;1H-NMR(DMSO-d6):δ 3.14(t,2H),4.47(t,2H),5.86(s,2H),6.67(d,1H),7.06(dd,1H),7.24-7.29(m,2H),7.34-7.38(m,1H),7.42-7.44(m,1H),7.48-7.55(m,2H),7.95-7.98(m,1H),8.65-8.97(m,4H)。
實施例15-216:2-[({2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N,N-二甲基-4-(三氟甲基)苯磺醯胺
TLC:Rf 0.57(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 2.76(s,6H),5.57(s,2H),7.26-7.32(m,2H),
7.38(dd,1H),7.51-7.64(m,3H),7.92-7.98(m,2H),8.61(s,1H),8.74(s,2H),8.99(s,1H),10.31(s,1H)。
實施例15-217:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:0.76分);MASS(ESI,Pos.):511(M+H)+;1H-NMR(DMSO-d6):δ 3.28(s,3H),5.87(s,2H),7.26-7.34(m,3H),7.42-7.45(m,1H),7.49-7.55(m,2H),7.66-7.73(m,1H),7.85(dd,1H),7.95-7.98(m,1H),8.15(d,1H),8.75(s,2H),8.77(s,1H),10.13(s,1H)。
實施例15-218:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.69分);MASS(ESI,Pos.):495(M+H)+;1H-NMR(DMSO-d6):δ 3.28(s,3H),5.57(s,2H),7.25-7.34(m,3H),7.38(dd,1H),7.51-7.57(m,2H),7.69(td,1H),7.85(dd,1H),7.94(d,1H),8.15(d,1H),8.75(s,2H),8.77(s,1H),10.13(s,1H)。
實施例15-219:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.85分);MASS(ESI,Pos.):545(M+H)+;1H-NMR(DMSO-d6):δ 3.28(s,3H),6.49(s,2H),7.26-7.33(m,3H),7.50-7.59(m,3H),7.69(td,1H),7.85(dd,1H),8.15(d,1H),8.26-8.30(m,1H),8.75-8.81(m,3H),10.13(s,1H)。
實施例15-220:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-(5-氯-2-甲基苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.82分);MASS(ESI,Pos.):465(M+H)+;1H-NMR(DMSO-d6):δ 2.22(s,3H),5.57(s,2H),7.00(dd,1H),7.20(d,1H),7.28(d,2H),7.38(dd,1H),7.52(d,2H),7.93(d,1H),7.97(d,1H),8.26(s,1H),8.74(s,2H),9.30(s,1H)。
實施例15-221:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[3’-(羥甲基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):99%(保持時間:1.01分);MASS(ESI,Pos.):641(M+H)+;1H-NMR(DMSO-d6):δ 4.58(d,2H),5.28(t,1H),6.48(s,2H),7.22-7.58(m,11H),8.06(s,1H),8.27(s,1H),8.42(s,1H),8.66(s,2H),9.42(s,1H)。
實施例15-222:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-{5-氯-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):635(M+H)+;1H-NMR(DMSO-d6):δ 6.48(s,2H),7.08(d,1H),7.22-7.35(m,3H),7.43-7.59(m,4H),8.18(d,1H),8.23-8.29(m,1H),8.36-8.42(m,2H),8.66(s,2H),9.44(s,1H)。
實施例15-223:2-{[(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-N-甲基-4-(三氟甲基)苯磺醯胺
TLC:Rf 0.36(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 3.27-3.38(m,3H),6.49(s,2H),7.27-7.34(m,2H),7.49-7.63(m,4H),7.93-7.99(m,1H),8.02-8.13(m,1H),8.28(s,1H),8.56(s,1H),8.75(s,2H),8.90(s,1H),10.23(s,1H)。
實施例15-224:2-[({2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N,N-二甲基-4-(三氟甲基)苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):608(M+H)+;1H-NMR(DMSO-d6):δ 2.76(s,6H),5.87(s,2H),7.28(d,2H),7.43(d,1H),7.52(d,2H),7.60(d,1H),7.92-7.98(m,2H),8.61(s,1H),8.75(s,2H),8.99(s,1H),10.31(s,1H)。
實施例15-225:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[5-甲基-2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.92分);MASS(ESI,Pos.):559(M+H)+;1H-NMR(DMSO-d6):δ 2.37(s,3H),3.24(s,3H),6.49(s,2H),7.12(d,1H),7.28(d,2H),7.52(d,2H),7.55(d,1H),7.73(d,1H),7.99(s,1H),8.26-8.29(m,1H),8.72(s,1H),8.75(s,2H),10.12(s,1H)。
實施例15-226:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[5-氯-2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.97分);MASS(ESI,Pos.):579(M+H)+。
實施例15-227:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-
嘧啶基}-3-[5-氟-2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.85分);MASS(ESI,Pos.):529(M+H)+;1H-NMR(DMSO-d6):δ 3.15(d,3H),5.87(s,2H),7.10-7.19(m,1H),7.28(d,2H),7.43(d,1H),7.52(d,2H),7.92(dd,1H),7.96(d,1H),8.11(dd,1H),8.75(s,2H),8.95(s,1H),10.29(s,1H)。
實施例15-228:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(甲硫基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.30(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 2.53(s,3H),6.47(s,2H),7.27(d,2H),7.40(dd,1H),7.48-7.57(m,4H),8.18(s,1H),8.24-8.28(m,1H),8.44(s,1H),8.73(s,2H),9.64(s,1H)。
實施例15-229:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[4-氟-3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.94分);MASS(ESI,Pos.):519(M+H)+;1H-NMR(DMSO-d6):δ 5.86(s,2H),7.27(d,2H),7.40-7.57(m,4H),7.64-7.72(m,1H),7.94-7.99(m,2H),8.73(s,2 H),9.03(s,1H),9.33(s,1H)。
實施例15-230:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[3’-(1-羥乙基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.05分);MASS(ESI,Pos.):655(M+H)+;1H-NMR(DMSO-d6):δ 1.36(d,3H),4.79(quint,1H),5.20(d,1H),
6.48(s,2H),7.27(d,2H),7.27-7.35(m,1H),7.39-7.58(m,8H),8.09(s,1H),8.27(d,1H),8.37(s,1H),8.66(s,2H),9.40(s,1H)。
實施例15-231:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[5-氯-2-(甲硫基)苯基]脲
TLC:Rf 0.55(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.42(s,3H),6.48(s,2H),7.08-7.14(m,1H),7.27(d,2H),7.43(d,1H),7.51(d,2H),7.55(d,1H),8.06(d,1H),8.25-8.28(m,1H),8.48(s,1H),8.73(s,2H),9.76(s,1H)。
實施例15-232:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(甲硫基)苯基]脲
TLC:Rf 0.42(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.42(s,3H),5.57(s,2H),7.10(dd,1H),7.27(d,2H),7.37(dd,1H),7.43(d,1H),7.52(d,2H),7.93(d,1H),8.06(d,1H),8.48(s,1H),8.73(s,2H),9.76(s,1H)。
實施例15-233:1-{2-[4-(2-胺基-5-氟-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(甲亞磺醯基)苯基]脲
TLC:Rf 0.61(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 2.85(s,3H),6.48(s,2H),7.27(d,2H),7.32-7.41(m,2H),7.53(d,2H),7.67(d,1H),7.93(d,1H),8.00(d,1H),8.73(s,2H),9.23(s,1H),9.69(s,1H)。
實施例15-234:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);
MASS(ESI,Pos.):615(M+H)+;1H-NMR(DMSO-d6):δ 3.65(s,3H),6.48(s,2H),7.27(d,2H),7.46-7.61(m,6H),7.62(d,1H),8.10(s,1H),8.27(d,1H),8.56(s,1H),8.68(s,2H),9.50(s,1H)。
實施例15-235:2-[({2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N-乙基-N-甲基-4-(三氟甲基)苯磺醯胺
TLC:Rf 0.65(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.04(t,3H),2.80(s,3H),3.20(q,2H),5.85(s,2H),7.26-7.32(m,2H),7.43(d,1H),7.50-7.55(m,2H),7.57-7.62(m,1H),7.94-8.01(m,2H),8.54-8.58(m,1H),8.75(s,2H),8.92(s,1H),10.30(s,1H)。
實施例15-236:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(四氫-2H-吡喃-4-基)脲
純度(LC-MS/ELSD):100%(保持時間:0.65分);MASS(ESI,Pos.):441(M+H)+;1H-NMR(DMSO-d6):δ 1.32-1.50(m,2H),1.71-1.83(m,2H),3.32-3.42(m,2H),3.60-3.89(m,3H),5.85(s,2H),6.48(d,1H),7.22-7.28(m,2H),7.42(d,1H),7.47-7.54(m,2H),7.95(d,1H),8.54(s,1H),8.65(s,2H)。
實施例15-237:rel-1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[(1R,2S,5R)-2-異丙基-5-甲基環己基]脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):495(M+H)+;1H-NMR(DMSO-d6):δ 0.70-1.15(m,12H),1.32-2.04(m,6H),3.31-3.50(m,1H),5.85(s,2H),6.21(d,1H),7.21-7.28(m,2H),7.42(d,1H),7.47-7.54(m,2H),7.95(d,1H),8.48(s,1H),8.65-8.69(m,2H)。
實施例15-238:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(2-羥基環己基)脲
純度(LC-MS/ELSD):100%(保持時間:0.67分);MASS(ESI,Pos.):455(M+H)+;1H-NMR(DMSO-d6):δ 1.00-1.35(m,4H),1.45-1.70(m,2H),1.78-1.97(m,2H),3.15-3.38(m,2H),4.68(d,1H),5.85(s,2H),6.28(d,1H),7.22-7.28(m,2H),7.41(d,1H),7.47-7.54(m,2H),7.94-7.98(m,1H),8.62-8.69(m,3H)。
實施例15-239:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-(2-羥基環己基)脲
純度(LC-MS/ELSD):100%(保持時間:0.65分);MASS(ESI,Pos.):455(M+H)+;
實施例15-240:2-[({2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N,N-二乙基-4-(三氟甲基)苯磺醯胺
TLC:Rf 0.45(氯仿:甲醇=19:1);
1H-NMR(DMSO-d6):δ 1.03(s,6H),3.30(q,4H),5.87(s,2H),7.25-7.31(m,2H),7.43(d,1H),7.49-7.56(m,2H),7.58(dd,1H),7.96(d,1H),8.00(d,1H),8.49(d,1H),8.75(s,2H),8.84(s,1H),10.30(s,1H)。
實施例15-241:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[5-氯-2-(4-氰基-1H-吡唑-1-基)苯基]脲
TLC:Rf 0.40(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 5.85(s,2H),7.23-7.32(m,3H),7.42(d,1H),7.47-7.54(m,3H),7.95(d,1H),8.24(d,1H),8.48(s,1H),8.56(s,1H),8.68(s,2H),9.04(s,1H),9.56(s,1H)。
實施例15-242:2-[({2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N-甲基苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:0.80分);MASS(ESI,Pos.):526(M+H)+;1H-NMR(DMSO-d6):δ 2.46(s,3H),6.04(brs,2H),7.19-7.33(m,3H),7.47-7.65(m,4H),7.72-7.80(m,2H),7.98(d,1H),8.12(d,1H),8.71-8.79(m,3H),10.06(s,1H)。
實施例15-243:2-[({2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N-丙基-4-(三氟甲基)苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):622(M+H)+;1H-NMR(DMSO-d6):δ 0.77(t,3H),1.32-1.47(m,2H),2.77-2.88(m,2H),6.15(brs,2H),7.27-7.35(m,2H),7.50-7.62(m,4H),7.96-8.04(m,2H),8.17-8.25(m,1H),8.54(s,1H),8.76(s,2H),8.89(s,1H),
10.22(s,1H)。
實施例15-244:2-[({2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N,N-二甲基苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:0.85分);MASS(ESI,Pos.):540(M+H)+;1H-NMR(DMSO-d6):δ 2.69(s,6H),5.86(s,2H),7.25-7.32(m,3H),7.43(d,1H),7.49-7.56(m,2H),7.62-7.78(m,2H),7.96(d,1H),8.14(d,1H),8.74(s,2H),8.80(s,1H),10.14(s,1H)。
實施例15-245:2-[({2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N-(2-羥丙基)-N-甲基-4-(三氟甲基)苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:0.97分);MASS(ESI,Pos.):652(M+H)+;
實施例15-246:2-{[(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-N-乙基-N-甲基-4-(三氟甲基)苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:1.07分);MASS(ESI,Pos.):656(M+H)+;1H-NMR(DMSO-d6):δ 1.04(s,3H),2.80(s,3H),3.20(q,2H),6.49(s,2H),7.25-7.32(m,2H),7.50-7.64(m,4H),7.97(d,1H),8.26-8.29(m,1H),8.55(d,1H),8.75(s,2H),8.93(s,1H),10.31(s,1H)。
實施例15-247:2-{[(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-N,N-二乙基-4-(三氟甲基)苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:1.09分);MASS(ESI,Pos.):670(M+H)+;1H-NMR(DMSO-d6):δ 1.03(s,6H),3.27-3.35(m,4H),6.48(s,2H),7.25-7.32(m,2H),7.50-7.61(m,4H),8.00(d,1H),8.27-8.30(m,1H),8.47-8.49(m,1H),8.75(s,2H),8.85(s,1H),10.30(s,1H)。
實施例15-248:1-(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)-3-[2-(1-氮雜環丁烷基磺醯基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.05分);MASS(ESI,Pos.):654(M+H)+;1H-NMR(DMSO-d6):δ 2.02-2.15(m,2H),3.77-3.82(m,4H),6.49(s,2H),7.25-7.32(m,2H),7.49-7.66(m,4H),7.99(d,1H),8.26-8.29(m,1H),8.68(d,1H),8.75(s,2H),8.94(s,1H),10.35(s,1H)。
實施例15-249:2-{[(2-{4-[2-胺基-5-(三氟甲基)-3-吡啶基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-N-(2-羥丙基)-N-甲基-4-(三氟甲基)苯磺醯胺
LC-MS/ELSD:保持時間:1.02分;MASS(ESI,Pos.):686(M+H)+;
實施例15-250:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(3-羥基-3-甲基丁基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.95分);MASS(ESI,Pos.):587(M+H)+;1H-NMR(DMSO-d6):δ 1.17(s,6H),1.61-1.70(m,2H),2.63-2.75(m,2H),4.37(s,1H),5.86(s,2H),7.27(d,2H),7.32-7.44(m,3H),7.51
(d,2H),7.95(d,1H),8.09(s,1H),8.39(s,1H),8.74(s,2H),9.28(s,1H)。
實施例15-251:1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(3-羥基-3-甲基-1-丁炔-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):583(M+H)+;1H-NMR(DMSO-d6):δ 1.54(s,6H),5.60(s,1H),5.86(s,2H),7.28(d,2H),7.35(dd,1H),7.43(d,1H),7.52(d,2H),7.58(d,1H),7.96(d,1H),8.32(s,1H),8.35(d,1H),8.74(s,2H),9.84(s,1H)。
