WO2021197250A1 - 作为转染期间重排激酶抑制剂的新的化合物 - Google Patents
作为转染期间重排激酶抑制剂的新的化合物 Download PDFInfo
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- WO2021197250A1 WO2021197250A1 PCT/CN2021/083528 CN2021083528W WO2021197250A1 WO 2021197250 A1 WO2021197250 A1 WO 2021197250A1 CN 2021083528 W CN2021083528 W CN 2021083528W WO 2021197250 A1 WO2021197250 A1 WO 2021197250A1
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- Prior art keywords
- alkyl
- optionally substituted
- cycloalkyl
- halogen
- amino
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 220
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 15
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 15
- 238000001890 transfection Methods 0.000 title abstract description 4
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- 230000002265 prevention Effects 0.000 claims abstract description 3
- -1 cyano, hydroxy Chemical group 0.000 claims description 232
- 229910052736 halogen Inorganic materials 0.000 claims description 166
- 150000002367 halogens Chemical class 0.000 claims description 166
- 125000001424 substituent group Chemical group 0.000 claims description 151
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 122
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 115
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 101
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- 125000003118 aryl group Chemical group 0.000 claims description 76
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 54
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- 125000003545 alkoxy group Chemical group 0.000 claims description 42
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 29
- 125000003342 alkenyl group Chemical group 0.000 claims description 27
- 125000000304 alkynyl group Chemical group 0.000 claims description 27
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
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- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 20
- 125000003107 substituted aryl group Chemical group 0.000 claims description 20
- 125000003277 amino group Chemical group 0.000 claims description 19
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 16
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
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- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
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- 229940125905 RET kinase inhibitor Drugs 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 20
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- 230000005764 inhibitory process Effects 0.000 description 47
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 46
- 230000015572 biosynthetic process Effects 0.000 description 45
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- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- HNINFCBLGHCFOJ-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NCC2CCC1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/444—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
- 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
- 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
- C07D471/08—Bridged 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
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to compounds, pharmaceutical compositions containing them, and their use as rearranged during transfection (RET) kinase inhibitors. More specifically, the present invention provides new compounds as RET kinase inhibitors, pharmaceutical compositions containing such compounds, and methods of using the compounds to treat or prevent related diseases mediated by RET kinases, such as Tumor. The present invention also relates to methods of preparing the compounds described below.
- RET transfection
- the RET (Rearranged during transfection) gene encodes the membrane receptor tyrosine kinase RET protein, which belongs to the cadherin superfamily. It is expressed in the neural crest source and cells of the urogenital system, and plays a vital role in the development of the neural crest. effect.
- RET kinase binds to one of the four glial cell-derived neurotrophic factor (GDNF) family receptor alpha (GFR ⁇ ) proteins to form a complex that homodimerizes, phosphorylates, and Activate its tyrosine kinase activity and activate the signal cascade of Ras/MAPK, PI3K/Akt, JNK, p38 and PLCg pathways (Mulligan, LMNature Reviews Cancer, 2014, 14, 173-186).
- GDNF glial cell-derived neurotrophic factor family receptor alpha
- Carcinogenic and activating mutations of RET gene can amplify the signal cascade without relying on ligand binding, and can also activate other signal cascades (such as STAT3 and STAT1).
- RET is a cancer driver gene. Mutations can lead to over-activity of the RET signaling pathway, causing uncontrolled cell growth, which in turn triggers the formation of tumors.
- RET protein mutations mainly include fusion mutations with genes such as KIF5B, TRIM33, CCDC6, and NCOA4, as well as point mutations at M918T, etc.
- the common RET mutations mainly occur in thyroid cancer, non-small cell lung cancer and other cancer types. Although its incidence in non-small cell lung cancer is only 2%, the number of patients in China is very large. Such patients are not uncommon in clinical treatment. RET fusion is more common in young patients, especially young non-small cell lung cancer. The incidence of smoking patients with lung adenocarcinoma is as high as 7%-17%.
- the developed selective RET kinase inhibitors mainly include Blu-667 (US20170121312A1, Subbiah, V.; Gainor, JF; et al. Cancer Discovery. 2018, 8(7), 836-849.) and Loxo-292 (WO2018071454A1, WO2018071447A1, WO2017011776A1, Subbiah, V.; Busaidy, NL; et al. Annal Oncolology, 2018, 29(8), 1869-1876.).
- Blu-667 US20170121312A1, Subbiah, V.; Gainor, JF; et al. Cancer Discovery. 2018, 8(7), 836-849.
- Loxo-292 WO2018071454A1, WO2018071447A1, WO2017011776A1, Subbiah, V.; Busaidy, NL; et al. Annal Oncolology, 2018, 29(8), 1869-1876.
- the purpose of the present invention is to provide a compound represented by formula (I), its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof that can be used as selective RET kinase inhibitors:
- X 1 is CR 1 or N; preferably CH or N;
- X 2 is CH or N
- the condition is that at most one of X 1 and X 2 is N;
- Y 1 is CR 2 or N; preferably CH or N; most preferably N;
- Y 2 is CR 3 or N; preferably CH or N; most preferably CH;
- Y 3 is CR 4 or N; preferably CH or N;
- Y 4 is CR 5 or N; preferably CH or N; most preferably CH;
- the condition is that at most 2 of Y 1 , Y 2 , Y 3 and Y 4 are N;
- Y 1 -Y 4 are not N; only Y 1 or Y 2 is N; Y 1 and Y 2 are both N; or Y 1 and Y 3 are both N;
- Y 1 or Y 2 is N; or both Y 1 and Y 3 are N; most preferably one of the following conditions: Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; Or Y 1 and Y 3
- R 1 to R 5 are each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, Aryl, heteroaryl, -OR 6 , -NR 7 R 8 , -OC(O)NR 7 R 8 , -C(O)OR 6 , -C(O)NR 7 R 8 , -NR 9 C( O)R 6 , -NR 9 C(O)NR 7 R 8 , -S(O) m R 6 , -NR 9 S(O) m R 6 , -SR 6 , -S(O) m NR 7 R 8 or -NR 9 S(O) m NR 7 R 8 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl group is optional
- A is selected from hydrogen, halogen, cyano or C1-C8 alkyl; preferably, A is selected from hydrogen, halogen, cyano or C1-C6 alkyl; more preferably, A is selected from hydrogen, cyano or C1-C4 Alkyl; most preferably, A is hydrogen;
- B is selected from hydrogen, halogen, cyano, C1-C4 alkyl, -OR 14 or optionally substituted Ar 1 ; preferably, B is selected from hydrogen, halogen, -OR 14 or optionally substituted Ar 1 ; Most preferably, B is selected from hydrogen, halogen, -OR 14 or
- R 14 is selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein the alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl are optionally substituted by one or more selected from halogen, cyano, hydroxy, C3-C8 cycloalkyl, and optionally substituted by C1-C6 alkyl.
- R 14 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic group, wherein said alkyl, cycloalkane
- the group and the heterocyclic group are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C3-C8 cycloalkyl, and 4-8 membered heterocyclic group optionally substituted by C1-C6 alkyl; further preferred
- R 14 is selected from C1-C4 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group, wherein said alkyl, cycloalkyl and heterocyclic group are optionally selected from halogen by one or more , Hydroxy, and 4-6 membered heterocyclic substituents optionally substituted by C1-C4 alkyl; most preferably, R 14 is C1- optionally substituted by 1-
- Ar 1 is selected from 5 or 6-membered heteroaryl groups containing 1-3 ring heteroatoms, wherein the heteroatoms are each independently selected from N, O, S; preferably, Ar 1 is selected from containing two rings 5- or 6-membered heteroaryl groups with N atoms; further preferably, Ar 1 is selected from 5-membered heteroaryl groups containing two N atoms on the ring; most preferably, Ar 1 is
- Ar 1 may be optionally substituted by one or more substituents, each of which is independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, Aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OR 6 , -NR 7 R 8 , -OC(O)NR 7 R 8 , -C(O)OR 6 , -C( O)R 6 , -C(O)NR 7 R 8 , -NR 9 C(O)R 6 , -NR 9 C(O)NR 7 R 8 , -S(O) m R 6 , -NR 9 S (O) m R 6 , -SR 6 , -S(O) m NR 7 R 8 or -NR 9 S(O) m NR 7 R 8 , wherein the alkyl group, cycloalkyl group, heterocyclic
- R 15 is selected from hydrogen, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, aryl or heteroaryl; preferably, R 15 is selected from hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic group; further preferably, R 15 is selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl , C3-C6 cycloalkyl or 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N, O or S; most preferably, R 15 is C1-C4 alkyl;
- D is selected from 4-8 membered heterocyclylene, 6-8 membered fused heterocyclylene or 7-11 membered spiro heterocyclylene containing 1-3 heteroatoms selected from N and O; preferably, D It is selected from 4-6 membered heterocyclylene containing 1-2 N or 6-8 membered fused heterocyclylene containing 1-2 N; most preferably, D is selected from:
- D is optionally substituted with a substituent selected from halogen, cyano, hydroxy, amino or C1-C8 alkyl, wherein the alkyl is optionally substituted with a substituent selected from the following: halogen, hydroxy, mono Or two (C1-C8 alkyl) amino, N-(C1-C8 alkyl)-N-(C1-C4 alkylcarbonyl) amino, optionally halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1 -C8 alkyl substituted 4-8 membered heterocyclic group; preferably, D is optionally substituted by a substituent selected from halogen, cyano, hydroxy, amino or C1-C6 alkyl, wherein the alkyl group is any It is selected to be substituted by a substituent selected from the group consisting of halogen, hydroxy, mono- or di-(C1-C6 alkyl)amino, N-(C1-C6 alky
- E is selected from amino, NHC(O)R X , -C(O)R y , -OR 6 , -NR 7 R 8 , -OC(O)NR 7 R 8 , -C(O)OR 6 , -C(O)NR 7 R 8 , -NR 9 C(O)NR 7 R 8 , -S(O) m R 6 , -NR 9 S(O) m R 6 , -SR 6 , -S(O) m NR 7 R 8 , -NR 9 S(O) m NR 7 R 8 , or- CH 2 -Ar 2 ; preferably, E is selected from amino, heteroaryloxy, -NHC(O)R X , -SO 2 (C1-C8)alkyl, -C(O)R y , Or -CH 2 -Ar 2 ; further preferably, E is selected from amino, pyridyloxy, -NHC(O)R
- D is When, E is selected from amino, -NHC(O)R X or -SO 2 (C1-C4) alkyl; when D is When E is pyridine-2-oxy; when D is When E is selected from -C(O)R y , -SO 2 (C1-C4) alkyl, or -CH 2 -Ar 2 ;
- R X is selected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1 -C8 alkyl, optionally substituted 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl or optionally substituted by C1-C8 alkyl
- the amino group; the optional substituent is selected from halogen, nitro, cyano, hydroxyl, C1-C8 alkoxy or C3-C8 cycloalkyl; preferably, R X is selected from C1-C6 alkoxy, Optionally substituted 6-membered aryl, optionally substituted 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N and O, optionally substituted C1-C6 alkyl, optionally A substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms
- R y is selected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, so The substituent is selected from C1-C8 alkyl optionally substituted by aryl or heteroaryl; preferably, R y is selected from optionally substituted amino, C1-C6 alkyl, containing 1 or 2 selected from N , O, S heteroatom 4-6 membered heterocyclic group, or C3-C6 cycloalkyl, the substituent is selected from C1-C6 alkyl optionally substituted by aryl; most preferably, R y is selected From amino optionally substituted by C1-C4 alkyl or benzyl, C1-C4 alkyl, 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O or C3-C6 cycloalkyl ;
- Ar 2 is selected from optionally substituted aryl or heteroaryl, and the substituent is selected from halogen, hydroxyl, amino or C1-C8 alkoxy; preferably, Ar 2 is selected from 5 optionally mono- or di-substituted -6-membered aryl or heteroaryl, the substituent is selected from halogen, C1-C6 alkoxy; most preferably, Ar 2 is selected from phenyl optionally mono- or di-substituted, optionally mono- or di-substituted Pyridyl, the substituent is selected from halogen, C1-C4 alkoxy;
- R m and R n are each independently selected from hydrogen, hydroxy, C1-C8 alkyl or hydroxy C1-C8 alkyl, or R m and R n together with the carbon atom to which they are attached form a C3-C8 cycloalkyl; preferably, R m and R n are each independently selected from hydrogen, hydroxyl, C1-C6 alkyl or hydroxy C1-C6 alkyl, or R m and R n together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; most preferably , R m and R n are each independently selected from hydrogen, hydroxyl or hydroxy C1-C4 alkyl, or R m and R n together with the carbon atom to which they are connected form a cyclopropyl group;
- R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 are each independently selected from hydrogen, halogen, hydroxyl, amino, C1-C8 alkyl, C1-C8 alkoxy, C3 -C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl or C2-C8 alkynyl;
- r is selected from 0, 1, 2 or 3; preferably, r is selected from 0, 1 or 2;
- n is selected from 1 or 2.