實施例16
使用4-胺基-5-溴嘧啶替代3-溴-5-氯吡啶-2-胺,使用相當之胺基甲酸酯化合物或異氰酸酯化合物替代實施例3製造之化合物,進行與實施例6→實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例16-1:1-(2-(4-(4-胺基嘧啶-5-基)苯氧基)嘧啶-5-基)-3-(2-氯-5-(三氟甲基)苯基)脲
TLC:Rf 0.58(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 6.66(s,2H),7.29(d,2H),7.40(d,1H),7.48(d,2H),7.75(d,1H),8.03(s,1H),8.36(s,1H),8.57(s,1H),8.75-8.79(m,3H),9.72(s,1H)。
實施例16-2:1-(2-(4-(4-胺基嘧啶-5-基)苯氧基)嘧啶-5-基)-3-(2-氟-5-(三氟甲基)苯基)脲
TLC:Rf 0.51(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 6.67(s,2H),7.28(d,2H),7.43-7.54(m,4H),8.03(s,1H),8.36(s,1H),8.52(d,1H),8.75(s,2H),9.10(s,1H),9.30(s,1H)。
實施例16-3:1-(2-(4-(4-胺基嘧啶-5-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.45(乙酸乙酯:甲醇:氨水=9:1:0.5);1H-NMR(DMSO-d6):δ 6.66(s,2H),7.26(d,2H),7.45-7.58(m,5H),7.89(d,1H),8.03(s,1H),8.24(s,1H),8.35(s,1H),8.38(s,1H),8.60-8.68(m,4H),9.24(s,1H)。
實施例16-4:1-(2-(4-(4-胺基嘧啶-5-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.51(乙酸乙酯:甲醇:氨水=9:1:0.5);1H-NMR(DMSO-d6):δ 6.67(s,2H),7.27-7.34(m,3H),7.47-7.54(m,3H),7.62(d,1H),7.97(s,1H),8.03(s,1H),8.36(s,1H),8.75(s,2H),8.99(s,1H),9.32(s,1H)。
實施例16-5:1-(2-(4-(4-胺基嘧啶-5-基)苯氧基)嘧啶-5-基)-3-(2-苯基-5-(三氟甲基)吡啶-3-基)脲
TLC:Rf 0.25(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.65(s,2H),7.26(d,2H),7.45-7.67(m,7H),8.02(s,1H),8.35(s,1H),8.55(s,1H),8.67(s,2H),8.72(s,1H),8.74(s,1H),9.60(s,1H)。
實施例16-6:1-(2-(4-(4-胺基嘧啶-5-基)苯氧基)嘧啶-5-基)-3-(2-(3,4-二甲基苯基)-5-(三氟甲基)吡啶-3-基)脲
TLC:Rf 0.68(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 2.31(s,6H),6.65(s,2H),7.25-7.48(m,7H),8.02(s,1H),8.35-8.40(m,2H),8.60-8.65(m,3H),8.77(s,1H),9.55(s,1H)。
實施例16-7:1-(2-(4-(4-胺基嘧啶-5-基)苯氧基)嘧啶-5-基)-3-(3-(第三丁基)-1-(2,3-二氫-1H-茚-5-基)-1H-吡唑-5-基)脲
TLC:Rf 0.49(乙酸乙酯:甲醇=10:1);1H-NMR(DMSO-d6):δ 1.25(s,9H),2.05(quint.,2H),2.85-2.95(m,4H),6.33(s,1H),6.65(s,2H),7.18-7.30(m,3H),7.30-7.36(m,2H),7.46(d,2H),8.02(s,1H),8.35(s,1H),8.56(s,1H),8.66(s,2H),
9.19(s,1H)。
實施例16-8:1-(2-(4-(4-胺基嘧啶-5-基)苯氧基)嘧啶-5-基)-3-(3-(第三丁基)-1-(鄰-甲苯基)-1H-吡唑-5-基)脲
TLC:Rf 0.48(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.25(s,9H),1.99(s,3H),6.34(s,1H),6.66(s,2H),7.25(d,2H),7.31-7.48(m,6H),8.02(s,1H),8.35(s,1H),8.40(s,1H),8.64(s,2H),9.07(s,1H)。
實施例17:3-溴-5-氯吡唑并[1,5-a]嘧啶
將5-氯吡唑并[1,5-a]嘧啶(9g)之THF(147mL)溶液於5℃攪拌。於反應混合物中加入N-溴丁二醯亞胺(11g),於室溫攪拌1小時。於反應混合物中加入亞硫酸氫鈉水溶液,攪拌5分鐘後減壓蒸餾除去THF。於獲得之殘渣中加入飽和碳酸鈉水溶液,以乙酸乙酯萃取。將獲得之有機層以飽和碳酸鈉水溶液洗淨2次,以水洗淨1次及以飽和食鹽水洗淨1次。獲得之有機層以硫酸鈉乾燥,過濾後蒸餾除去溶劑,獲得具有以下物性值之標題化合物(13.6g)。
TLC:Rf 0.40(己烷:乙酸乙酯=4:1);1H-NMR(CD CL3):δ 6.85(d,1H),8.12(s,1H),8.54(d,1H)。
實施例18:3-溴-5-(吡咯啶-1-基)吡唑并[1,5-a]嘧啶
於實施例17製造之化合物(2.5g)之二甲亞碸(以下,簡稱為DMSO)(20mL)溶液中加入三乙胺(2.25mL)及吡咯啶(1.3mL),於室溫攪拌1小時。將反應混合物倒入碳酸氫鈉水溶液
中,以乙酸乙酯萃取。獲得之有機層以水及飽和食鹽水洗淨,以無水硫酸鈉乾燥。將獲得之有機層過濾後蒸餾除去溶劑。於獲得之殘渣中加入第三丁基甲醚,濾取,獲得具有以下物性值之標題化合物(2.49g)。
TLC:Rf 0.30(己烷:乙酸乙酯=2:1);1H-NMR(DMSO-d6):δ 1.95-2.12(br s,4H),3.35-3.85(br s,4H),6.14(d,1H),7.80(s,1H),8.18(d,1H)。
實施例19:2-(4-(5-(吡咯啶-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-胺
使用實施例18製造之化合物替代3-溴-5-氯吡啶-2-胺,進行與實施例6相同之操作,獲得具有以下物性值之標題化合物。
TLC:Rf 0.52(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 1.94-2.08(br s,4H),3.40-3.74(br s,4H),5.05-5.35(br s,2H),6.41(d,1H),7.04(d,2H),7.96(s,2H),8.05(d,2H),8.33(s,1H),8.61(d,1H)。
實施例20:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(5-(吡咯啶-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
使用實施例19製造之化合物替代實施例6製造之化合物,進行與實施例7相同之操作,獲得具有以下物性值之本發明化合物。
TLC:Rf 0.50(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.94-2.08(br s,4H),3.40-3.72(br s,4H),6.42(d,1H),6.67(dd,1H),7.15(d,2H),7.51(dd,1H),7.74(d,1H),7.95(d,1H),8.10(d,2H),8.36(s,1H),8.40(d,1H),8.58(d,1H),8.62(d,1H),8.67(s,2H),9.68(br s,1H),9.92(br s,1H)。
實施例21
使用實施例19製造之化合物,或者使用相當之胺化合物替代實施例19製造之化合物,使用實施例3製造之化合物,或者使用相當之胺基甲酸酯化合物或異氰酸酯化合物替代實施例3製造之化合物,進行與實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例21-1:1-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.22(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.12-4.18(m,4H),6.23(d,1H),7.10-7.16(m,2H),7.46-7.58(m,3H),7.86-7.90(m,1H),8.03-8.09(m,2H),8.22(s,1H),8.35-8.39(m,2H),8.60-8.68(m,5H),9.21(s,1H)。
實施例21-2:1-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.33(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.37(t,2H),3.65(s,3H),4.15(t,4H),6.23(d,1H),6.44(d,1H),7.14(d,2H),7.48(d,2H),7.61(d,1H),8.04-8.10(m,3H),8.36(s,1H),8.55(s,1H),8.62(d,1H),8.64(s,2H),9.46(s,1H)。
實施例21-3:1-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(3-甲基-1H-吡唑-1-基)-5-(三氟
甲基)苯基)脲
TLC:Rf 0.66(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.35-2.44(m,5H),4.15(t,4H),6.24(d,1H),6.44(d,1H),7.14(d,2H),7.48(dd,1H),7.69(d,1H),8.06(d,2H),8.26(d,1H),8.36(s,1H),8.56(d,1H),8.62(d,1H),8.67(s,2H),9.78(s,1H),9.87(s,1H)。
實施例21-4:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.47(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.37(t,2H),4.15(t,4H),6.24(d,1H),6.68(d,1H),7.14(d,2H),7.51(dd,1H),7.74(d,1H),7.95(d,1H),8.07(d,2H),8.36(s,1H),8.40(d,1H),8.58-8.67(m,4H),9.68(s,1H),9.92(s,1H)。
實施例21-5:1-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.19(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.33-2.43(m,2H),4.06-4.12(m,4H),6.25(d,1H),7.13-7.20(m,2H),7.33(d,1H),7.52(t,1H),7.62(d,1H),7.98(s,1H),8.05-8.12(m,2H),8.39(s,1H),8.65(d,1H),8.71(s,2H),
8.96(s,1H),9.31(s,1H)。
實施例21-6:1-(2-(吡啶-3-基)-5-(三氟甲基)苯基)-3-(2-(4-(5-(吡咯啶-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.34(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.94-2.05(m,4H),3.51-3.67(m,4H),6.43(d,1H),7.14(d,2H),7.47-7.58(m,3H),7.89(dd,1H),8.10(d,2H),8.23(s,1H),8.38(d,2H),8.61-8.68(m,5H),9.22(s,1H)。
實施例21-7:1-(2-(4-(5-(吡咯啶-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.68(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.95-2.04(m,4H),3.52-3.65(m,4H),6.44(d,1H),7.24(d,2H),7.46(d,1H),7.57(t,2H),7.72(d,1H),7.93(s,1H),8.16(d,2H),8.36(s,1H),8.64(d,1H),8.76(s,2H),10.23(s,1H)。
實施例21-8:1-(2-苯基-5-(三氟甲基)吡啶-3-基)-3-(2-(4-(5-(吡咯啶-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.76(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.92-2.05(m,4H),3.52-3.65(m,4H),6.43(d,1H),7.15(d,2H),7.56(d,3H),7.65-7.68(m,2H),8.11(d,2H),8.39(s,1H),8.41(s,1H),8.62(d,1H),8.65(s,2H),8.72(s,1H),8.76(s,1H),9.44(s,1H)。
實施例21-9:1-(2-(4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.45(乙酸乙酯);1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.21(d,2H),7.46-7.58(m,3H),7.89(dt,1H),8.10(d,2H),8.23(s,1H),8.39(s,1H),8.58(s,1H),8.64-8.68(m,4H),8.93(d,1H),9.23(s,1H)。
實施例21-10:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.45(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 4.04(s,3H),6.62(d,1H),6.68(t,1H),7.20-7.26(m,2H),7.53(dd,1H),7.76(d,1H),7.96(d,1H),8.09-8.14(m,2H),8.42(d,1H),8.58-8.61(m,2H),8.70(s,2H),8.94(d,1H),9.71(s,1H),9.96(s,1H)。
實施例21-11:1-(2-(4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.45(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 4.04(s,3H),6.62(d,1H),7.21-7.27(m,2H),7.33(d,1H),7.52(t,1H),7.63(d,1H),7.96-8.00(m,1H),8.10-8.15(m,2H),8.59(s,1H),8.72(s,2H),8.94(d,1H),8.99(s,1H),9.32(s,1H)。
實施例21-12:1-(2-(4-(5-((2-羥基-2-甲基丙基)胺基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.41(氯仿:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.19(s,6H),3.43(d,2H),4.62(s,1H),6.48(d,1H),7.14-7.20(m,2H),7.33(d,1H),7.48-7.56(m,2H),7.63(d,1H),7.96-8.00(m,1H),8.06-8.12(m,2H),8.31(s,1H),8.47(d,1H),8.71(s,2H),8.97(s,1H),9.32(s,1H)。
實施例21-13:1-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.22(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.11(dd,1H),7.24(d,2H),7.47-7.58(m,3H),7.86-7.91(m,1H),8.16(d,2H),8.22(s,1H),8.39(s,1H),8.60-8.68(m,5H),8.76(s,1H),9.16(dd,1H),9.23(s,1H)。
實施例21-14:1-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.65(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.11(dd,1H),7.25(d,2H),7.32(d,1H),7.51(t,1H),7.61(d,1H),7.97(s,1H),8.17(d,2H),8.66(dd,1H),8.71(s,
2H),8.76(s,1H),8.98(s,1H),9.16(dd,1H),9.32(s,1H)。
實施例21-15:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.74(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.67(t,1H),7,11(dd,1H),7.25(d,2H),7.52(dd,1H),7.74(d,1H),7.95(d,1H),8.17(d,2H),8.40(d,1H),8.58(d,1H),8.64-8.70(m,3H),8.75(s,1H),9.15(dd,1H),9.67(s,1H),9.94(s,1H)。
實施例21-16:1-(2-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.60(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.10(dd,1H),7.24(d,2H),7.61(d,1H),7.73(d,1H),8.09(s,1H),8.16(d,2H),8.57(s,1H),8.66(s,2H),8.67-8.70(m,2H),8.75(s,2H),9.15(s,1H),9.63(s,1H)。
實施例21-17:1-(2-氟-5-(三氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.65(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.11(dd,1H),7.26(d,2H),7.37-7.44(m,1H),7.46(t,1H),8.17(d,2H),8.51(dd,1H),8.65(dd,1H),8.72(s,2H),8.75(s,1H),9.08(s,1H),9.15(dd,1H),9.28(s,1H)。
實施例21-18:1-(2-氯-5-(三氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.69(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.10(dd,1H),7.26(d,2H),7.40(dd,1H),
7.72(d,1H),8.17(d,2H),8.56(d,1H),8.66(dd,1H),8.73(s,2H),8.75(s,1H),8.77(s,1H),9.15(dd,1H),9.69(s,1H)。
實施例21-19:1-(2-甲基-5-(三氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.72(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.32(s,3H),7.11(dd,1H),7.26(d,2H),7.29(d,1H),7.42(d,1H),8.17(d,2H),8.27(s,1H),8.37(s,1H),8.66(dd,1H),8.73(s,2H),8.76(s,1H),9.16(dd,1H),9.31(s,1H)。
實施例21-20:1-(3-氟-5-(三氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.76(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.11(dd,1H),7.20-7.30(m,3H),7.54-7.72(m,2 H),8.18(d,2H),8.65-8.76(m,4 H),9.09(s,1H),9.16-9.20(m,1H),9.51(s,1H)。
實施例21-21:1-(4-甲基-3-(三氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.76(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.36(s,3H),7.10(dd,1H),7.25(d,2H),7.33(d,1H),7.52(dd,1H),7.88(d,1H),8.17(d,2H),8.65(dd,1H),8.70(s,2H),8.75(s,1H),8.91(s,1H),9.15(d,1H),9.17(d,1H)。
實施例21-22:1-(2-苯基-5-(三氟甲基)吡啶-3-基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.77(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.11(dd,1H),7.25(d,2H),7.52-7.62(m,3
H),7.62-7.69(m,2 H),8.17(d,2H),8.41(s,1H),8.62-8.80(m,6 H),9.16(dd,1H),9.45(d,1H)。
實施例21-23:1-(3-(二氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.73(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.00(t,1H),7.11(dd,1H),7.18(d,1H),7.26(d,2H),7.42(t,1H),7.52(d,1H),7.77(s,1H),8.17(d,2H),8.66(dd,1H),8.71-8.76(m,3H),8.89(s,1H),9.17(d,2H)。
實施例21-24:1-(3,5-二氟苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.74(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.80(dt,1H),7.11(dd,1H),7.19(dd,2H),7.26(d,2H),8.17(d,2H),8.66(dd,1H),8.70(s,2H),8.75(s,1H),9.00(s,1H),9.16(dd,1H),9.30(s,1H)。