- the present invention provides a compound of formula (I), its isomer, prodrug, stable isotope derivative or its pharmaceutically Acceptable salt, where
- X 1 is CR 1 or N
- X 2 is CH or N
- the condition is that at most one of X 1 and X 2 is N;
- Y 1 is CR 2 or N
- Y 2 is CR 3 or N
- Y 3 is CR 4 or N
- Y 4 is CR 5 or N
- Y 1 -Y 4 are not N; only Y 1 or Y 2 is N; Y 1 and Y 2 are both N; or Y 1 and Y 3 are both N;
- R 1 -R 5 are each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, C2-C8 alkenyl , C2-C8 alkynyl, -OR 6 , -NR 7 R 8 , -OC(O)NR 7 R 8 , -C(O)OR 6 , -C(O)NR 7 R 8 ,
- A is selected from hydrogen, halogen, cyano or C1-C6 alkyl
- B is selected from hydrogen, halogen, -OR 14 or optionally substituted Ar 1 ;
- R 14 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein the alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C3-C8 cycloalkyl, optionally C1 -C6 alkyl substituted 4-8 membered heterocyclic group;
- Ar 1 is selected from 5 or 6-membered heteroaryl groups containing 1-3 ring heteroatoms, wherein the heteroatoms are each independently selected from N, O, S;
- Ar 1 may be optionally substituted by one or more substituents, each of which is independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, heterocyclyl, aryl, hetero Aryl, C2-C8 alkenyl, C2-C8 alkynyl, -OR 6 , -NR 7 R 8 , -OC(O)NR 7 R 8 , -C(O)OR 6 , -C(O)R 6 , -C(O)NR 7 R 8 , -NR 9 C(O)R 6 , -NR 9 C(O)NR 7 R 8 , -S(O) m R 6 , -NR 9 S(O) m R 6 , -SR 6 , -S(O) m NR 7 R 8 or -NR 9 S(O) m NR 7 R 8 ;
- D is selected from 4-6 membered heterocyclylene containing 1-2 N or 6-8 membered fused heterocyclylene containing 1-2 N, and when X 2 is CH, D is not
- D is optionally substituted with a substituent selected from halogen, cyano, hydroxy, amino, or C1-C8 alkyl, wherein the alkyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, Mono or di(C1-C8 alkyl)amino, N-(C1-C8 alkyl)-N-(C1-C4 alkylcarbonyl)amino, optionally halogen, hydroxy, (C1-C4 alkyl)carbonyl or C1-C8 alkyl substituted 4-8 membered heterocyclic group;
- E is selected from amino, NHC(O)R X , -C(O)R y , -OR 6 , -NR 7 R 8 , -OC(O)NR 7 R 8 , -C(O)OR 6 , -C(O)NR 7 R 8 , -NR 9 C(O)NR 7 R 8 , -S(O) m R 6 , -NR 9 S(O) m R 6 , -SR 6 , -S(O) m NR 7 R 8 , -NR 9 S(O) m NR 7 R 8 , or- CH 2 -Ar 2 ;
- R X is selected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1 -C8 alkyl, optionally substituted 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl or optionally substituted by C1-C8 alkyl
- the amino group; the optional substituent is selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
- R y is selected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, so The substituent is selected from C1-C8 alkyl optionally substituted by aryl or heteroaryl;
- Ar 2 is selected from optionally substituted aryl or heteroaryl, and the substituent is selected from halogen, hydroxyl, amino or C1-C8 alkoxy;
- R m and R n are each independently selected from hydrogen, hydroxyl, C1-C8 alkyl, hydroxy C1-C8 alkyl, or R m and R n together with the carbon atom to which they are connected form a C3-C8 cycloalkyl;
- R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, halogen, hydroxyl, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycle Group, heteroaryl, aryl, C2-C8 alkenyl or C2-C8 alkynyl;
- n 1 or 2;
- r 0, 1, 2 or 3.
- the present invention provides a compound of formula (I), its isomers, prodrugs, stable isotope derivatives, or pharmacological agents thereof that can be used as a selective RET kinase inhibitor as described above.
- Acceptable salt of which
- X 1 is CR 1 or N
- X 2 is CH or N
- the condition is that at most one of X 1 and X 2 is N;
- Y 1 is CR 2 or N
- Y 2 is CR 3 or N
- Y 3 is CR 4 or N
- Y 4 is CR 5 or N
- Y 1 -Y 4 are not N; only Y 1 or Y 2 is N; Y 1 and Y 2 are both N; or Y 1 and Y 3 are both N;
- R 1 -R 5 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, -OR 6 or -NR 7 R 8 ;
- A is selected from hydrogen, halogen, cyano or C1-C6 alkyl
- B is selected from hydrogen, halogen, -OR 14 or optionally substituted Ar 1 ;
- R 14 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein the alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C3-C8 cycloalkyl, or optionally substituted by C1-C6 alkyl substituted 4-8 membered heterocyclic group;
- Ar 1 is selected from 5 or 6-membered heteroaryl groups containing two N atoms on the ring;
- Ar 1 may be optionally substituted by one or more substituents, each of which is independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, Aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OR 6 , -NR 7 R 8 , -OC(O)NR 7 R 8 , -C(O)OR 6 , -C( O)R 6 , -C(O)NR 7 R 8 , -NR 9 C(O)R 6 , -NR 9 C(O)NR 7 R 8 , -S(O) m R 6 , -NR 9 S (O) m R 6 , -SR 6 , -S(O) m NR 7 R 8 or -NR 9 S(O) m NR 7 R 8 ;
- D is selected from 4-6 membered heterocyclylene containing 1-2 N or 6-8 membered fused heterocyclylene containing 1-2 N, and when X 2 is CH, D is not
- D is optionally substituted with a substituent selected from halogen, cyano, hydroxy, amino, C1-C8 alkyl, wherein the alkyl is optionally substituted with a substituent selected from the following: halogen, hydroxy, mono Or two (C1-C8 alkyl) amino, N-(C1-C8 alkyl)-N-(C1-C4 alkylcarbonyl) amino, optionally halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1 -C8 alkyl substituted 4-8 membered heterocyclic group;
- E is selected from amino, heteroaryloxy, -NHC(O)R X , -SO 2 (C1-C8)alkyl, -C(O)R y , Or -CH 2 -Ar 2 ;
- R X is selected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1 -C8 alkyl, optionally substituted 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl or optionally substituted by C1-C8 alkyl
- the amino group; the optional substituent is selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
- R y is selected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, so The substituent is selected from C1-C8 alkyl optionally substituted by aryl or heteroaryl;
- Ar 2 is selected from optionally substituted aryl or heteroaryl, and the substituent is selected from halogen, hydroxyl, amino, C1-C8 alkoxy;
- R m and R n are each independently selected from hydrogen, hydroxyl, C1-C8 alkyl, hydroxy C1-C8 alkyl, or R m and R n together with the carbon atom to which they are connected form a C3-C8 cycloalkyl;
- R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, halogen, hydroxyl, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycle Group, heteroaryl, aryl, C2-C8 alkenyl or C2-C8 alkynyl;
- n 1 or 2;
- r 0, 1, 2 or 3.
- the present invention provides a compound of formula (I), its isomers, prodrugs, stable isotope derivatives, or its derivatives, as described above, which can be used as selective RET kinase inhibitors
- a pharmaceutically acceptable salt wherein
- X 1 is CR 1 or N
- X 2 is CH or N
- the condition is that at most one of X 1 and X 2 is N;
- Y 1 is CR 2 or N
- Y 2 is CR 3 or N
- Y 3 is CR 4 or N
- Y 4 is CR 5 or N
- Y 1 -Y 4 are not N; only Y 1 or Y 2 is N; or Y 1 and Y 3 are both N;
- R 1 -R 5 are each independently selected from hydrogen, halogen or C1-C4 alkyl
- A is selected from hydrogen, cyano or C1-C4 alkyl
- B is selected from hydrogen, halogen, -OR 14 or optionally substituted Ar 1 ;
- R 14 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein the alkyl, cycloalkyl, Heterocyclyl, aryl or heteroaryl, alkenyl, alkynyl are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C3-C8 cycloalkyl, optionally C1 -C6 alkyl substituted 4-8 membered heterocyclic group;
- Ar 1 is selected from 5-membered heteroaryl groups containing two N atoms on the ring;
- Ar 1 may be optionally substituted by one or more substituents, each of which is independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, Aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OR 6 , -NR 7 R 8 , -OC(O)NR 7 R 8 , -C(O)OR 6 , -C( O)R 6 , -C(O)NR 7 R 8 , -NR 9 C(O)R 6 , -NR 9 C(O)NR 7 R 8 , -S(O) m R 6 , -NR 9 S (O) m R 6 , -SR 6 , -S(O) m NR 7 R 8 , -NR 9 S(O) m NR 7 R 8 ;
- D is selected from 4-6 membered heterocyclylene containing 1-2 N or 6-8 membered fused heterocyclylene containing 1-2 N, and when X 2 is CH, D is not
- D is optionally substituted with a substituent selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, wherein the alkyl is optionally substituted with a substituent selected from the following: halogen, hydroxy, mono Or two (C1-C6 alkyl) amino, N-(C1-C6 alkyl)-N-(C1-C4 alkylcarbonyl) amino, optionally halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1 -C6 alkyl substituted 4-6 membered heterocyclic group;
- E is selected from amino, heteroaryloxy, -NHC(O)R X , -SO 2 (C1-C8)alkyl, -C(O)R y , Or -CH 2 -Ar 2 ;
- R X is selected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1 -C8 alkyl, optionally substituted 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl or optionally substituted by C1-C8 alkyl
- the amino group; the optional substituent is selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
- R y is selected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, so The substituent is selected from C1-C8 alkyl optionally substituted by aryl or heteroaryl;
- Ar 2 is selected from optionally substituted aryl or heteroaryl, and the substituent is selected from halogen, hydroxyl, amino, C1-C8 alkoxy;
- R m and R n are each independently selected from hydrogen, hydroxyl, C1-C8 alkyl, hydroxy C1-C8 alkyl, or R m and R n together with the carbon atom to which they are connected form a C3-C8 cycloalkyl;
- R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, halogen, hydroxyl, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycle Group, heteroaryl, aryl, C2-C8 alkenyl or C2-C8 alkynyl;
- n 1 or 2;
- r 0, 1, 2 or 3.
- the present invention provides a compound of formula (I), its isomers, prodrugs, stable isotope derivatives or the like, which can be used as a selective RET kinase inhibitor as described above.
- a pharmaceutically acceptable salt wherein
- X 1 is CH or N
- X 2 is CH or N
- the condition is that at most one of X 1 and X 2 is N;
- Y 1 is CH or N
- Y 2 is CH or N
- Y 3 is CH or N
- Y 4 is CH or N
- Y 1 , Y 2 , Y 3 and Y 4 are all CH; only Y 1 or Y 2 is N; or Y 1 and Y 3 are both N;
- A is hydrogen
- B is selected from hydrogen, halogen, -OR 14 or
- R 14 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein the alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C3-C8 cycloalkyl, optionally C1 -C6 alkyl substituted 4-8 membered heterocyclic group;
- R 15 is selected from hydrogen, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group containing 1-2 heteroatoms selected from N, O, S, Aryl or heteroaryl;
- D is selected from:
- D is optionally substituted with a substituent selected from halogen, cyano, hydroxy, amino or C1-C6 alkyl, wherein the alkyl is optionally substituted with a substituent selected from the following: halogen, hydroxy, mono Or two (C1-C6 alkyl) amino, N-(C1-C6 alkyl)-N-(C1-C4 alkylcarbonyl) amino, optionally halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1 -C6 alkyl substituted 4-6 membered heterocyclic group;
- E is selected from amino, pyridyloxy, -NHC(O)R X , SO 2 (C1-C6)alkyl, -C(O)R y , Or -CH 2 -Ar 2 ;
- R X is selected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1 -C8 alkyl, optionally substituted 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl or optionally substituted by C1-C8 alkyl
- the amino group; the optional substituent is selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
- R y is selected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, so The substituent is selected from C1-C8 alkyl optionally substituted by aryl or heteroaryl;
- Ar 2 is selected from optionally substituted aryl or heteroaryl, and the substituent is selected from halogen, hydroxyl, amino or C1-C8 alkoxy;
- R m and R n are each independently selected from hydrogen, hydroxyl, C1-C8 alkyl, hydroxy C1-C8 alkyl, or R m and R n together with the carbon atom to which they are connected form a C3-C8 cycloalkyl;
- r 0, 1, 2 or 3.