實施例21-25:1-(2-(1H-吡唑-1-基)-4-(三氟甲基)苯基)-3-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.63(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.45-2.42(m,2H),4.15(t,4H),6.24(d,1H),6.65(t,1H),7.15(d,2H),7.74(dd,1H),7.82(d,1H),7.93(d,1H),
8.60(d,2H),8.36(s,1H),8.43(dd,2H),8.63(d,1H),8.67(s,2H),9.54(s,1H),9.26(s,1H)。
實施例21-26:1-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-(2-氯-4-(三氟甲基)苯基)脲
TLC:Rf 0.44(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 2.36-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.16(d,2H),7.68(dd,1H),7.87(s,1H),8.07(d,2H),8.37(s,1H),8.42(d,1H),8.63(d,1H),8.72(s,2H),8.78(s,1H),9.73(s,1H)。
實施例21-27:1-(2-(4-(5-(氮雜環丁烷-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)-3-苯基脲
TLC:Rf 0.20(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.33-2.43(m,2H),4.11-4.19(m,4H),6.25(d,1H),6.95-7.02(m,1H),7.13-7.19(m,2H),7.25-7.34(m,2H),7.42-7.47(m,2H),8.06-8.10(m,2H),8.38(s,1H),8.64(d,1H),8.70(s,2H),8.82(s,1H),8.91(s,1H)。
實施例21-28:1-(2-氯-4-(三氟甲基)苯基)-3-(2-(4-(5-(吡咯啶-1-基)吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.62(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 1.92-2.06(br s,4H),3.40-3.70(br s,4H),6.43(d,1H),7.17(d,2H),7.69(dd,1H),7.88(d,1H),8.12(d,2H),8.37(s,1H),8.43(d,1H),8.63(d,1H),8.72(s,2H),8.79(s,1H),9.75(s,1H)。
實施例21-29:1-(2-氯-4-(三氟甲基)苯基)-3-(2-(4-(吡唑并[1,5-a]嘧啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.80(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.10(dd,1H),7.26(d,2H),7.68(dd,1H),7.87(s,1H),8.17(d,2H),8.42(d,1H),8.66(dd,1H),8.73(s,2H),8.75(s,1H),8.78(s,1H),9.16(d,1H),9.74(s,1H)。
實施例21-30:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):602(M+H)+;1H-NMR(DMSO-d6):δ 3.65(s,3H),4.03(s,3H),6.45(d,1H),6.61(d,1H),7.22(d,2H),7.46-7.52(m,2H),7.62(d,1H),8.09-8.12(m,3H),8.56(s,1H),8.59(s,1H),8.66(s,2H),8.93(d,1H),9.48(s,1H)。
實施例21-31:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
1H-NMR(DMSO-d6):δ 2.37(s,3H),4.03(s,3H),6.45(d,1H),6.61(d,1H),7.20-7.25(m,2H),7.48(dd,1H),7.69(d,1H),8.09-8.13(m,2H),8.28(d,1H),8.57(d,1H),8.58(s,1H),8.68(s,2H),8.93(d,1H),9.80(s,1H),9.90(s,1H)。
實施例21-32:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(4-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.08分);
MASS(ESI,Pos.):602(M+H)+;1H-NMR(DMSO-d6):δ 2.14(s,3H),4.03(s,3H),6.61(d,1H),7.22(d,2H),7.49(dd,1H),7.70(d,1H),7.78(s,1H),8.11(d,2H),8.18(s,1H),8.57-8.58(m,2H),8.69(s,2H),8.93(d,1H),9.83(s,1H),9.95(s,1H)。
實施例21-33:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-吡啶基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.92分);MASS(ESI,Pos.):599(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.19-7.24(m,2H),7.53-7.57(m,2H),7.75(dd,1H),7.88-7.92(m,1H),8.08-8.12(m,2H),8.24-8.29(m,2H),8.58(s,1H),8.64-8.68(m,4H),8.93(d,1H),9.28(brs,1H)。
實施例21-34:1-[2-氯-5-(三氟甲基)苯基]-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.05分);MASS(ESI,Pos.):556(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.24(d,2H),7.40(dd,1H),7.73(d,1H),8.11(d,2H),8.57-8.59(d,2H),8.73(s,2H),8.78(s,1H),8.94(d,1H),9.70(s,1H)。
實施例21-35:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-甲基-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):536(M+H)+;
1H-NMR(DMSO-d6):δ 2.32(s,3H),4.03(s,3H),6.61(d,1H),7.24(d,2H),7.30(d,1H),7.41(d,1H),8.09-8.13(m,2H),8.28(s,1H),8.37(s,1H),8.59(s,1H),8.73(s,2H),8.94(d,1H),9.32(s,1H)。
實施例21-36:1-(2,4-二氯苯基)-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.03分);MASS(ESI,Pos.):522(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.23(d,2H),7.39(dd,1H),7.63(d,1H),8.10-8.16(m,3H),8.57(s,1H),8.59(s,1H),8.71(s,2H),8.93(d,1H),9.58(s,1H)。
實施例21-37:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.32(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 3.19(s,6H),6.62(d,1H),7.12-7.17(m,2H),7.46-7.57(m,3H),7.86-7.90(m,1H),8.06-8.11(m,2H),8.22(s,1H),8.37-8.38(m,2H),8.61-8.68(m,5H),9.21(s,1H)。
實施例21-38:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.30(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),6.67-6.68(m,1H),7.14-7.17(m,2H),7.52(dd,1H),7.75(d,1H),7.95(d,1H),8.08-8.11(m,2H),8.39(s,1H),8.41(d,1H),8.59(d,1H),8.64(d,1H),8.68(s,2H),9.69(s,1H),9.93(s,1H)。
實施例21-39:1-[2-氟-5-(三氟甲基)苯基]-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):540(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.21-7.26(m,2H),7.39-7.53(m,2H),8.09-8.14(m,2H),8.53(dd,1H),8.59(s,1H),8.73(s,2H),8.93(d,1H),9.02-9.36(br s,2H)。
實施例21-40:1-[5-氯-2-(3-吡啶基)苯基]-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):565(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.60(d,1H),7.20-7.30(m,4H),7.53(dd,1H),7.81-7.85(m,1H),8.08-8.12(m,4H),8.55-8.64(m,5H),8.93(d,1H),9.18(s,1H)。
實施例21-41:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)
苯氧基]-5-嘧啶基}-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.09分);MASS(ESI,Pos.):656(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.12(d,1H),7.20-7.24(m,2H),7.58(dd,1H),7.10(d,1H),8.09-8.13(m,2H),8.47-8.48(m,2H),8.58(s,2H),8.65(s,2H),8.93(d,1H),9.46(s,1H)。
實施例21-42:1-{2-[4-(5-乙氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):613(M+H)+;1H-NMR(DMSO-d6):δ 1.40(t,3H),4.49(q,2H),6.58(d,1H),7.18-7.22(m,2H),7.47-7.58(m,3H),7.87-7.91(m,1H),8.05-8.10(m,2H),8.23(s,1H),8.39(s,1H),8.57(s,1H),8.64-8.68(m,4H),8.92(d,1H),9.23(s,1H)。
實施例21-43:1-{2-[4-(5-環丁基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:1.03分);MASS(ESI,Pos.):623(M+H)+;1H-NMR(DMSO-d6):δ 1.85-2.12(m,2H),2.33-2.42(m,4H),3.73-
3.84(m,1H),6.97(d,1H),7.24(d,2H),7.47-7.58(m,3H),7.87-7.91(m,1H),8.18-8.23(m,3H),8.39(s,1H),8.64-8.68(m,5H),9.01(d,1H),9.23(s,1H)。
實施例21-44:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.09分);MASS(ESI,Pos.):589(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.62(d,1H),7.23(d,2H),7.58(dd,1H),8.05-8.13(m,3H),8.33(s,2H),8.59(s,1H),8.65(d,1H),8.70(s,2H),8.93(d,1H),9.66(s,1H),10.00(s,1H)。
實施例21-45:1-[5-氯-2-(2H-1,2,3-三唑-2-基)苯基]-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):99%(保持時間:1.08分);MASS(ESI,Pos.):555(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.20-7.25(m,2H),7.29(dd,1H),7.80(d,1H),8.09-8.13(m,2H),8.26(s,2H),8.33(d,1H),8.58(s,1H),8.69(s,2H),8.93(d,1H),9.36(s,1H),9.91(s,1H)。
實施例21-46:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.24(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.31-2.44(m,2H),4.10-4.19(m,4H),6.24(d,1H),7.10-7.18(m,2H),7.39-7.59(d,7H),8.03-8.12(m,3H),8.37(s,1H),8.41(s,1H),8.60-8.66(m,3H),9.37(s,1H)。
實施例21-47:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(6-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.33(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.32-2.43(m,2H),2.55(s,3H),4.10-4.19(m,4H),6.24(d,1H),7.11-7.18(m,2H),7.40-7.51(m,3H),7.76(dd,1H),8.03-8.10(m,2H),8.18(s,1H),8.37(s,1H),8.41-8.43(m,1H),8.51(d,1H),8,61-8.69(m,3H),9.25(s,1H)。
實施例21-48:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(6-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.30(二氯甲烷:乙酸乙酯:甲醇=8:4:1);1H-NMR(DMSO-d6):δ 2.55(s,3H),3.19(s,6H),6.63(d,1H),7.15(d,2H),7.38-7.52(m,3H),7.76(dd,1H),8.10(d,2H),8.18(s,1H),8.38(s,1H),8.42(s,1H),8.50(d,1H),8.64(s,2H),8.64(d,1H),9.25(s,1H)。
實施例21-49:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[4’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.32(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.30-2.45(m,5H),4.10-4.19(m,4H),6.24(d,1H),7.11-7.18(m,2H),7.30-7.47(m,6H),8.01-8.10(m,3H),8.37(s,1H),8.42-8.45(m,1H),8.62-8.66(m,3H),9.39(s,1H)。
實施例21-50:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-
基]苯氧基}-5-嘧啶基)-3-[2-苯基-5-(三氟甲基)-3-吡啶基]脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):612(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),7.12-7.19(m,2H),7.51-7.68(m,5H),8.05-8.13(m,2H),8.36-8.47(m,2H),8.62-8.67(m,3H),8.71-8.73(m,1H),8.75-8.78(m,1H),9.45(s,1H)。
實施例21-51:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):615(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),3.65(s,3H),6.45(d,1H),6.63(d,1H),7.13-7.19(m,2H),7.44-7.54(m,2H),7.62(d,1H),8.06-8.14(m,3H),8.38(s,1H),8.56(s,1H),8.63-8.68(m,3H),9.47(s,1H)。
實施例21-52:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.04分);MASS(ESI,Pos.):615(M+H)+;
1H-NMR(DMSO-d6):δ 2.37(s,3H),3.19(s,6H),6.45(d,1H),6.63(d,1H),7.14-7.21(m,2H),7.48(dd,1H),7.69(d,1H),8.07-8.14(m,2H),8.28(d,1H),8.39(s,1H),8.57(d,1H),8.63-8.70(m,3H),9.80(s,1H),9.89(s,1H)。
實施例21-53:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.07分);MASS(ESI,Pos.):669(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),7.10-7.20(m,3H),7.58(dd,1H),7.70(d,1H),8.07-8.14(m,2H),8.38(s,1H),8.45-8.50(m,2H),8.57(s,1H),8.63-8.67(m,3H),9.45(s,1H)。
實施例21-54:1-[2-(4-氯-1H-吡唑-1-基)-5-(三氟甲基)苯基]-3-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):635(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),7.14-7.20(m,2H),7.53(dd,1H),7.70(d,1H),8.06-8.14(m,3H),8.39(s,1H),8.56-8.71(m,5H),9.09(s,1H),9.78(s,1H)。
實施例21-55:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-1,2,4-三唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);
MASS(ESI,Pos.):670(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),7.13-7.20(m,2H),7.60-7.65(m,1H),7.81(d,1H),8.05-8.14(m,2H),8.38(s,1H),8.50(d,1H),8.57-8.68(m,4H),9.21(s,1H),9.33(s,1H)。
實施例21-56:1-[5-氯-2-(2H-1,2,3-三唑-2-基)苯基]-3-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);MASS(ESI,Pos.):568(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),7.13-7.21(m,2H),7.29(dd,1H),7.80(d,1H),8.07-8.14(m,2H),8.26(s,2H),8.32(d,1H),8.38(s,1H),8.64(d,1H),8.68(s,2H),9.36(s,1H),9.90(s,1H)。
實施例21-57:1-[5-氯-2-(3-吡啶基)苯基]-3-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.83分);MASS(ESI,Pos.):578(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.62(d,1H),7.15(d,2H),7.21-7.30(m,2H),7.49-7.55(m,1H),7.80-7.85(m,1H),8.06-8.12(m,4H),8.38(s,1H),8.56-8.66(m,5H),9.17(s,1H)。
實施例21-58:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(1H-吡唑-1-基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);MASS(ESI,Pos.):601(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.60-6.68(m,2H),7.16(d,2H),
7.74(dd,1H),7.80-7.85(m,1H),7.92-7.95(m,1H),8.10(d,2H),8.37-8.46(m,3H),8.61-8.69(m,3H),9.55(s,1H),9.94(s,1H)。
實施例21-59:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-氟-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):553(M+H)+;1H-NMR(DMSO-d6):δ 3.16(s,6H),6.62(d,1H),7.17(d,2H),7.54(d,1H),7.70(d,1H),8.06-8.16(m,2H),8.32-8.42(m,2H),8.64(d,1H),8.72(s,2H),9.17(s,1H),9.40(s,1H)。
實施例21-60:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.97分);MASS(ESI,Pos.):535(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),7.17(d,2H),7.32(d,1H),7.51(t,1H),7.62(d,1H),7.97(s,1H),8.10(d,2H),8.39(s,1H),8.64(d,1H),8.70(s,2H),8.96(s,1H),9.31(s,1H)。
實施例21-61:1-[2-氯-5-(三氟甲基)苯基]-3-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:1.03分);MASS(ESI,Pos.):569(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),7.17(d,2H),7.39(d,1H),7.72(d,1H),8.11(d,2H),8.39(s,1H),8.57(d,1H),8.65(d,1H),8.72(s,2H),8.78(s,1H),9.69(s,1H)。
實施例21-62:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-
基]苯氧基}-5-嘧啶基)-3-[2-甲基-5-(三氟甲基)苯基]脲
TLC:Rf 0.18(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 2.32(s,3H),3.19(s,6H),6.62(d,1H),7.16(d,2H),7.29(d,1H),7.41(d,1H),8.10(d,2H),8.27(s,1H),8.37(d,2H),8.64(d,1H),8.71(s,2H),9.30(s,1H)。
實施例21-63:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-氟-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.99分);MASS(ESI,Pos.):553(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.62(d,1H),7.16(d,2H),7.36-7.43(m,1H),7.45-7.54(m,1H),8.10(d,2H),8.38(s,1H),8.49-8.56(m,1H),8.64(d,1H),8.71(s,2H),9.08(s,1H),9.27(s,1H)。
實施例21-64:1-(2,4-二氯苯基)-3-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):535(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.62(d,1H),7.16(d,2H),7.38(dd,1H),7.62(d,1H),8.09(d,2H),8.13(d,1H),8.38(s,1H),8.56(s,1H),8.64(d,1H),8.70(s,2H),9.56(s,1H)。
實施例21-65:1-{2-[4-(5-甲基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.43(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 2.60(s,3H),6.99(d,1H),7.23(d,2H),7.45-7.59(m,3H),7.89(d,1H),8.14(d,2H),8.23(s,1H),8.39(s,1H),8.61-8.72(m,5H),9.00(d,1H),9.23(s,1H)。
實施例21-66:1-(2-{4-[5-(乙胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.31(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.22(t,3H),3.38-3.47(m,2H),6.26(d,1H),7.11-7.18(m,2H),7.46-7.65(m,4H),7.86-7.92(m,1H),8.04-8.11(m,2H),8.23(s,1H),8.31(s,1H),8.37-8.41(m,1H),8.46(d,1H),8.61-8.69(m,4H),9.22(s,1H)。
實施例21-67:1-(2-{4-[5-(乙胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.36(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.22(t,3H),2.38(s,3H),3.36-3.48(m,2H),6.26(d,1H),7.11-7.46(m,8H),7.60(t,1H),8.00-8.11(m,3H),8.30
(s,1H),8.42-8.48(m,2H),8.63(s,2H),9.39(s,1H)。
實施例21-68:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.43(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.32-2.44(m,2H),3.38(s,3H),4.10-4.20(m,4H),6.24(d,1H),7.13-7.20(m,2H),7.61-7.66(m,1H),8.04-8.11(m,3H),8.38(s,1H),8.61-8.67(m,2H),8.73(s,2H),8.96(s,1H),10.27(s,1H)。
實施例21-69:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.48(乙酸乙酯);1H-NMR(DMSO-d6):δ 3.19(s,6H),3.38(s,3H),6.63(d,1H),7.15-7.22(m,2H),7.61-7.69(m,1H),8.05-8.15(m,3H),8.39(s,1H),8.63-8.68(m,2H),8.73(s,2H),8.96(s,1H),10.27(s,1H)。
實施例21-70:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.09分);MASS(ESI,Pos.):611(M+H)+;
1H-NMR(DMSO-d6):δ 3.19(s,6H),6.62(d,1H),7.15(d,2H),7.40-7.58(m,7H),8.06-8.12(m,3H),8.38(s,1H),8.41(s,1H),8.61-8.66(m,3H),9.36(s,1H)。
實施例21-71:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[4’-甲基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.13分);MASS(ESI,Pos.):625(M+H)+;1H-NMR(DMSO-d6):δ 2.39(s,3H),3.19(s,6H),6.62(d,1H),7.15(d,2H),7.28-7.47(m,6H),8.03(s,1H),8.09(d,2H),8.38(s,1H),8.43(s,1H),8.61-8.66(m,3H),9.39(s,1H)。
實施例21-72:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[4’-乙基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.16分);MASS(ESI,Pos.):639(M+H)+;1H-NMR(DMSO-d6):δ 1.24(t,3H),2.68(q,2H),3.19(s,6H),6.62(d,1H),7.14(d,2H),7.35-7.49(m,6H),8.03-8.12(m,3H),8.38(s,1H),8.41(s,1H),8.61-8.66(m,3H),9.38(s,1H)。
實施例21-73:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-甲基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.13分);MASS(ESI,Pos.):625(M+H)+;1H-NMR(DMSO-d6):δ 2.38(s,3H),3.19(s,6H),6.62(d,1H),7.14(d,2H),7.19-7.32(m,3H),7.36-7.47(m,3H),8.02(s,1H),8.09(s,1H),8.11(s,1H),8.38(s,1H),8.44(s,1H),8.64(s,2H),8.66(s,1H),9.40(s,1H)。
實施例21-74:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-乙基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.17分);MASS(ESI,Pos.):639(M+H)+;1H-NMR(DMSO-d6):δ 1.22(t,3H),2.68(q,2H),3.19(s,6H),6.62(d,1H),7.15(d,2H),7.22-7.36(m,3H),7.40-7.49(m,3H),8.05(s,1H),8.10(d,2H),8.38(s,1H),8.40(s,1H),8.63(s,2H),8.66(d,1H),9.38(s,1H)。
實施例21-75:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2’-甲基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.14分);MASS(ESI,Pos.):625(M+H)+;1H-NMR(DMSO-d6):δ 2.04(s,3H),3.19(s,6H),6.62(d,1H),7.10-
7.22(m,3H),7.26-7.46(m,5H),7.70(s,1H),8.09(d,2H),8.38(s,1H),8.53(s,1H),8.62(s,2H),8.65(s,1H),9.42(s,1H)。
實施例21-76:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’,4’-二甲基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.17分);MASS(ESI,Pos.):639(M+H)+;1H-NMR(DMSO-d6):δ 2.29(s,6H),3.19(s,6H),6.62(d,1H),7.12-7.19(m,3H),7.19-7.22(m,1H),7.30(d,1H),7.36(d,1H),7.42(dd,1H),8.00(s,1H),8.09(d,2H),8.38(s,1H),8.44-8.48(m,1H),8.62-8.67(m,3H),9.42(s,1H)。
實施例21-77:1-(2-{4-[5-(甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):599(M+H)+;1H-NMR(DMSO-d6):δ 2.93(d,3H),3.41(s,3H),6.27(d,1H),7.17(d,2H),7.56-7.67(m,1H),8.03-8.17(m,4H),8.32(s,1H),8.43-8.55(m,2H),8.73(s,2H),9.03(s,1H),10.33(s,1H)。
實施例21-78:1-(2-{4-[5-(甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2’-甲基-4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.38(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.04(s,3H),2.92(d,3H),6.28(d,1H),7.11-7.45(m,8H),7.56-7.73(m,2H),8.06-8.13(m,2H),8.31(s,1H),8.46(d,1H),8.51-8.54(m,1H),8.62(s,2H),9.42(s,1H)。
實施例21-79:1-(2-{4-[5-(甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.30(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.92(d,3H),6.27(d,1H),7.11-7.18(m,2H),7.46-7.65(m,4H),7.89(dt,1H),8.06-8.14(m,2H),8.23(s,1H),8.31(s,1H),8.39(s,1H),8.46(d,1H),8.61-8.69(m,4H),9.22(s,1H)。
實施例21-80:1-(2-{4-[5-(甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[4-(三氟甲基)-2-聯苯基]脲
TLC:Rf 0.42(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.92(d,3H),6.26(d,1H),7.11-7.17(m,2H),7.38-7.64(m,8H),8.04-8.12(m,3H),8.31(s,1H),8.39-8.42(m,1H),8.46(d,1H),8.63(s,2H),9.35(s,1H)。
實施例21-81:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲亞磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.14(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.89(s,3H),3.19(s,6H),6.62(d,1H),7.15(d,2H),7.64(d,1H),7.90(d,1H),8.09(d,2H),8.26(s,1H),8.38(s,1H),8.63(d,1H),8.70(s,2H),9.22(s,1H),9.65(s,1H)。
實施例21-82:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-(1-羥乙基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):99%(保持時間:1.07分);MASS(ESI,Pos.):655(M+H)+;1H-NMR(DMSO-d6):δ 1.36(d,3H),3.19(s,6H),4.74-4.83(m,1H),
5.20-5.23(m,1H),6.62(d,1H),7.15(d,2H),7.27-7.36(m,1H),7.38-7.56(m,5H),8.04-8.26(m,3H),8.37(s,1H),8.38(s,1H),8.63(s,2H),8.66(s,1H),9.36(s,1H)。
實施例21-83:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(1H-吡唑-1-基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.05分);MASS(ESI,Pos.):588(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),6.65-6.66(m,1H),7.20-7.25(m,2H),7.73-7.83(m,2H),7.93(d,1H),8.00-8.13(m,2H),8.41-8.44(m,2H),8.58(s,1H),8.69(s,2H),8.93(d,1H),9.56(brs,1H),9.95(brs,1H)。
實施例21-84:1-[3-(二氟甲基)苯基]-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.92分);MASS(ESI,Pos.):504(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.00-7.24(m,4H),7.42(t,1H),7.52(d,1H),7.78(s,1H),8.10-8.13(m,2H),8.59(s,1H),8.71(s,2H),8.90-8.95(m,2H),9.16(s,1H)。
實施例21-85:1-(2,5-二氯苯基)-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.04分);MASS(ESI,Pos.):522(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.12(dd,1H),7.21-7.26(m,2H),7.51(d,1H),8.09-8.14(m,2H),8.26(s,1H),8.59(s,
1H),8.63(s,1H),8.72(s,2H),8.93(d,1H),9.66(s,1H)。
實施例21-86:1-(2,5-二氟苯基)-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.94分);MASS(ESI,Pos.):490(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),6.81-6.89(m,1H),7.21-7.34(m,3H),7.93-8.00(m,1H),8.10-8.14(m,2H),8.59(s,1H),8.72(s,2H),8.92-8.96(m,2H),9.25(s,1H)。
實施例21-87:1-[2-氯-4-(三氟甲基)苯基]-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):556(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.22-7.26(m,2H),7.69(dd,1H),7.89(d,1H),8.00-8.14(m,2H),8.43(d,1H),8.59(s,1H),8.73(s,2H),8.79(s,1H),8.93(d,1H),9.76(s,1H)。
實施例21-88:1-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-[2-(4-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):603(M+H)+;1H-NMR(DMSO-d6):δ 2.38(s,3H),4.03(s,3H),6.62(d,1H),7.20-7.24(m,2H),7.58-7.71(m,2H),8.08-8.13(m,2H),8.33(s,1H),8.51-8.60(m,2H),8.67(s,2H),8.75(s,1H),8.93(d,1H),9.68(s,1H)。
實施例21-89:1-[5-氯-2-(1H-吡唑-1-基)苯基]-3-{2-[4-(5-
甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.05分);MASS(ESI,Pos.):554(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.59-6.62(m,2H),7.19-7.24(m,3H),7.51(d,1H),7.89(d,1H),8.08-8.12(m,2H),8.26(d,1H),8.27(d,1H),8.58(s,1H),8.67(s,2H),8.92(d,1H),9.36(s,1H),9.87(s,1H)。
實施例21-90:1-(2-{4-[5-(3-氧雜環丁烷基氧基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):94%(保持時間:0.89分);MASS(ESI,Pos.):641(M+H)+;1H-NMR(DMSO-d6):δ 4.67-4.71(m,2H),4.99(t,2H),5.71-5.79(m,1H),6.69(d,1H),7.21-7.26(m,2H),7.47-7.58(m,3H),7.83-7.91(m,1H),8.00-8.04(m,2H),8.24(s,1H),8.39(s,1H),8.60(s,1H),8.64-8.69(m,4H),9.00(d,1H),9.24(s,1H)。
實施例21-91:1-[5-氯-2-(1H-1,2,3-三唑-1-基)苯基]-3-{2-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.95分);MASS(ESI,Pos.):555(M+H)+;1H-NMR(DMSO-d6):δ 4.03(s,3H),6.61(d,1H),7.22(d,2H),7.31(dd,1H),7.51(d,1H),8.06-8.12(m,3H),8.27(d,1H),8.49(s,1H),8.59(s,1H),8.65(s,2H),8.70(s,1H),8.93(d,1H),9.58(s,1H)。
實施例21-92:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]
嘧啶-3-基]苯氧基}-5-嘧啶基)-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):99%(保持時間:1.10分);MASS(ESI,Pos.):681(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.23(d,1H),7.12-7.17(m,3H),7.58(dd,1H),7.70(d,1H),8.04-8.09(m,2H),8.37(s,1H),8.48(s,2H),8.57(s,1H),8.62-8.65(m,3H),9.45(s,1H)。
實施例21-93:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(4-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):98%(保持時間:1.10分);MASS(ESI,Pos.):627(M+H)+;1H-NMR(DMSO-d6):δ 2.15(s,3H),2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.15(d,2H),7.49(dd,1H),7.70(d,1H),7.78(s,1H),8.05-8.09(m,2H),8.18(s,1H),8.37(s,1H),8.58(d,1H),8.62-8.68(m,3H),9.82(s,1H),9.94(s,1H)。
實施例21-94:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):97%(保持時間:0.93分);MASS(ESI,Pos.):624(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.11-7.16(m,2H),7.53-7.58(m,2H),7.76(dd,1H),7.88-7.92(m,1H),8.06(d,2H),8.23(s,1H),8.28(d,1H),8.37(s,1H),8.62-8.68