- the present invention provides a compound represented by formula (I), its isomers, prodrugs, stable isotope derivatives, or its derivatives as described above, which can be used as selective RET kinase inhibitors A pharmaceutically acceptable salt, wherein
- X 1 is CH or N
- X 2 is CH or N
- the condition is that at most one of X 1 and X 2 is N;
- Y 1 is CH or N
- Y 2 is CH or N
- Y 3 is CH or N
- Y 4 is CH or N
- Y 1 , Y 2 , Y 3 and Y 4 are all CH; only Y 1 or Y 2 is N; or Y 1 and Y 3 are both N;
- A is hydrogen
- B is selected from hydrogen, halogen, -OR 14 or
- R 14 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic group, wherein said alkyl, cycloalkyl, and heterocyclic group are optionally selected from one or more of the following Substituents substituted by: halogen, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclic group optionally substituted by C1-C6 alkyl;
- R 15 is selected from hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic group containing 1-2 heteroatoms selected from N, O, S ;
- D is selected from:
- D is optionally substituted by a substituent selected from hydroxy, amino or C1-C6 alkyl, wherein the alkyl is optionally substituted by a substituent selected from the following: mono- or di(C1-C6 alkyl) Amino, N-(C1-C6 alkyl)-N-(C1-C4 alkyl)carbonylamino, 4-6 membered heterocyclic group optionally substituted by C1-C6 alkyl or acetyl;
- E is selected from amino, pyridyloxy, -NHC(O)R X , SO 2 (C1-C6)alkyl, -C(O)R y , Or -CH 2 -Ar 2 ;
- R X is selected from C1-C6 alkoxy, optionally substituted 6-membered aryl, optionally substituted 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N and O, optionally Substituted C1-C6 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C3-C6 cycloalkyl or optionally C1- C6 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C6 alkoxy or C3-C6 cycloalkyl;
- R y is selected from optionally substituted amino, C1-C6 alkyl, 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, or C3-C6 cycloalkyl, so The substituents are selected from C1-C6 alkyl groups optionally substituted by aryl groups;
- Ar 2 is selected from 5-6 membered aryl or heteroaryl optionally mono- or di-substituted, and the substituent is selected from halogen or C1-C6 alkoxy;
- R m and R n are each independently selected from hydrogen, hydroxy, C1-C6 alkyl or hydroxy C1-C6 alkyl, or R m and R n together with the carbon atom to which they are connected form a C3-C6 cycloalkyl;
- r 0, 1, 2 or 3.
- the present invention provides a compound represented by formula (I), its isomers, prodrugs, stable isotope derivatives, or its derivatives as described above, which can be used as selective RET kinase inhibitors A pharmaceutically acceptable salt, wherein
- X 1 is CH or N
- X 2 is CH or N
- the condition is that at most one of X 1 and X 2 is N;
- Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; or Y 1 and Y 3 are N, Y 2 and Y 4 are CH;
- A is hydrogen
- B is selected from hydrogen, halogen, -OR 14 or
- R 14 is selected from C1-C4 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group, wherein said alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or more selected from the following Group substituted: halogen, hydroxy, 4-6 membered heterocyclic group optionally substituted by C1-C4 alkyl;
- R 15 is selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycles containing 1-2 heteroatoms each independently selected from N, O or S Ring base
- D is selected from:
- D is optionally substituted by a substituent selected from hydroxy, amino or C1-C4 alkyl, and the alkyl is optionally substituted with a substituent selected from hydroxy, di(C1-C4 alkyl)amino, N-acetyl-N -Substituted by substituents of methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
- E is selected from amino, pyridyloxy, -NHC(O)R X , SO 2 (C1-C6)alkyl, -C(O)R y , Or -CH 2 -Ar 2 ;
- R X is selected from C1-C4 alkoxy, optionally mono- or di-substituted phenyl, optionally mono- or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O , Optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, C3-C6 cycloalkyl or optionally C1 -C4 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
- R y is selected from amino optionally substituted by C1-C4 alkyl or benzyl, C1-C4 alkyl, 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, or C3-C6 Cycloalkyl
- Ar 2 is selected from phenyl optionally mono- or di-substituted, and pyridyl optionally mono- or di-substituted, and the substituent is selected from halogen or C1-C4 alkoxy;
- R m and R n are each independently selected from hydrogen, hydroxyl, hydroxy C1-C4 alkyl, or R m and R n together with the carbon atom to which they are connected form a cyclopropyl group;
- r 0, 1, or 2.
- the present invention provides a compound represented by formula (I), its isomers, prodrugs, stable isotope derivatives, or its derivatives as described above, which can be used as selective RET kinase inhibitors A pharmaceutically acceptable salt, wherein
- X 1 is CH or N
- X 2 is CH or N
- the condition is that at most one of X 1 and X 2 is N;
- Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; or Y 1 and Y 3 are N, Y 2 and Y 4 are CH;
- A is hydrogen
- B is selected from hydrogen, halogen, -OR 14 or
- R 14 is selected from C1-C4 alkyl optionally substituted by 1-methylpiperidin-4-yl;
- R 15 is C1-C4 alkyl
- D is optionally substituted with a substituent selected from hydroxyl, amino or C1-C4 alkyl, and the alkyl is optionally substituted with a substituent selected from hydroxyl, di(C1-C4 alkyl)amino, N-acetyl-N- Substituted by substituents of methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
- the substituent is a hydroxyl group, it is substituted at the 3-position; if the substituent is a substituent other than the hydroxyl group, it is substituted at the 4-position; for The substituent is a hydroxyl group or an amino group, which is substituted at its 4-position;
- R X is selected from C1-C4 alkoxy, optionally mono- or di-substituted phenyl, optionally mono- or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O , Optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, C3-C6 cycloalkyl or optionally C1 -C4 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
- R y is selected from amino optionally substituted by C1-C4 alkyl or benzyl, C1-C4 alkyl, 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, or C3-C6 Cycloalkyl
- Ar 2 is selected from phenyl optionally mono- or di-substituted, pyridyl optionally mono- or di-substituted, and the substituent is selected from halogen, C1-C4 alkoxy;
- R m and R n are each independently selected from hydrogen, hydroxyl, hydroxy C1-C4 alkyl, or R m and R n together with the carbon atom to which they are connected form a cyclopropyl group;
- r 0, 1, or 2.
- the present invention provides a compound of formula (I), its isomer, prodrug, stable isotope derivative or The pharmaceutically acceptable salt thereof, wherein the compound is:
- the present invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising the compound of formula (I) or isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable compounds of formula (I) described in any one of the embodiments of the present invention
- the present invention also relates to the compound of formula (I) or its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof according to any one of the embodiments of the present invention in preparation for use as RET kinase inhibitors Use in medicines.
- the present invention also relates to the use of the compound of formula (I) or its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof in the preparation of medicines according to any one of the embodiments of the present invention, wherein
- the drug is used to treat or prevent diseases mediated by RET kinase, such as cancer, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.
- the present invention also relates to the use of the pharmaceutical composition according to the present invention in the preparation of medicaments, wherein the medicament is used to treat or prevent diseases mediated by RET kinase, such as cancer, especially hematological malignancies, lung cancer, and breast cancer. , Ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.
- the present invention also relates to a method for treating or preventing RET kinase-mediated diseases (such as tumors, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma), which comprises administering A patient in need of a therapeutically effective amount of the compound or isomers, prodrugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts thereof described in any one of the embodiments of the present invention, or the compounds described in the present invention Pharmaceutical composition.
- RET kinase-mediated diseases such as tumors, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma
- Another aspect of the present invention relates to the compounds described in any one of the embodiments of the present invention, or isomers, prodrugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts thereof, for use in therapy or Prevent RET kinase-mediated diseases, such as tumors, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.
- RET kinase-mediated diseases such as tumors, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the compound of formula (I) or an isomer, prodrug, stable isotope derivative or the compound of formula (I) described in any one of the embodiments of the present invention
- Pharmaceutically acceptable salts and pharmaceutically acceptable carriers, diluents, excipients which are used to treat or prevent RET kinase-mediated diseases, such as tumors, especially hematological malignancies, lung cancer, breast cancer, and ovarian cancer , Prostate cancer, pancreatic cancer, brain glioma.
- Another aspect of the present invention relates to the compound represented by formula (I) or its tautomer described in any one of the embodiments of the present invention as a treatment and/or prevention of RET kinase-mediated diseases (e.g., tumors, etc.) , Mesosomes, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof.
- the tumors are especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.
- Another aspect of the present invention relates to a pharmaceutical composition for treating and/or preventing RET kinase-mediated diseases (such as tumors, etc.), the pharmaceutical composition comprising the compound of formula (I) described in any one of the embodiments of the present invention Or its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers, diluents, excipients, and optionally further comprising one or more other RET Kinase inhibitors.
- the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, freeze-dried preparations, and injections.
- the pharmaceutical preparation of the present invention can be administered in the form of a dosage unit containing a predetermined amount of active ingredient per dosage unit.
- a dosage unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 300 mg of the compound of the present invention, or a drug according to the condition to be treated, the method of administration, and the age, weight and condition of the patient.
- the formulation can be administered in the form of a dosage unit containing a predetermined amount of active ingredient per dosage unit.
- Preferred dosage unit formulations are those containing the active ingredient in daily doses or divided doses or corresponding fractions thereof as indicated above.
- this type of pharmaceutical preparation can be prepared using methods well known in the pharmaceutical field.
- the pharmaceutical preparations of the present invention may be suitable for administration by any desired suitable method, such as oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (Including subcutaneous, intramuscular, intravenous or intradermal) method of administration. All methods known in the pharmaceutical field can be used to prepare such formulations by, for example, combining the active ingredient with one or more excipients or one or more adjuvants.
- the present invention also provides a method for preparing the compound.
- the compounds of the present invention can be prepared by various methods known in the art. For example, the compounds of the present invention can be synthesized as shown in Schemes 1-10.
- R 16 is selected from C1-C4 alkyl
- P 1 and P 2 are each independently selected from halogens, such as chlorine, bromine, iodine, etc.;
- Compound (I) is added to a solvent selected from 1,4-dioxane, tetrahydrofuran, water, etc., with a base (such as sodium bicarbonate) and R 16 OCOCl, and heated at room temperature or in an oil bath (20-50°C) The reaction is carried out to obtain compound (II);
- the seventh step is a first step.
- P 1 , P 2 , and P 3 are each independently selected from halogens, such as chlorine, bromine, iodine, etc.;
- Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; or Y 1 and Y 3 are N, Y 2 and Y 4 are CH;
- PG 1 is selected from tert-butoxycarbonyl
- Ar 1 is selected from Wherein R 15 is selected from C1-C4 alkyl;
- R 17 is selected from hydrogen and hydroxyl
- R 18 is selected from hydrogen, amino or C1-C4 alkyl, and the alkyl is optionally selected from hydroxyl, di(C1-C4 alkyl)amino, N-acetyl-N-methylamino, morpholine- 4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl substituents;
- R 19 is selected from C1-C4 alkoxy, optionally mono- or di-substituted phenyl, optionally mono- or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O , Optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, C3-C6 cycloalkyl or optionally C1 -C4 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
- R 20 and R 21 are each independently selected from hydrogen and C1-C4 alkyl groups
- the starting material (IX) (P 1 is chlorine, P 2 is bromine or iodine), N-substituted pyrazole borate (or boric acid) is dissolved in a solvent (dioxane and water), and palladium is used for complexation
- a solvent dioxane and water
- palladium is used for complexation
- tetrakis (triphenylphosphine) palladium is used as a catalyst
- sodium carbonate or potassium carbonate is used as a base, heated in an oil bath under the protection of nitrogen or argon, and stirred at a temperature of 70-100°C for 2-12 hours.
- the starting material (X), boric acid ester (or boric acid) (XI) is dissolved in a solvent (dioxane or N,N-dimethylformamide and water), and a palladium complex such as tetrakis Phenylphosphine) palladium is used as a catalyst, potassium carbonate or potassium phosphate is used as a base, heated in an oil bath or microwave under the protection of nitrogen or argon, and stirred at a temperature of 90-140°C for 1-12 hours to carry out the Suzuki coupling reaction.
- a solvent dioxane or N,N-dimethylformamide and water
- a palladium complex such as tetrakis Phenylphosphine
- pinacol borate dissolve the starting material (X) and pinacol diborate in a solvent (such as dioxane), and use a palladium complex such as 1,1'-bis(dioxane).