(m,5H),9.27(s,1H)。
實施例21-95:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[5-氯-2-(1H-吡唑-1-基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.03分);MASS(ESI,Pos.):579(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),6.62(t,1H),7.13-7.17(m,2H),7.22(dd,1H),7.51(d,1H),7.89(d,1H),8.04-8.09(m,2H),8.26(d,1H),8.28(d,1H),8.37(s,1H),8.62-8.66(m,3H),9.37(s,1H),9.87(s,1H)。
實施例21-96:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[5-氯-2-(3-吡啶基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.86分);MASS(ESI,Pos.):590(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.11-7.16(m,2H),7.23(dd,1H),7.28(d,1H),7.53(dd,1H),7.80-7.85(m,1H),8.04-8.12(m,4H),8.37(s,1H),8.59-8.65(m,5H),9.17(s,1H)。
實施例21-97:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.08分);MASS(ESI,Pos.):614(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.13-7.18(m,2H),7.58(dd,1H),8.05-8.09(m,3H),8.32(s,2H),
8.38(s,1H),8.62-8.66(m,2H),8.69(s,2H),9.66(s,1H),9.99(s,1H)。
實施例21-98:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[5-氯-2-(1H-1,2,3-三唑-1-基)苯基]脲
純度(LC-MS/ELSD):96%(保持時間:0.94分);MASS(ESI,Pos.):580(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.12-7.17(m,2H),7.31(dd,1H),7.51(d,1H),8.05-8.08(m,3H),8.27(d,1H),8.37(s,1H),8.48(s,1H),8.59-8.65(m,4H),9.57(s,1H)。
實施例21-99:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[5-氯-2-(2H-1,2,3-三唑-2-基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):580(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.13-7.18(m,2H),7.29(dd,1H),7.80(d,1H),8.05-8.09(m,2H),8.26(s,2H),8.33(d,1H),8.37(s,1H),8.64(d,1H),8.68(s,2H),9.36(s,1H),9.90(s,1H)。
實施例21-100:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-氯-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.03分);MASS(ESI,Pos.):581(M+H)+;
1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.14-7.19(m,2H),7.40(dd,1H),7.72(d,1H),8.05-8.09(m,2H),8.38(s,1H),8.57(d,1H),8.64(d,1H),8.72(s,2H),8.78(s,1H),9.69(s,1H)。
實施例21-101:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-氟-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.00分);MASS(ESI,Pos.):565(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.13-7.18(m,2H),7.38-7.53(m,2H),8.04-8.09(m,2H),8.37(s,1H),8.52(dd,1H),8.63(d,1H),8.71(s,2H),9.08(s,1H),9.27(s,1H)。
實施例21-102:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-甲基-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:1.03分);MASS(ESI,Pos.):561(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,5H),4.15(t,4H),6.24(d,1H),7.14-7.18(m,2H),7.29(dd,1H),7.41(d,1H),8.05-8.09(m,2H),8.27(s,1H),8.37-8.38(m,2H),8.64(d,1H),8.72(s,2H),9.31(s,1H)。
實施例21-103:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-(2,5-二氯苯基)脲
純度(LC-MS/ELSD):97%(保持時間:1.06分);MASS(ESI,Pos.):547(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),
7.10-7.18(m,3H),7.50(d,1H),8.05-8.09(m,2H),8.26(d,1H),8.38(s,1H),8.63-8.71(m,4H),9.66(s,1H)。
實施例21-104:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-(2,4-二氯苯基)脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);MASS(ESI,Pos.):547(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),7.13-7.17(m,2H),7.38(dd,1H),7.63(d,1H),8.04-8.09(m,2H),8.14(d,1H),8.37(s,1H),8.56(brs,1H),8.66(d,1H),8.70(s,2H),9.57(brs,1H)。
實施例21-105:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-(2,5-二氟苯基)脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):515(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),6.81-6.88(m,1H),7.13-7.18(m,2H),7.25-7.34(m,1H),7.94-8.00(m,1H),8.05-8.09(m,2H),8.38(s,1H),8.64(d,1H),8.70(s,2H),8.95(s,1H),9.25(s,1H)。
實施例21-106:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3-(二氟甲基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:0.90分);MASS(ESI,Pos.):529(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.15(t,4H),6.24(d,1H),6.81-7.19(m,4H),7.41(t,1H),7.51(d,1H),7.77(s,1H),8.05-8.09
(m,2H),8.38(s,1H),8.64(d,1H),8.70(s,2H),8.89(s,1H),9.16(s,1H)。
實施例21-107:1-{6-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-3-吡啶基}-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.96分);MASS(ESI,Pos.):598(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.60(d,1H),6.99(d,1H),7.10-7.15(m,2H),7.45-7.58(m,3H),7.87-7.91(m,1H),7.97(dd,1H),8.07-8.09(m,4H),8.42(s,1H),8.56(s,1H),8.64-8.69(m,2H),8.92(d,1H),9.16(s,1H)。
實施例21-108:1-{6-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-3-吡啶基}-3-[2-(1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.08分);MASS(ESI,Pos.):587(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.60(d,1H),6.66-6.68(m,1H),7.01(d,1H),7.11-7.16(m,2H),7.49(dd,1H),7.73(d,1H),7.94(d,1H),7.99(dd,1H),8.06-8.11(m,2H),8.16(d,1H),8.40(d,1H),8.56(s,1H),8.60(s,1H),8.92(d,1H),9.54(s,1H),9.80(s,1H)。
實施例21-109:1-{6-[4-(5-甲氧基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-3-吡啶基}-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.13分);MASS(ESI,Pos.):655(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.60(d,1H),7.01(d,1H),7.12-
7.15(m,3H),7.55(dd,1H),7.68(d,1H),7.96(dd,1H),8.07-8.13(m,3H),8.43(s,1H),8.47(d,1H),8.52(d,1H),8.56(s,1H),8.92(d,1H),9.38(s,1H)。
實施例21-110:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(4-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):615(M+H)+;
實施例21-111:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.89分);MASS(ESI,Pos.):612(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),6.63(d,1H),7.12-7.19(m,2H),7.52-7.60(m,2H),7.75(dd,1H),7.90(dt,1H),8.07-8.13(m,2H),8.22(s,1H),8.28(d,1H),8.38(s,1H),8.62-8.70(m,5H),9.26(s,1H)。
實施例21-112:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)-4-(三氟甲基)苯基]脲
TLC:Rf 0.50(乙酸乙酯);1H-NMR(DMSO-d6):δ 3.32(s,6H),3.41(s,3H),6.63(d,1H),7.15-7.22(m,2H),8.04-8.15(m,4H),8.39(s,1H),8.48-8.55(m,1H),8.65(d,1H),8.73(s,2H),9.03(s,1H),10.33(s,1H)。
實施例21-113:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)-4-(三氟甲基)苯基]
脲
TLC:Rf 0.37(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.31-2.42(m,2H),3.41(s,3H),4.12-4.18(m,4H),6.24(d,1H),7.10-7.19(m,2H),8.01-8.11(m,4H),8.37(s,1H),8.49(d,1H),8.63(d,1H),8.73(s,2H),9.02(s,1H),10.32(s,1H)。
實施例21-114:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(5-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.89分);MASS(ESI,Pos.):626(M+H)+;1H-NMR(DMSO-d6):δ 2.38(s,3H),3.19(s,6H),6.63(d,1H),7.13-7.19(m,2H),7.44-7.53(m,2H),7.69-7.73(m,1H),8.07-8.13(m,2H),8.18(s,1H),8.38(s,1H),8.42-8.45(m,2H),8.51-8.54(m,1H),8.63-8.67(m,3H),9.25(s,1H)。
實施例21-115:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(5-甲基-3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:0.90分);MASS(ESI,Pos.):638(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.47(m,5H),4.12-4.19(m,4H),6.24(d,1H),7.12-7.18(m,2H),7.43-7.53(m,2H),7.70-7.73(m,1H),8.04-8.10(m,2H),8.18(s,1H),8.37(s,1H),8.42-8.46(m,2H),8.51-8.54(m,1H),8.63-8.66(m,3H),9.26(s,1H)。
實施例21-116:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]
嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’,4’-二甲基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):99%(保持時間:1.19分);MASS(ESI,Pos.):651(M+H)+;1H-NMR(DMSO-d6):δ 2.30(s,6H),2.33-2.44(m,2H),4.11-4.19(m,4H),6.24(d,1H),7.12-7.18(m,3H),7.20-7.22(m,1H),7.28-7.46(m,3H),8.00(s,1H),8.04-8.10(m,2H),8.37(s,1H),8.45-8.48(m,1H),8.62-8.66(m,3H),9.42(s,1H)。
實施例21-117:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-甲基-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.15分);MASS(ESI,Pos.):637(M+H)+;1H-NMR(DMSO-d6):δ 2.32-2.43(m,5H),4.11-4.20(m,4H),6.24(d,1H),7.12-7.18(m,2H),7.20-7.32(m,3H),7.37-7.48(m,3H),8.00-8.11(m,3H),8.37(s,1H),8.43-8.46(m,1H),8.63-8.66(m,3H),9.41(s,1H)。
實施例21-118:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.86分);MASS(ESI,Pos.):545(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),3.28(s,3H),6.63(d,1H),7.14-7.20(m,2H),7.27(td,1H),7.65-7.71(m,1H),7.85(dd,1H),8.09-8.18(m,3H),8.39(s,1H),8.65(d,1H),8.72-8.78(m,3H),
10.09(s,1H)。
實施例21-119:1-(2-{4-[5-(甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.92分);MASS(ESI,Pos.):599(M+H)+;1H-NMR(DMSO-d6):δ 2.93(d,3H),3.38(s,3H),6.27(d,1H),7.17(d,2H),7.56-7.68(m,2H),8.03-8.18(m,3H),8.32(s,1H),8.47(d,1H),8.63(s,1H),8.73(s,2H),8.96(s,1H),10.28(s,1H)。
實施例21-120:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(乙磺醯基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.24(己烷:乙酸乙酯=1:4);1H-NMR(DMSO-d6):δ 1.14(t,3H),3.18(s,6H),3.45(q,2H),6.61(d,1H),7.16(d,2H),7.62(dd,1H),8.01(d,1H),8.10(d,2H),8.38(s,1H),8.61-8.67(m,2H),8.72(s,2H),8.99(s,1H),10.28(s,1H)。
實施例21-121:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[2-(甲硫基)-5-(三氟甲基)苯基]脲
TLC:Rf 0.28(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.53(s,3H),3.19(s,6H),6.62(d,1H),7.16(d,2H),7.40(dd,1H),7.54(d,1H),8.10(d,2H),8.19(d,1H),8.38(s,1H),8.42(s,1H),8.63(d,1H),8.70(s,2H),9.62(s,1H)。
實施例21-122:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[5-氟-2-(甲磺醯基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.93分);MASS(ESI,Pos.):599(M+H)+;
1H-NMR(DMSO-d6):δ 3.20(s,6H),3.30(s,3H),6.63(d,1H),7.09-7.21(m,3H),7.91(dd,1H),8.08-8.17(m,3H),8.39(s,1H),8.65(d,1H),8.72(s,2H),8.93(s,1H),10.26(s,1H)。
實施例21-123:2-{[(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-N,N-二甲基-4-(三氟甲基)苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:1.04分);MASS(ESI,Pos.):642(M+H)+;1H-NMR(DMSO-d6):δ 2.75(s,6H),3.19(s,6H),6.63(d,1H),7.17(d,2H),7.59(dd,1H),7.94(d,1H),8.11(d,2H),8.39(s,1H),8.61(d,1H),8.65(d,1H),8.72(s,2H),8.98(s,1H),10.28(s,1H)。
實施例21-124:2-{[(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-N,N-二甲基-4-(三氟甲基)苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):654(M+H)+;1H-NMR(DMSO-d6):δ 2.31-2.44(m,2H),2.75(s,6H),4.15(t,4H),6.24(d,1H),7.16(d,2H),7.60(dd,1H),7.95(d,1H),8.08(d,2H),8.38(s,1H),8.61(d,1H),8.64(d,1H),8.72(s,2H),8.98(s,1H),
10.28(s,1H)。
實施例21-125:2-{[(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)胺基甲醯基]胺基}-4-氟-N,N-二甲基苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:0.98分);MASS(ESI,Pos.):592(M+H)+;
實施例21-126:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-(羥甲基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.04分);MASS(ESI,Pos.):641(M+H)+;1H-NMR(DMSO-d6):δ 3.19(s,6H),4.58(d,2H),5.28(t,1H),6.63(d,1H),7.15(d,2H),7.31(d,1H),7.36(s,1H),7.37-7.56(m,4H),8.04(s,1H),8.10(d,2H),8.38(s,1H),8.42(s,1H),8.62-8.68(m,3H),9.39(s,1H)。
實施例21-127:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-(羥甲基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.05分);MASS(ESI,Pos.):653(M+H)+;1H-NMR(DMSO-d6):δ 2.37(quint,2H),4.15(t,4H),4.58(d,2H),5.30(t,1H),6.24(s,1H),7.14(d,2H),7.24-7.56(m,6H),8.02-8.09(m,3H),8.37(s,1H),8.42(s,1H),8.60-8.63(m,3H),9.38(s,1H)。