- Phenylphosphino) ferrocene palladium dichloride as a catalyst, or use tris(dibenzylideneacetone) dipalladium as a catalyst, and then add a phosphine ligand such as tricyclohexylphosphine, use potassium acetate as a base, in nitrogen or Under the protection of argon, heating in an oil bath, stirring at a temperature of 60-100°C for 2-12 hours to obtain compound (XII);
- the starting material (XII) and heterocyclic aryl halide (XIII) are dissolved in a solvent (dioxane or N,N-dimethylformamide and water), using a palladium complex such as tetrakis (triphenyl) Phosphine) palladium is used as a catalyst, potassium carbonate or potassium phosphate is used as a base, under the protection of nitrogen or argon, heating in an oil bath or microwave, stirring at a temperature of 90-140°C for 1-12 hours, and performing Suzuki coupling reaction to obtain Compound (XIV);
- a solvent dioxane or N,N-dimethylformamide and water
- a palladium complex such as tetrakis (triphenyl) Phosphine
- the deprotection of PG 1 for example, the deprotection reaction of tert-butoxycarbonyl uses trifluoroacetic acid or hydrochloric acid as the acid; in a solvent such as dichloromethane or dioxane, the reaction is carried out at 0-25°C; the reaction obtains the compound (XV);
- the seventh step is a first step.
- the starting material (IX) (P 1 is bromine or iodine, P 2 is chlorine), boric acid ester (or boric acid) (XI) is dissolved in a solvent (dioxane and water), and a palladium complex such as Tetrakis(triphenylphosphine) palladium is used as a catalyst, sodium carbonate or potassium carbonate is used as a base, heated in an oil bath under the protection of nitrogen or argon, and stirred at a temperature of 50-100°C for 2-12 hours to carry out Suzuki coupling reaction. , To obtain compound (XVIII);
- P 3 is selected from halogens, such as chlorine, bromine, iodine, etc.;
- Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; or Y 1 and Y 3 are N, Y 2 and Y 4 are CH;
- PG 1 is selected from tert-butoxycarbonyl
- R 15 is selected from C1-C4 alkyl
- R 17 is selected from hydrogen and hydroxyl
- R 18 is selected from amino or C1-C4 alkyl, wherein the alkyl is optionally selected from hydroxyl, di(C1-C4 alkyl)amino, N-acetyl-N-methylamino, morpholine-4 -Substituted by substituents of-radical, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
- R 19 is selected from C1-C4 alkoxy, optionally mono- or di-substituted phenyl, optionally mono- or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O , Optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, C3-C6 cycloalkyl or optionally C1 -C4 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
- the deprotection reaction of the tert-butoxycarbonyl group uses trifluoroacetic acid or hydrochloric acid as the acid; the deprotection of PG 1 is carried out in a solvent such as dichloromethane or dioxane, and the reaction is carried out at 0-25°C to obtain the compound ( XXVII);
- the substitute (XIII) is dissolved in a solvent (dioxane or N,N-dimethylformamide and water), using a palladium complex such as tetrakis(triphenylphosphine)palladium as a catalyst, using potassium carbonate or potassium phosphate As a base, under the protection of nitrogen or argon, heating in an oil bath or microwave, stirring at a temperature of 90 to 140° C. for 1 to 12 hours to perform Suzuki coupling reaction to obtain compound (XXV).
- P 3 is selected from halogens, such as chlorine, bromine, iodine, etc.;
- Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; or Y 1 and Y 3 are N, Y 2 and Y 4 are CH;
- PG 1 is selected from tert-butoxycarbonyl
- R 17 is selected from hydrogen and hydroxyl
- R 18 is selected from amino or C1-C4 alkyl, wherein the alkyl is optionally selected from hydroxyl, di(C1-C4 alkyl)amino, N-acetyl-N-methylamino, morpholine-4 -Substituted by substituents of-radical, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
- R 19 is selected from C1-C4 alkoxy, optionally mono- or di-substituted phenyl, optionally mono- or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O , Optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, C3-C6 cycloalkyl or optionally C1 -C4 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
- the starting materials 5-chloro-7-ethoxyquinazoline (XXXI) and pinacol diborate are dissolved in a solvent (such as dioxane), and a palladium complex such as 1,1'-bis (Diphenylphosphino)ferrocene palladium dichloride as a catalyst, or use tris(dibenzylideneacetone) dipalladium as a catalyst, then add a phosphine ligand such as tricyclohexylphosphine, and use potassium acetate as a base. Under the protection of nitrogen or argon, heating in an oil bath, stirring at a temperature of 60-100°C for 2-12 hours to obtain compound (XXXII);
- the starting material (XXXII) and heterocyclic aryl halide (XIII) are dissolved in a solvent (dioxane or N,N-dimethylformamide and water), and a palladium complex such as tetrakis (triphenyl) is used.
- a palladium complex such as tetrakis (triphenyl) is used.
- Phosphine) palladium is used as a catalyst
- potassium carbonate or potassium phosphate is used as a base, heated in an oil bath or microwave under the protection of nitrogen or argon, and stirred at a temperature of 90 to 140°C for 1 to 12 hours to perform Suzuki coupling reaction to obtain Compound (XXXIII);
- the deprotection of PG 1 for example, the deprotection reaction of tert-butoxycarbonyl uses trifluoroacetic acid or hydrochloric acid as the acid; in a solvent such as dichloromethane or dioxane, the reaction is carried out at 0-25°C; the reaction obtains the compound (XXXIV);
- Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; or Y 1 and Y 3 are N, Y 2 and Y 4 are CH;
- PG 1 is selected from tert-butoxycarbonyl
- R 17 is selected from hydrogen and hydroxyl
- R 18 is selected from amino or C1-C4 alkyl, wherein the alkyl is optionally selected from hydroxyl, di(C1-C4 alkyl)amino, N-acetyl-N-methylamino, morpholine-4 -Substituted by substituents of-radical, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
- R 19 is selected from C1-C4 alkoxy, optionally mono- or di-substituted phenyl, optionally mono- or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O , Optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, C3-C6 cycloalkyl or optionally C1 -C4 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
- Step 1 Dissolve the starting material 5,7-dichloro-1,6-naphthalene (synthesis reference: PCT Int.Appl., 2011134971) (XXXVI), boric acid ester (or boric acid) (XI)
- solvent dioxane or N,N-dimethylformamide and water
- palladium complexes such as tetrakis(triphenylphosphine)palladium as catalyst or tris(dibenzylideneacetone)dipalladium as Catalyst, tricyclohexylphosphine as ligand, potassium carbonate or potassium phosphate as base, under the protection of nitrogen or argon, heating in oil bath or microwave, stirring at 80 ⁇ 90°C for 12 ⁇ 16 hours for Suzuki coupling Reaction to obtain compound (XXXVII);
- the starting material (XXXVII), N-methylpyrazole borate (or boric acid) is dissolved in a solvent (dioxane or N,N-dimethylformamide and water), and a palladium complex such as Tetra(triphenylphosphine) palladium is used as a catalyst, potassium carbonate or potassium phosphate is used as a base, under the protection of nitrogen or argon, heated in an oil bath or microwave, and stirred at a temperature of 120-140°C for 1-12 hours to perform Suzuki coupling.