實施例21-128:1-(2-{4-[5-(1-氮雜環丁烷基)吡唑并[1,5-a]
嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-(羥乙基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.08分);MASS(ESI,Pos.):667(M+H)+;1H-NMR(DMSO-d6):δ 1.36(d,3H),2.37(quint,2H),4.15(t,4H),4.75-4.82(m,1H),5.21(d,1H),6.24(d,1H),7.14(d,2H),7.29-7.34(m,1H),7.38-7.53(m,5H),8.02-8.10(m,3H),8.37(s,2H),8.62-8.64(m,3H),9.37(s,1H)。
實施例21-129:1-(2-{4-[5-(二甲胺基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧啶基)-3-[3’-(2-羥基-2-丙烷基)-4-(三氟甲基)-2-聯苯基]脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):669(M+H)+;
實施例21-130:1-[3’-(羥甲基)-4-(三氟甲基)-2-聯苯基]-3-{2-[4-(5-甲基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.02分);MASS(ESI,Pos.):612(M+H)+;1H-NMR(DMSO-d6):δ 2.60(s,3H),4.58(d,2H),5.28(t,1H),6.98(d,1H),7.23(d,2H),7.30(d,1H),7.34-7.56(m,5H),8.05(s,1H),8.14(d,2H),8.42(d,1H),8.65(s,2H),8.66(s,1H),9.00(d,1H),9.40(s,1H)。
實施例21-131:1-[3’-(1-羥乙基)-4-(三氟甲基)-2-聯苯基]-3-{2-[4-(5-甲基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.04分);
MASS(ESI,Pos.):626(M+H)+;1H-NMR(DMSO-d6):δ 1.36(d,3H),2.60(s,3H),4.74-4.83(m,1H),5.21(d,1H),6.98(d,1H),7.23(d,2H),7.27-7.35(m,1H),7.39-7.52(m,5H),8.07(s,1H),8.10-8.17(m,2H),8.37(s,1H),8.64(s,2H),8.66(s,1H),9.00(d,1H),9.38(s,1H)。
實施例21-132:1-[3’-(2-羥基-2-丙烷基)-4-(三氟甲基)-2-聯苯基]-3-{2-[4-(5-甲基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:1.06分);MASS(ESI,Pos.):640(M+H)+;1H-NMR(DMSO-d6):δ 1.45(s,6H),2.60(s,3H),5.07(s,1H),6.98(d,1H),7.23(d,2H),7.24-7.31(m,1H),7.41-7.59(m,5H),8.08(s,1H),8.11-8.18(m,2H),8.34(s,1H),8.64(s,2H),8.66(s,1H),9.00(d,1H),9.37(s,1H)。
實施例21-133:1-{2-[4-(5-甲基吡唑并[1,5-a]嘧啶-3-基)苯氧基]-5-嘧啶基}-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.09分);MASS(ESI,Pos.):640(M+H)+;1H-NMR(DMSO-d6):δ 2.60(s,3H),6.98(d,1H),7.12(d,1H),7.23(d,2H),7.58(dd,1H),7.70(d,1H),8.14(d,2H),8.47(s,2H),8.57(s,1H),8.63-8.67(m,3H),9.00(d,1H),9.46(s,1H)。
實施例21-134:1-[2-(甲磺醯基)-5-(三氟甲基)苯基]-3-(2-{4-[5-(3-氧雜環丁烷基氧基)吡唑并[1,5-a]嘧啶-3-基]苯氧基}-5-嘧
啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.97分);MASS(ESI,Pos.):642(M+H)+;1H-NMR(DMSO-d6):δ 3.38(s,3H),4.63-4.76(m,2H),4.96-5.04(m,2H),5.76(quint,1H),6.70(d,1H),7.26(d,2H),7.64(d,1H),7.99-8.11(m,3H),8.59-8.64(m,2H),8.75(s,2H),8.93-9.03(m,2H),10.29(s,1H)。
實施例22
使用藉由使用6-氯咪唑并[1,2-b]嗒所製造之相當之胺化合物替代藉由使用5-氯吡唑并[1,5-a]嘧啶所製造之實施例19,使用實施例3製造之化合物,或者使用相當之胺基甲酸酯化合物或異氰酸酯化合物替代實施例3製造之化合物,進行與實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例22-1:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(6-(氮雜環丁烷-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.50(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.08(t,4H),6.64-6.68(m,2H),7.27(d,2H),7.51(d,1H),7.74(d,1H),7.88(d,1H),7.95(s,
2H),8.21(d,2H),8.40(d,1H),8.58(s,1H),8.69(s,2H),9.69(s,1H),9.95(s,1H)。
實施例22-2:1-(2-(4-(6-(氮雜環丁烷-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.52(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.08(t,4H),6.66(d,1H),7.24-7.27(m,2H),7.47-7.58(m,3H),7.87-7.95(m,3H),8.20-8.23(m,3H),8.38(s,1H),8.65-8.68(m,4H),9.24(s,1H)。
實施例22-3:1-(2-(4-(6-(氮雜環丁烷-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.28(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.33-2.43(m,2H),4.06-4.12(m,4H),6.67(d,1H),7.25-7.36(m,3H),7.52(t,1H),7.62(d,1H),7.90(d,1H),7.96-7.99(m,2H),8.19-8.26(m,2H),8.73(s,2H),8.99(s,1H),9.31(s,1H)。
實施例22-4:1-(2-(4-(6-(氮雜環丁烷-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(2-苯基-5-(三氟甲基)吡啶-3-基)脲
TLC:Rf 0.34(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 2.33-2.43(m,2H),4.06-4.11(m,4H),6.68(d,1H),7.25-7.29(m,2H),7.53-7.61(m,3H),7.64-7.69(m,2H),7.90(d,1H),7.97(s,1H),8.20-8.25(m,2H),8.43(s,1H),8.69(s,2H),8.72-8.75(m,1H),8.76-8.79(m,1H),9.47(s,1H)。
實施例22-5:1-(2-(吡啶-3-基)-5-(三氟甲基)苯基)-3-(2-
(4-(6-(吡咯啶-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.59(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.96-2.01(m,4H),3.47-3.52(m,4H),6.87(d,1H),7.25-7.28(m,2H),7.50-7.58(m,3H),7.85-7.94(m,3H),8.23-8.28(m,3H),8.39(s,1H),8.65-8.68(m,4H),9.24(s,1H)。
實施例22-6:1-(2-(4-(6-(吡咯啶-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.40(乙酸乙酯);1H-NMR(DMSO-d6):δ 1.96-2.02(m,4H),3.47-3.54(m,4H),6.88(d,1H),7.26-7.36(m,3H),7.53(t,1H),7.61(dd,1H),7.87(d,1H),7.95-7.99(m,2H),8.28(d,2H),8.73(s,2H),8.98(s,1H),9.31(s,1H)。
實施例22-7:1-(2-苯基-5-(三氟甲基)吡啶-3-基)-3-(2-(4-(6-(吡咯啶-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.50(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.96-2.03(m,4H),3.46-3.55(m,4H),6.87(d,1H),7.27(d,2H),7.52-7.69(m,5H),7.86(d,1H),7.94(s,1H),8.26(d,2H),8.40-8.44(m,1H),8.67-8.78(m,4H),9.45(s,1H)。
實施例22-8:1-(2-(4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)
苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.27(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 4.01(s,3H),6.95(d,1H),7.29-7.32(m,2H),7.47-7.58(m,3H),7.87-7.91(m,1H),8.07-8.10(m,2H),8.20-8.24(m,3H),8.39(s,1H),8.65-8.69(m,4H),9.25(s,1H)。
實施例22-9:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.68(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 4.02(s,3H),6.68(t,1H),6.95(d,1H),7.31-7.34(m,2H),7.52(dd,1H),7.75(d,1H),7.96(d,1H),8.07-8.10(m,2H),8.21-8.24(m,2H),8.41(d,1H),7.58(d,1H),8.71(s,2H),9.70(s,1H),9.97(s,1H)。
實施例22-10:1-(2-(4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.59(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 4.02(s,3H),6.95(d,1H),7.31-7.34(m,3H),7.51(t,1H),7.62(d,1H),7.98(s,1H),8.07-8.10(m,2H),8.21-8.24(m,2H),8.74(s,2H),8.99(s,1H),9.31(s,1H)。
實施例22-11:1-(2-(4-(6-(2-羥基丙烷-2-基)咪唑并[1,2-b]
嗒-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.20(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.59(s,6H),5.61(s,1H),7.31-7.38(m,3H),7.50-7.64(m,3H),7.97-8.00(m,1H),8.17(d,1H),8.22-8.28(m,3H),8.75(s,2H),9.00(s,1H),9.32(s,1H)。
實施例22-12:1-(2-(4-(6-(1-羥乙基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.19(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.49(d,3H),4.85-4.93(m,1H),5.74(d,1H),7.31-7.37(m,3H),7.41(d,1H),7.52(t,1H),7.60-7.65(m,1H),7.97-8.00(m,1H),8.18-8.25(m,4H),8.75(s,2H),9.00(s,1H),9.32(s,1H)。
實施例22-13:1-(2-(4-(6-((2-羥基-2-甲基丙基)胺基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.35(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 1.19(s,6H),3.27(d,2H),4.57(s,1H),6.87-6.90(m,2H),7.26-7.34(m,3H),7.51(t,1H),7.62(d,1H),7.73(d,1H),7.85(s,1H),7.97(s,1H),8.20-8.25(m,2H),8.73(s,2H),8.98(s,1H),9.31(s,1H)。
實施例22-14:1-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.50(乙酸乙酯:甲醇=19:1);1H-NMR(DMSO-d6):δ 7.26-7.34(m,3H),7.47-7.58(m,3H),7.87-7.93(m,1H),8.15-8.28(m,5H),8.38(s,1H),8.63-8.70(m,5H),9.24(s,1H)。
實施例22-15:1-(2-(1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.45(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.27-7.38(m,4H),7.59-7.65(m,1H),7.74(d,1H),8.10(s,1H),8.16-8.28(m,4H),8.58(s,1H),8.63-8.73(m,4H),9.66(s,1H)。
實施例22-16:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.38(己烷:乙酸乙酯=1:2);1H-NMR(DMSO-d6):δ 6.67-6.72(m,1H),7.26-7.40(m,3H),7.50-
7.57(m,1H),7.75(d,1H),7.95-8.00(m,1H),8.16-8.30(m,4H),8.40-8.45(m,1H),8.59(s,1H),8.64-8.68(m,1H),8.70(s,2H),9.70(s,1H),9.96(s,1H)。
實施例22-17:1-(2-氯-5-(三氟甲基)苯基)-3-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.27(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.28-7.43(m,4H),7.74(d,1H),8.16-8.27(m,4H),8.56(dd,1H),8.64(dd,1H),8.75(s,2H),8.78(s,1H),9.72(s,1H)。
實施例22-18:1-(2-氟-5-(三氟甲基)苯基)-3-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.30(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.27-7.54(m,5H),8.16-8.27(m,4H),8.53(dd,1H),8.63(dd,1H),8.75(s,2H),9.08(s,1H),9.31(s,1H)。
實施例22-19:1-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(2-甲基-5-(三氟甲基)苯基)脲
TLC:Rf 0.43(乙酸乙酯);1H-NMR(DMSO-d6):δ 2.32(s,3H),7.27-7.41(m,6H),8.17-8.26(m,6H),8.64(dd,1H),8.75(s,2H)。
實施例22-20:1-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.47(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.27-7.36(m,4H),7.51(t,1H),7.62(d,1H),7.97(s,1H),8.17-8.26(m,4H),8.64(d,1H),8.74(s,2H),8.99(s,
1H),9.31(s,1H)。
實施例22-21:1-(3-氟-5-(三氟甲基)苯基)-3-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.22(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.22-7.37(m,4H),7.62(d,1H),7.70(s,1H),8.15-8.27(m,4H),8.26(d,1H),8.63(dd,1H),8.73(s,2H),9.12(s,1H),9.52(s,1H)。
實施例22-22:1-(2-(4-(6-(氮雜環丁烷-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(2-氯-4-(三氟甲基)苯基)脲
TLC:Rf 0.57(乙酸乙酯:甲醇=9:1;CHROMATOREX NH TLC PLATE);1H-NMR(DMSO-d6):δ 2.32-2.42(m,2H),4.08(t,4H),6.67(d,1H),7.27-7.30(m,2H),7.69(dd,1H),7.88-7.91(m,2H),7.97(s,1H),8.21-8.24(m,2H),8.44(d,1H),8.75(s,2H),8.82(br s,1H),9.76(brs,1H)。
實施例22-23:1-(2-氯-4-(三氟甲基)苯基)-3-(2-(4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.53(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 4.02(s,3H),6.95(d,1H),7.32-7.35(m,2H),7.69(dd,1H),7.89(d,1H),8.07-8.10(m,2H),8.21-8.24(m,2H),8.43(d,1H),8.76(s,2H),8.80(s,1H),9.78(s,1H)。
實施例22-24:1-(2-氯-4-(三氟甲基)苯基)-3-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.33(乙酸乙酯);
1H-NMR(DMSO-d6):δ 7.31(dd,1H),7.36(d,2H),7.68(dd,1H),7.88-7.92(m,1H),8.17-8.28(m,4H),8.43(d,1H),8.64(dd,1H),8.75(s,2H),8.79(s,1H),9.78(s,1H)。
實施例22-25:1-(2-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(4-(三氟甲基)苯基)脲
TLC:Rf 0.20(己烷:乙酸乙酯=1:3);1H-NMR(DMSO-d6):δ 7.28(dd,1H),7.35(d,2H),7.61-7.69(m,4H),8.16-8.28(m,4H),8.64(d,1H),8.74(s,2H),8.99(s,1H),9.37(s,1H)。
實施例22-26:1-(2-(4-(6-(氮雜環丁烷-1-基)咪唑并[1,2-b]嗒-3-基)苯氧基)嘧啶-5-基)-3-(3,5-二氟苯基)脲
TLC:Rf 0.25(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.76-6.85(m,1H),7.19(dd,2H),7.27-7.35(m,3H),8.17-8.27(m,4H),8.64(dd,1H),8.72(s,2H),9.15(s,1H),9.46(s,1H)。
實施例22-27:1-(6-(4-(咪唑并[1,2-b]嗒-3-基)苯氧基)吡啶-3-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.51(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.07(d,1H),7.22-7.31(m,4H),7.50(t,1H),7.59(d,1H),7.97-8.00(m,1H),8.03(dd,1H),8.14-8.25(m,5H),
8.63(dd,1H),8.90(s,1H),9.14(s,1H)。
實施例22-28:1-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-(1-甲基-1H-吡唑-5-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):96%(保持時間:0.87分);MASS(ESI,Pos.):602(M+H)+;1H-NMR(DMSO-d6):δ 3.65(s,3H),4.01(s,3H),6.45(d,1H),6.95(d,1H),7.30-7.33(m,2H),7.46-7.52(m,2H),7.62(d,1H),8.07-8.23(m,5H),8.56(s,1H),8.69(s,2H),9.50(s,1H)。
實施例22-29:1-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:0.94分);MASS(ESI,Pos.):602(M+H)+;1H-NMR(DMSO-d6):δ 2.37(s,3H),4.02(s,3H),6.45(d,1H),6.95(d,1H),7.30-7.35(m,2H),7.49(dd,1H),7.70(d,1H),8.07-8.11(m,2H),8.23-8.25(m,2H),8.28(d,1H),8.57(d,1H),8.71(s,2H),9.81(s,1H),9.93(s,1H)。
實施例22-30:1-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-(4-甲基-1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):96%(保持時間:0.95分);MASS(ESI,Pos.):602(M+H)+;1H-NMR(DMSO-d6):δ 2.14(s,3H),4.02(s,3H),6.95(d,1H),7.32
(d,2H),7.49(dd,1H),7.70(d,1H),7.79(s,1H),8.07-8.11(m,2H),8.19-8.24(m,3H),8.57(d,1H),8.71(s,2H),9.84(s,1H),9.98(s,1H)。
實施例22-31:1-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-吡啶基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.78分);MASS(ESI,Pos.):599(M+H)+;1H-NMR(DMSO-d6):δ 4.01(s,3H),6.95(d,1H),7.31(d,2H),7.54-7.57(m,2H),7.76(dd,1H),7.88-7.92(m,1H),8.07-8.10(m,2H),8.20-8.29(m,4H),8.65-8.69(m,4H),9.30(s,1H)。
實施例22-32:1-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-甲基-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):536(M+H)+;1H-NMR(DMSO-d6):δ 2.32(s,3H),4.02(s,3H),6.95(d,1H),7.29-7.34(m,3H),7.42(d,1H),8.08-8.11(m,2H),8.20-8.25(m,2H),8.28(s,1H),8.38(s,1H),8.75(s,2H),9.34(s,1H)。
實施例22-33:1-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:0.97分);MASS(ESI,Pos.):656(M+H)+;1H-NMR(DMSO-d6):δ 4.01(s,3H),6.93(d,1H),7.12(s,1H),7.31(d,2H),7.58(d,1H),7.70(d,1H),8.07-8.10(m,2H),8.21(d,2H),
8.47(s,2H),8.59(s,1H),8.67(s,2H),9.49(s,1H)。
實施例22-34:1-{2-[4-(6-乙氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:0.86分);MASS(ESI,Pos.):613(M+H)+;1H-NMR(DMSO-d6):δ 1.41(t,3H),4.40(q,2H),6.92(d,1H),7.28-7.32(m,2H),7.47-7.58(m,3H),7.87-7.91(m,1H),8.05-8.09(m,2H),8.16-8.20(m,2H),8.24(s,1H),8.38(s,1H),8.64-8.68(m,4H),9.24(s,1H)。
實施例22-35:1-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:0.79分);MASS(ESI,Pos.):641(M+H)+;1H-NMR(DMSO-d6):δ 4.70(dd,2H),4.95(t,2H),5.62-5.71(m,1H),7.02(d,1H),7.32-7.36(m,2H),7.36-7.59(m,3H),7.87-7.91(m,1H),8.06-8.10(m,3H),8.15(d,1H),8.25(s,1H),8.39(s,1H),8.65-8.69(m,4H),9.26(s,1H)。
實施例22-36:1-{2-[4-(6-甲基咪唑并[1,2-b]嗒-3-基)
苯氧基]-5-嘧啶基}-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.76分);MASS(ESI,Pos.):583(M+H)+;1H-NMR(DMSO-d6):δ 2.59(s,3H),7.19(d,1H),7.29-7.34(m,2H),7.47-7.58(m,3H),7.87-7.91(m,1H),8.09(d,1H),8.16-8.24(m,4H),8.39(s,1H),8.64-8.69(m,4H),9.25(s,1H)。
實施例22-37:1-[2-氟-5-(三氟甲基)苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
TLC:Rf 0.31(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 4.70(dd,2H),4.96(dd,2H),5.63-5.71(m,1H),7.03(d,1H),7.34-7.55(m,4H),8.06-8.13(m,3H),8.15(d,1H),8.53(dd,1H),8.76(s,2H),9.13(s,1H),9.32(s,1H)。
實施例22-38:1-[3’-(2-羥基-2-丙烷基)-4-(三氟甲基)-2-聯苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.94分);MASS(ESI,Pos.):698(M+H)+;1H-NMR(DMSO-d6):δ 1.45(s,6H),4.70(dd,2H),4.95(dd,2H),5.07(s,1H),5.61-5.72(m,1H),7.02(d,1H),7.29(d,1H),7.35(d,2H),7.41-
7.60(m,5H),8.03-8.19(m,5H),8.34(s,1H),8.67(s,2H),9.39(s,1H)。
實施例22-39:1-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-(1H-吡唑-1-基)-4-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):98%(保持時間:0.91分);MASS(ESI,Pos.):588(M+H)+;1H-NMR(DMSO-d6):δ 4.01(s,3H),6.65-6.66(m,1H),6.95(d,1H),7.32(d,2H),7.75(d,1H),7.83(s,1H),7.94(d,1H),8.07-8.11(m,2H),8.22(d,2H),8.41-8.44(m,2H),8.71(s,2H),9.57(s,1H),9.98(s,1H)。
實施例22-40:1-[3-(二氟甲基)苯基]-3-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.77分);MASS(ESI,Pos.):504(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.82-7.19(m,3H),7.31-7.35(m,2H),7.42(t,1H),7.52(d,1H),7.78(s,1H),8.08-8.11(m,2H),8.20-8.25(m,2H),8.74(s,2H),8.92(s,1H),9.17(s,1H)。
實施例22-41:1-[2-氯-5-(三氟甲基)苯基]-3-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.91分);MASS(ESI,Pos.):556(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.95(d,1H),7.31-7.36(m,2H),7.40(dd,1H),7.73(d,1H),8.08-8.11(m,2H),8.21-8.25(m,2H),8.57(d,1H),8.76(s,2H),8.79(s,1H),9.72(s,1H)。
實施例22-42:1-[2-氟-5-(三氟甲基)苯基]-3-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):540(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.95(d,1H),7.31-7.36(m,2H),7.38-7.54(m,2H),8.08-8.11(m,2H),8.20-8.25(m,2H),8.53(dd,1H),8.75(s,2H),9.10(d,1H),9.31(s,1H)。
實施例22-43:1-(2,5-二氯苯基)-3-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.89分);MASS(ESI,Pos.):522(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.95(d,1H),7.11(dd,1H),7.31-7.35(m,2H),7.50(d,1H),8.07-8.10(m,2H),8.20-8.26(m,3H),8.64(s,1H),8.74(s,2H),9.68(s,1H)。
實施例22-44:1-(2,4-二氯苯基)-3-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.89分);MASS(ESI,Pos.):522(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.95(d,1H),7.31-7.35(m,2H),7.39(dd,1H),7.64(d,1H),8.07-8.11(m,2H),8.14(d,1H),8.20-8.25(m,2H),8.58(s,1H),8.74(s,2H),9.60(s,1H)。
實施例22-45:1-(2,5-二氟苯基)-3-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.79分);
MASS(ESI,Pos.):490(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.81-6.90(m,1H),6.95(d,1H),7.26-7.35(m,3H),7.94-8.00(m,1H),8.08-8.12(m,2H),8.20-8.25(m,2H),8.74(s,2H),8.97(s,1H),9.28(s,1H)。
實施例22-46:1-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-(4-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):99%(保持時間:0.86分);MASS(ESI,Pos.):603(M+H)+;1H-NMR(DMSO-d6):δ 2.38(s,3H),4.01(s,3H),6.95(d,1H),7.30-7.34(m,2H),7.59(dd,1H),7.70(d,1H),8.07-8.10(m,2H),8.20-8.24(m,2H),8.39(s,1H),8.60(s,1H),8.69(s,2H),8.76(s,1H),9.70(s,1H)。
實施例22-47:1-[5-氯-2-(1H-吡唑-1-基)苯基]-3-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.88分);MASS(ESI,Pos.):554(M+H)+;1H-NMR(DMSO-d6):δ 4.01(s,3H),6.61-6.63(m,1H),6.94(d,1H),7.22(dd,1H),7.30-7.34(m,2H),7.51(d,1H),7.89(d,1H),8.07-8.10(m,2H),8.19-8.24(m,2H),8.26(d,1H),8.27(d,1H),8.69(s,2H),9.37(s,1H),9.89(s,1H)。
實施例22-48:1-[5-氯-2-(3-吡啶基)苯基]-3-{2-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):77%(保持時間:0.75分);
MASS(ESI,Pos.):565(M+H)+;1H-NMR(DMSO-d6):δ 4.02(s,3H),6.95(d,1H),7.22-7.34(m,4H),7.54(dd,1H),7.80-7.85(m,1H),8.07-8.23(m,6H),8.59-8.66(m,4H),9.20(brs,1H)。
實施例22-49:1-{6-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-3-吡啶基}-3-[2-(3-吡啶基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):98%(保持時間:0.83分);MASS(ESI,Pos.):598(M+H)+;1H-NMR(DMSO-d6):δ 4.00(s,3H),6.94(d,1H),7.05(d,1H),7.18-7.23(m,2H),7.45-7.59(m,3H),7.87-7.91(m,1H),8.00(dd,1H),8.06-8.21(m,6H),8.42(s,1H),8.64-8.69(m,2H),9.18(s,1H)。
實施例22-50:1-{6-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-3-吡啶基}-3-[2-(1H-吡唑-1-基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.95分);MASS(ESI,Pos.):587(M+H)+;1H-NMR(DMSO-d6):δ 4.01(s,3H),6.67-6.68(m,1H),6.94(d,1H),7.07(d,1H),7.19-7.24(m,2H),7.50(dd,1H),7.73(d,1H),7.95(d,1H),8.00-8.10(m,3H),8.18-8.21(m,3H),8.40(d,1H),8.59(s,1H),9.56(s,1H),9.83(s,1H)。
實施例22-51:1-{6-[4-(6-甲氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-3-吡啶基}-3-{5-(三氟甲基)-2-[3-(三氟甲基)-1H-吡唑-1-基]苯基}脲
純度(LC-MS/ELSD):100%(保持時間:1.01分);MASS(ESI,Pos.):655(M+H)+;
1H-NMR(DMSO-d6):δ 4.01(s,3H),6.94(d,1H),7.07(d,1H),7.13(d,1H),7.19-7.24(m,2H),7.55(dd,1H),7.69(d,1H),7.99(dd,1H),8.01-8.21(m,5H),8.45-8.52(m,3H),9.40(s,1H)。
實施例22-52:1-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)-3-[3-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.84分);MASS(ESI,Pos.):564(M+H)+;1H-NMR(DMSO-d6):δ 4.68-4.72(m,2H),4.93-4.98(m,2H),5.63-5.72(m,1H),7.02(d,1H),7.31-7.40(m,3H),7.51(t,1H),7.61(d,1H),7.96-8.00(m,1H),8.07-8.17(m,4H),8.74(s,2H),9.00(s,1H),9.32(s,1H)。
實施例22-53:1-[2-氯-5-(三氟甲基)苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.90分);MASS(ESI,Pos.):598(M+H)+;1H-NMR(DMSO-d6):δ 4.68-4.73(m,2H),4.93-4.99(m,2H),5.63-5.72(m,1H),7.03(d,1H),7.35-7.43(m,3H),7.73(d,1H),8.07-8.17(m,4H),8.57(d,1H),8.76(s,2H),8.80(s,1H),9.73(s,1H)。
實施例22-54:1-[2-甲基-5-(三氟甲基)苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.86分);MASS(ESI,Pos.):578(M+H)+;1H-NMR(DMSO-d6):δ 2.32(s,3H),4.67-4.74(m,2H),4.93-4.99(m,2H),5.63-5.71(m,1H),7.03(d,1H),7.27-7.45(m,4H),8.07-8.18(m,
4H),8.27-8.30(m,1H),8.39(s,1H),8.76(s,2H),9.35(s,1H)。
實施例22-55:1-(2,4-二氯苯基)-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.87分);MASS(ESI,Pos.):564(M+H)+;1H-NMR(DMSO-d6):δ 4.67-4.74(m,2H),4.92-5.00(m,2H),5.63-5.72(m,1H),7.03(d,1H),7.34-7.43(m,3H),7.64(dd,1H),8.06-8.19(m,5H),8.59(s,1H),8.75(s,2H),9.61(s,1H)。
實施例22-56:1-(5-氯-2-甲基苯基)-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.84分);MASS(ESI,Pos.):544(M+H)+;1H-NMR(DMSO-d6):δ 2.22(s,3H),4.70(dd,2H),4.96(dd,2H),5.63-5.72(m,1H),6.98-7.05(m,2H),7.20(d,1H),7.36(d,2H),7.98(d,1H),8.05-8.19(m,4H),8.27(s,1H),8.75(s,2H),9.31(s,1H)。
實施例22-57:1-(2,5-二氟苯基)-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):99%(保持時間:0.81分);MASS(ESI,Pos.):532(M+H)+;1H-NMR(DMSO-d6):δ 4.70(dd,2H),4.96(dd,2H),5.62-5.72(m,1H),6.81-6.92(m,1H),7.03(d,1H),7.23-7.32(m,1H),7.38(d,2H),7.93-8.01(m,1H),8.04-8.19(m,4H),8.75(s,2H),8.98(s,1H),9.29(s,1H)。
實施例22-58:1-[5-甲基-2-(甲磺醯基)苯基]-3-(2-{4-[6-(3-
氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.77分);MASS(ESI,Pos.):588(M+H)+;1H-NMR(DMSO-d6):δ 2.37(s,3H),3.24(s,3H),4.71(dd,2H),4.96(dd,2H),5.62-5.72(m,1H),7.03(d,1H),7.12(d,1H),7.37(d,2H),7.73(d,1H),7.99(s,1H),8.05-8.20(m,4H),8.73(s,1H),8.77(s,2H),10.13(s,1H)。
實施例22-59:1-[5-氯-2-(甲磺醯基)苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):100%(保持時間:0.83分);MASS(ESI,Pos.):608(M+H)+;1H-NMR(DMSO-d6):δ 3.32(s,3H),4.70(dd,2H),4.95(dd,2H),5.63-5.71(m,1H),7.03(d,1H),7.23-7.31(m,3H),7.85(d,1H),8.03-8.19(m,4H),8.33(d,1H),8.77(s,2H),8.88(s,1H),10.14(s,1H)。
實施例22-60:1-[5-氟-2-(甲磺醯基)苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):99%(保持時間:0.79分);MASS(ESI,Pos.):592(M+H)+;1H-NMR(DMSO-d6):δ 3.32(s,3H),4.71(dd,2H),4.96(dd,2H),5.62-5.72(m,1H),7.03(d,1H),7.20-7.30(m,1H),7.37(d,2H),7.92(dd,1H),8.03-8.20(m,5H),8.76(s,2H),8.95(s,1H),10.30(s,1H)。
實施例22-61:1-[2-(甲磺醯基)-5-(三氟甲基)苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-
嘧啶基)脲
純度(LC-MS/ELSD):98%(保持時間:0.87分);MASS(ESI,Pos.):642(M+H)+;1H-NMR(DMSO-d6):δ 3.39(s,3H),4.70(dd,2H),4.95(dd,2H),5.62-5.73(m,1H),7.03(d,1H),7.37(d,2H),7.64(d,1H),8.03-8.20(m,5H),8.63(s,1H),8.77(s,2H),8.98(s,1H),10.32(s,1H)。
實施例22-62:1-[2-(甲磺醯基)苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):93%(保持時間:0.73分);MASS(ESI,Pos.):574(M+H)+;1H-NMR(DMSO-d6):δ 3.28(s,3H),4.70(dd,2H),4.96(dd,2H),5.62-5.73(m,1H),7.03(d,1H),7.25-7.33(m,1H),7.37(d,2H),7.62-7.72(m,1H),7.85(dd,1H),8.04-8.20(m,5H),8.77(s,3H),10.14(s,1H)。
實施例22-63:2-[({2-[4-(6-乙氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}胺基甲醯基)胺基]-N,N-二甲基-4-(三氟甲基)苯磺醯胺
純度(LC-MS/ELSD):100%(保持時間:0.99分);MASS(ESI,Pos.):643(M+H)+;1H-NMR(DMSO-d6):δ 1.41(t,3H),2.76(s,6H),4.42(q,2H),6.92(d,1H),7.33(d,2H),7.60(dd,1H),7.94(d,1H),8.05-8.10(m,2H),8.20(d,2H),8.61(s,1H),8.75(s,2H),8.99(s,1H),10.31(s,1H)。
實施例22-64:1-{2-[4-(6-乙氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲
純度(LC-MS/ELSD):100%(保持時間:0.94分);MASS(ESI,Pos.):614(M+H)+;1H-NMR(DMSO-d6):δ 1.41(t,3H),3.38(s,3H),4.42(q,2H),6.93(d,1H),7.33(d,2H),7.64(d,1H),8.03-8.26(m,3H),8.20(d,2H),8.63(s,1H),8.76(s,2H),8.97(s,1H),10.31(s,1H)。
實施例22-65:1-[5-氯-2-(甲磺醯基)苯基]-3-{2-[4-(6-乙氧基咪唑并[1,2-b]嗒-3-基)苯氧基]-5-嘧啶基}脲
純度(LC-MS/ELSD):100%(保持時間:0.91分);MASS(ESI,Pos.):580(M+H)+;1H-NMR(DMSO-d6):δ 1.43(t,3H),3.32(s,3H),4.45(q,2H),7.26(d,1H),7.35-7.41(m,3H),7.85(d,1H),8.18(d,2H),8.27(d,1H),8.33(d,1H),8.40(s,1H),8.77(s,2H),8.89(s,1H),10.33(s,1H)。
實施例22-66:1-[3’-(羥甲基)-4-(三氟甲基)-2-聯苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):99%(保持時間:1.07分);MASS(ESI,Pos.):670(M+H)+;1H-NMR(DMSO-d6):δ 4.58(d,2H),4.70(dd,2H),4.95(dd,2H),5.29(t,1H),5.67(quint,1H),7.03(d,1H),7.27-7.56(m,8H),8.04-8.15(m,4H),8.15(d,1H),8.42(d,1H),8.68(s,2H),9.43(s,1H)。
實施例22-67:1-[3’-(1-羥乙基)-4-(三氟甲基)-2-聯苯基]-3-(2-{4-[6-(3-氧雜環丁烷基氧基)咪唑并[1,2-b]嗒-3-基]苯氧基}-5-嘧啶基)脲
純度(LC-MS/ELSD):99%(保持時間:0.94分);MASS(ESI,Pos.):684(M+H)+;1H-NMR(DMSO-d6):δ 1.36(d,3H),4.70(dd,2H),4.76-4.83(m,1H),4.95(dd,2H),5.21(d,1H),5.67(quint,1H),7.02(d,1H),7.27-7.56(m,8H),8.03-8.13(m,4H),8.15(d,1H),8.37(s,1H),8.67(s,2H),9.41(s,1H)。
實施例23
使用藉由使用相當之二環式雜環化合物所製造之相當之胺化合物替代藉由使用5-氯吡唑并[1,5-a]嘧啶所製造之實施例19,使用實施例3製造之化合物,或者使用相當之胺基甲酸酯化合物或異氰酸酯化合物替代實施例3製造之化合物,進行與實施例7相同之操作,獲得具有以下物性值之本發明化合物。
實施例23-1:1-(2-(4-(6-甲氧基咪唑并[1,2-a]吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.52(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 3.81(s,3H),7.10(dd,1H),7.30-7.37(m,3H),7.52(t,1H),7.54-7.65(m,2H),7.71(s,1H),7.73-7.77(m,2H),7.98-8.03(m,2H),8.75(s,2H),9.00(s,1H),9.32(s,1H)。
實施例23-2:1-(2-(4-(6-(2-羥基丙烷-2-基)咪唑并[1,2-a]吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.26(氯仿:甲醇=19:1);1H-NMR(DMSO-d6):δ 1.48(s,6H),5.30(s,1H),7.30-7.43(m,4H),7.49-7.74(m,6H),7.95-7.99(m,1H),8.50-8.53(m,1H),8.75(s,2H),9.00(s,1H),9.32(s,1H)。
實施例23-3:1-(2-(1H-吡唑-1-基)-5-(三氟甲基)苯基)-3-(2-(4-(咪唑并[1,2-a]吡啶-3-基)苯氧基)嘧啶-5-基)脲
TLC:Rf 0.59(乙酸乙酯:甲醇=9:1);1H-NMR(DMSO-d6):δ 6.67(t,1H),6.96(t,1H),7.27-7.37(m,3H),7.51(d,1H),7.64-7.77(m,5H),7.95(s,1H),8.41(d,1H),8.55-8.58(m,2H),8.71(s,2H),9.70(s,1H),9.97(s,1H)。
實施例23-4:1-(2-(4-(咪唑并[1,2-a]吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.27(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.95-7.00(m,1H),7.27-7.36(m,3H),7.48-7.60(m,3H),7.64-7.72(m,3H),7.77(s,1H),7.88(dt,1H),8.24(s,1H),8.39(s,1H),8.56(d,1H),8.65-8.69(m,4H),9.25(s,1H)。
實施例23-5:1-(2-(4-(咪唑并[1,2-a]吡啶-3-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.46(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.95-7.05(m,1H),7.28-7.38(m,4H),7.52(t,1H),7.60-7.74(m,4H),7.78(s,1H),7.98(s,1H),8.57(d,1H),8.74(s,2H),9.02(s,1H),9.34(s,1H)。
實施例23-6:1-(2-(4-(咪唑并[1,2-a]吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-苯基-5-(三氟甲基)吡啶-3-基)脲
TLC:Rf 0.29(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.95-7.01(m,1H),7.27-7.37(m,3H),7.54-7.78(m,9H),8.43(s,1H),8.56(d,1H),8.70(s,2H),8.73(s,1H),8.76(d,1H),9.48(s,1H)。
實施例23-7:1-(2-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.23(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.49(d,1H),7.26(d,2H),7.47-7.58(m,4H),7.73(d,2H),7.90(d,1H),8.19-8.25(m,2H),8.39(s,1H),8.49-8.51(m,1H),8.65-8.68(m,4H),9.24(s,1H),11.7(s,1H)。
實施例23-8:1-(2-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯氧基)嘧啶-5-基)-3-(3-(三氟甲基)苯基)脲
TLC:Rf 0.60(乙酸乙酯);1H-NMR(DMSO-d6):δ 6.49-6.50(m,1H),7.26-7.36(m,3H),7.46-7.54(m,2H),7.62(d,1H),7.74(d,2H),7.97(s,1H),8.21(s,1H),8.50-8.53(m,1H),8.73(s,2H),8.98(s,1H),9.31(s,1H),11.7(s,1H)。
實施例23-9:1-(2-(4-(6-胺基-1H-吡咯并[2,3-b]吡啶-5-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.35(乙酸乙酯);1H-NMR(DMSO-d6):δ 5.19(s,2H),6.20-6.24(m,1H),6.99(t,1H),7.23(d,2H),7.46-7.58(m,6H),7.88-7.92(m,1H),8.23(s,1H),8.38(s,1H),8.63-8.68(m,4H),9.23(s,1H),10.9(s,1H)。
實施例23-10:1-(2-(4-(咪唑并[1,2-a]吡-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.34(二氯甲烷:甲醇=9:1);1H-NMR(DMSO-d6):δ 7.38(d,2H),7.46-7.59(m,3H),7.78(d,2H),7.85-7.91(m,1H),7.92(d,1H),8.06(s,1H),8.24(s,1H),8.38(s,1H),8.58-8.69(m,5H),9.13(d,1H),9.25(s,1H)。
實施例23-11:1-(2-(4-(吡唑并[1,5-a]吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.29(乙酸乙酯);
1H-NMR(DMSO-d6):δ 6.94(t,1H),7.74-7.35(m,3 H),7.46-7.58(m,3H),7.71(d,2H),7.89(d,1H),7.96(d,1H),8.23(s,1H),8.36-8.38(m,2H),8.64-8.74(m,5H),9.22(s,1H)。
實施例23-12:1-(2-(4-(1H-吡唑并[3,4-b]吡啶-5-基)苯氧基)嘧啶-5-基)-3-(2-(吡啶-3-基)-5-(三氟甲基)苯基)脲
TLC:Rf 0.23(乙酸乙酯);1H-NMR(DMSO-d6):δ 7.29(d,2H),7.47-7.58(m,3H),7.79(d,2H),7.87-7.93(m,1H),8.18-8.21(m,1H),8.24(s,1H),8.38(s,1H),8.47(d,1H),8.64-8.68(m,4H),8.83(d,1H),9.23(s,1H),13.7(s,1H)。
對於細胞系之TrkA激酶之抑制活性係使用人類TrkA及表現NFAT-bla之CHO-K1細胞(CellSenserTM TrkA-NFAT-bla CHO-K1細胞,Invitrogen公司製造)實施。
在分析的前一天將CellSenserTM TrkA-NFAT-bla CHO-K1細胞懸浮於分析培養基(含有0.5%透析處理完成之牛胎兒血清(Invitrogen公司製造)、0.1mM非必需胺基酸(Invitrogen公司製造)、1mM丙酮酸鈉(Invitrogen公司製造)及抗生物質(100U/mL盤尼西林(penicillin)及100μg/mL鏈黴素(streptomycin)(Invitrogen公司製造))
之加轉染試劑無血清介質(Opti-MEM1 Reduced Serum Medium)(Invitrogen公司製造))中,以2.4×104細胞/40μL/洞之密度播種於96洞透明底盤(Corning公司製造,產品編號:3882)。又,於一部分的洞只添加40μL/洞之分析培養基(無細胞)。在分析當天於96洞盤(Costar公司製造,產品編號:3363)中分注10mM之本發明化合物(DMSO溶液)後,以DMSO階段稀釋,調製3倍公比之稀釋系列。將該稀釋系列以分析培養基稀釋100倍,調製10倍濃度之本發明化合物溶液(DMSO濃度1%)。於已播種細胞之盤中添加本發明化合物5μL/洞,於5%CO2、95%空氣、37℃之CO2恆溫箱內培養30分鐘。對照組及空白組係添加5μL/洞之含有1%DMSO之分析培養基替代本發明化合物溶液。然後於盤中添加含有NGF(小鼠2.5s、天然型、Invitrogen公司製造)之分析培養基5μL/洞(NGF之最終濃度:50ng/mL),於5%CO2、95%空氣、37℃之CO2恆溫箱內培養5小時。空白群係添加5μL/洞之分析培養基替代NGF。於盤中添加報導基因分析(reporter assay)檢測用試藥10μL/洞後,於遮光下,於室溫培養120分鐘。又,報導基因分析檢測用試藥以LiveBLAzerTM-FRET B/G Loading Kit(Invitrogen公司製造)調製。使用Analyst GT((Molecular Devices日本(股)公司製造),於各洞掃射405nm之激發光,測定460nm及530nm之螢光強度。使用下述之數式1算出各洞之時差性螢光共振能量轉移(TR-FRET)比。
[數1]TR-FRET比=(A460X-A460F)/(A530X-A530F)
A460X:本發明化合物、對照組或空白組460nm之螢光強度
A460F:無細胞460nm之螢光強度
A530X:本發明化合物、對照組或空白組530nm之螢光強度
A530F:無細胞530nm之螢光強度
本發明化合物之TR-FRET抑制率(%)係使用下述之數式2算出。
[數2]抑制率(%)={1-(AX-AB)/(AC-AB)}×100
AX:添加本發明化合物時之TR-FRET比
AB:空白組之TR-FRET比
AC:對照組之TR-FRET比
本發明化合物之IC50值係根據本發明化合物各濃度之抑制率,從抑制曲線算出。
該結果,本發明化合物之IC50值在0.5μM以下,明瞭本發明化合物具有TrkA抑制活性。例如,數個本發明化合物之IC50值為如下述表1及表2所示。
將被驗物質(本發明化合物)溶解於二甲亞碸,調製3μM試驗濃度之100倍濃度之溶液。將該溶液更以分析緩衝液(20mM HEPES、0.01%TritonX-100、2mM DTT,pH7.5)稀釋25倍,作為被驗物質溶液。陽性對照物質亦同樣操作,調製陽性對照物質溶液。
將以分析緩衝液調製之5μL之4倍濃度被驗物質溶液、5μL之4倍濃度基質/ATP/金屬溶液(鎂)及10μL之2倍濃度激酶溶液於聚丙烯製造之384洞盤之洞內混合,於室溫進行反應1小時。添加60μL之終止緩衝液(termination buffer)(QuickScout Screening Assist MSA;Carna Biosciences)將反應停止。將反應溶液中之基質肽與磷酸化肽分離、定量。激酶反應係以從基質肽高峰高度(S)與磷酸化肽高峰高度(P)計算之生成物比(P/(P+S))評估。作為其他之激酶係使用例如b-Raf及KDR之激酶,進行激酶選擇性實驗。以下之表3表示於各個激酶酵素抑制活性試驗中使用之基質、基質濃度、ATP濃度及陽性對照物質。
將含有所有反應組成之對照洞之平均信號作為0%抑制、背景洞(未添加酵素)之平均信號作為100%抑制,從各被驗物質試驗洞之平均信號計算抑制率。其結果,在3μM濃度之本發明化合物對於各激酶之抑制率如以下表4所示。
從該結果明瞭,本發明化合物對於TrkA以外之其他激酶,例如b-Raf及KDR之激酶之抑制弱,對於TrkA有強的抑制。換言之,本發明化合物從藥理實施例1之結果,對於TrkA抑制係強力到IC50在0.5μM以下,另一方面,從藥理實施例2之結果,對於TrkA以外之上述激酶,即使於3μM濃度之化合物,仍只抑制0%至約58%。所以,明瞭本發明化合物對於TrkA抑制之選擇性高,具有優越之激酶選擇性。
評估本發明化合物於體內之對於TrkA之抑制活性。於剃掉背部毛的雄性CD(SD)IGS大鼠(7至9週齡、日本Charles River公司製造)經口投予溶解於介質之本發明化合物(投予容量:5mL/kg)。對於對照群及正常群,經口投予介質(投予容量:5mL/kg)。投予6、12小時或14小時後,在鹵神(halothane)麻醉下,於背部3個地方皮內投予使用含有0.1%BSA(Sigma-Aldrich公司製造)之生理食鹽液調製之3μg/mL之NGF(小鼠2.5s、天然型、Invitrogen公司製造)溶液(投予容量;50μL/site)。對於正常群,於背部3個地方皮內投予含有0.1%BSA之生理食鹽液(投予容量;50μL/site)。皮內投予後馬上於尾靜脈內投予以生理食鹽液溶解之1%伊凡斯藍(Evans blue)(東京化成(股)公司製造)(投予容量:3mL/kg)。投予10分鐘後切斷腹部大動脈,放血致死。切取皮內投予部位(3個地方)之背部皮膚,將該皮膚試樣一個個移至48洞盤(旭硝子公司製造)之各洞中。於盤中每個洞加入甲醯胺0.8mL/洞,蓋上蓋子後,於60℃培養一晚。將200μL之甲醯胺萃取液移至96洞盤,使用吸光微量盤分析儀(Microplate reader)(SpectraMAX190,Molecular
Devices日本(股)公司製造)測定甲醯胺中所萃取出之伊凡斯藍之吸光度(波長:620nm)。同時測定溶解於甲醯胺之伊凡斯藍之標品(0、0.78、1.56、3.13、6.25、12.5、25及50μg/mL)之吸光度(波長:620nm)作成校正曲線。從該校正曲線與各試樣之吸光度算出各試樣之伊凡斯藍濃度。算出從同一個體採取之3個地方之皮膚試樣之伊凡斯藍濃度之平均值,作為該個體之值。使用以下之式算出本發明化合物之大鼠NGF誘發血管滲透性亢進抑制率。
[數3]抑制率(%)={1-(AX-AN)/(AC-AN)}×100
AX:被驗化合物之伊凡斯藍濃度(同一個體之3試樣之平均值)
AN:正常群之伊凡斯藍濃度(同一個體之3試樣之平均值)
AC:對照群之伊凡斯藍濃度(同一個體之3試樣之平均值)
其結果,本發明化合物(3mg/kg;投予6小時後)之大鼠NGF誘發血管滲透性亢進抑制率為約70%,明瞭本發明化合物即使經過長時間,亦強力抑制血管滲透性之亢進。
例如,數個本發明化合物(1mg/kg;投予14小時後或12小時後)之大鼠NGF誘發血管滲透性亢進抑制率為如以下之表5及表6所示。
使用單碘代乙酸鈉(以下,簡稱為MIA)(Sigma-Aldrich Japan)誘發之模型大鼠,評估本發明化合物之鎮痛作用。
(1)製作MIA誘發之模型大鼠
在異氟烷(isoflurane)麻醉下剃除大鼠右後腳膝周邊的毛,使用附有29G注射針之注射筒(BD Rhoads、日本Becton‧Dickinson公司製造),於右後腳關節腔內投予120mg/mL之MIA溶液25μL。於正常對照群投予生理食鹽液25μL。
(2)群構成及群分組
以正常對照群、發病對照群、被驗物質投予群及曲馬多(Tramadol)投予群或嗎啡投予群之群構成進行。除了正常對照群以外,測定以上述(1)之方法製作之MIA誘發14日後之模型大鼠右後腳之負荷重量比率(測定方法於後述),以各群右後腳負荷重量比率無偏差之方式進行群分組。
(3)投予被驗物質、曲馬多或嗎啡
將被驗物質之本發明化合物以Wellsolve(Celeste公司製造)溶解,調製成0.1、0.3或1mg/mL溶液。將調製之0.1、0.3或1mg/mL溶液以蒸餾水稀釋5倍,調製成0.02、0.06或0.2mg/mL溶液(Wellsolve之最終濃度:20%)。將陽性對照藥之曲馬多以生理食鹽液溶解,調製成2mg/mL溶液。或將陽性對照藥之嗎啡以生理食鹽液溶解,調製成0.6mg/mL溶液。對於被驗物質投予群,從MIA誘發14日至23日後為止,將被驗物質溶液(0.1、0.3或1mg/kg)每日2次,反覆經口投予10日。另,於測定MIA誘發24日後之右後腳負荷重量比率之3小時前經口投予被驗物質溶液,於1小時前皮下投予生理食鹽液。對於曲馬多投予群或嗎啡投予群,從MIA誘發14日至23日後為止,1日2次,反覆經口投予20%Wellsolve10日。另,於測定MIA誘發24日後之右後腳負荷重量比率之3小時前經口投予20%Wellsolve,於1小時前皮下投予曲馬多溶液(10mg/kg)或嗎啡溶液(3mg/kg)。又,對於正常對照群及發病對照群,從MIA誘發14日至23日後為止,1日2次,反覆經口投予20% Wellsolve 10日。另,於測定MIA誘發24日後之右後腳負荷重量比率之3小時前經口投予20%Wellsolve,於1
小時前皮下投予生理食鹽液。
(4)右後腳負荷重量比率之測定
使用Linton Incapacitance Tester(MJS Technology Inc.,UK)測定左右後腳之負荷重量。亦即,將大鼠移至Linton Incapacitance Tester上之專用籠子,左右之後腳以正確姿勢分別站在2對之重量測定感測器上。確認大鼠之姿勢無左右及前後偏差後,測定左及右後腳各個之負荷重量3秒鐘。將每個個體反覆操作負荷重量測定3次。為了獲得安定之測定值,在從MIA誘發當日至誘發14日後為止之間,5日以上將大鼠放在專用籠子內馴服20分鐘以上。另,於負荷重量測定前亦馴化約10分鐘,測定負荷重量。測定於MIA誘發14日後之群分組前及於24日後之正常對照群、發病對照群、被驗物質投予群(投予3小時後)、曲馬多投予群(投予1小時後)及嗎啡投予群(投予1小時後)之左右後腳負荷重量。依據左右後腳負荷重量之平均值以下述之數式4算出於兩後腳負荷重量中之右後腳之負荷重量比率。測定在盲檢下實施。依據MIA誘發24日後之各群之右後腳負荷重量比率以下述之數式5算出被驗物質之本發明化合物之改善率,評估被驗物質(本發明化合物)之鎮痛作用。
[數4]右後肢負荷重量比率B(%)={AR/(AR+AL)×100}
AR:右後腳之負荷重量(同一個體測定3次之值之平均值)
AL:左後腳之負荷重量(同一個體測定3次之值之平均值)
[數5]被驗物質的改善率(%)={1-(BT-BC)/(BN-BC)}×100
BC:正常對照群之平均值
BN:發病對照群之平均值
BT:被驗物質投予群之平均值
其結果,本發明化合物之改善率具有與作為鎮痛藥廣泛使用之曲馬多及嗎啡同等以上之改善率。因此,明瞭本發明化合物之鎮痛作用具有與曲馬多及嗎啡同等以上之鎮痛作用。
例如,數個本發明化合物對於MIA誘發模型大鼠之鎮痛作用(改善率)如以下之表7(使用曲馬多作為陽性對照藥時之結果)及表8(使用嗎啡作為陽性對照藥時之結果)所示。
將以下之各成分根據常法混合後打錠,獲得每錠中含有10mg活性成分之錠劑1萬錠。
‧1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(4-甲基-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)脲…………………100g
‧羧甲基纖維素鈣(崩解劑)…………………………………20g
‧硬脂酸鎂(潤滑劑)…………………………………………10g
‧微結晶纖維素………………………………………………870g
將以下之各成分根據常法混合後以除塵過濾器過濾,每支安瓿填充5mL,以高壓釜加熱滅菌,獲得每安瓿中含有20mg活性成分之安瓿1萬支。
‧1-(2-(4-(2-胺基-5-氯吡啶-3-基)苯氧基)嘧啶-5-基)-3-(2-(4-甲基
-1H-1,2,3-三唑-1-基)-5-(三氟甲基)苯基)脲…………………200g
‧甘露糖醇……………………………………………………20g
‧蒸餾水………………………………………………………50L
本發明之化合物具有Trk抑制活性,對於Trk參予之疾病,例如疼痛、搔癢症、下泌尿道障礙、氣喘、過敏性鼻炎、炎症性腸疾病或查加斯病等疾病之預防及/或治療有效。
Claims (2)
- 一種1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲。
- 一種1-{2-[4-(2-胺基-5-氯-3-吡啶基)苯氧基]-5-嘧啶基}-3-[2-(甲磺醯基)-5-(三氟甲基)苯基]脲之鹽。
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TW201350479A (zh) * | 2012-04-26 | 2013-12-16 | Ono Pharmaceutical Co | Trk阻害化合物 |
TW201437206A (zh) * | 2013-02-19 | 2014-10-01 | Ono Pharmaceutical Co | TrK阻礙化合物 |
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