- a solvent dioxane or N,N-dimethylformamide and water
- a palladium complex such as Tetra(triphenylphosphine) palladium
- potassium carbonate or potassium phosphate is used as a base, under the protection of nitrogen or argon, heated in an oil bath or microwave, and stirred at a temperature of 120-140°C for 1-12 hours to perform Suzuki coupling.
- the deprotection of PG 1 uses hydrogen chloride dioxane solution or hydrogen chloride ethyl acetate solution as the acid; in a solvent such as methanol, ethyl acetate or dioxane, the reaction is between 0 and Carried out under the condition of 25°C;
- the starting material (XXXIX) and the corresponding carboxylic acid are dissolved in a solvent (tetrahydrofuran, dichloromethane or N,N-dimethylformamide, etc.), and a condensing agent such as 2-(7-oxybenzotriazole) is added.
- a condensing agent such as 2-(7-oxybenzotriazole) is added.
- alkali such as triethylamine, etc.
- Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; or Y 1 and Y 3 are N, Y 2 and Y 4 are CH;
- PG 1 is selected from tert-butoxycarbonyl
- R 14 is selected from C1-C4 alkyl or C1-C4 alkyl optionally substituted by 1-methylpiperidin-4-yl;
- R 17 is selected from hydrogen and hydroxyl
- R 18 is selected from amino or C1-C4 alkyl, wherein the alkyl is optionally selected from hydroxyl, di(C1-C4 alkyl)amino, N-acetyl-N-methylamino, morpholine-4 -Substituted by substituents of-radical, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
- R 19 is selected from C1-C4 alkoxy, optionally mono- or di-substituted phenyl, optionally mono- or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O , Optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, C3-C6 cycloalkyl or optionally C1 -C4 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
- the starting material XXXVII (R 14 is ethyl) is dissolved in an ethanol solution of sodium ethoxide freshly prepared using sodium and ethanol, heated in an oil bath, and stirred at a temperature of 100°C for about 16 hours to obtain compound (XXXXI); or
- the starting material XXXVII and 1-methyl-4-piperidine methanol were dissolved in 1,4-dioxane, and a metal complex such as tris(dibenzylideneacetone) dipalladium was used as a catalyst, and cesium carbonate was used as a catalyst. Alkali, the reaction solution was bubbled with nitrogen for ten minutes, heated and stirred under a microwave at 110°C for 1 hour under the protection of nitrogen, to obtain compound (XXXXI);
- Deprotection of PG 1 for example, the deprotection reaction of tert-butoxycarbonyl uses hydrogen chloride ethyl acetate solution as the acid; in a solvent such as ethyl acetate, the reaction is carried out at 0-25°C;
- Y 1 is N, Y 2 , Y 3 and Y 4 are all CH; or Y 1 and Y 3 are N, Y 2 and Y 4 are CH;
- PG 1 is selected from tert-butoxycarbonyl
- R 19 is selected from C1-C4 alkoxy, optionally mono- or di-substituted phenyl, optionally mono- or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O , Optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, C3-C6 cycloalkyl or optionally C1 -C4 alkyl substituted amino; the optional substituent is selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
- R 22 is selected from phenyl optionally mono- or di-substituted, pyridyl optionally mono- or di-substituted, and the substituent is selected from halogen, C1-C4 alkoxy;
- R 23 is selected from C1-C4 alkyl
- the starting material 5,7-dichloro-1,6-naphthalene (synthesis reference: PCT Int.Appl., 2011134971) (XXXVI), boric acid ester (or boric acid) (XXXXIV) are dissolved in the solvent (two Oxane or N,N-dimethylformamide and water), using palladium complexes such as tetrakis(triphenylphosphine)palladium as catalyst or tris(dibenzylideneacetone)dipalladium as catalyst, tricyclic Hexylphosphine is used as a ligand, potassium carbonate or potassium phosphate is used as a base, heated in an oil bath or microwave under the protection of nitrogen or argon, and stirred at a temperature of 80 to 90°C for 12 to 16 hours, and Suzuki coupling reaction is carried out to obtain the compound (XXXXV);
- the deprotection of PG 1 such as the deprotection reaction of tert-butoxycarbonyl, uses hydrogen chloride dioxane solution or hydrogen chloride ethyl acetate solution as the acid; in a solvent such as methanol, ethyl acetate or dioxane, the reaction is between 0 and
- the compound (XXXXVII) can be obtained by proceeding under the condition of 25°C;
- the starting material (XXXXVII) and the corresponding carboxylic acid are dissolved in a solvent (tetrahydrofuran, dichloromethane or N,N-dimethylformamide, etc.), and a condensing agent such as 2-(7-oxybenzotriazole) is added.
- a condensing agent such as 2-(7-oxybenzotriazole) is added.
- alkali such as triethylamine, etc.
- stir at room temperature for 20 minutes to 18 hours to condense; compound (XXXXIX) can be obtained.
- R 23 is selected from C1-C4 alkyl
- the starting material 5,7-dichloro-1,6-naphthalene (synthesis reference: PCT Int.Appl., 2011134971) (XXXVI), boric acid ester (or boric acid) (XXXXXI) are dissolved in the solvent (two Oxane or N,N-dimethylformamide and water), using palladium complexes such as tetrakis(triphenylphosphine)palladium as catalyst or tris(dibenzylideneacetone)dipalladium as catalyst, tricyclic Hexylphosphine is used as a ligand, potassium carbonate or potassium phosphate is used as a base, and under the protection of nitrogen or argon, stirring is carried out at 80-90°C for 12-16 hours to perform Suzuki coupling reaction to obtain compound (XXXXXII);
- R 17 is selected from hydrogen, hydroxyl or amino
- the starting material (XXXXXIV) was dissolved in N,N-dimethylformamide, sodium hydrogen was added, stirred at room temperature for half an hour, then 2-fluoropyridine was added, and the mixture was stirred at 80-90°C for 4-16 hours to obtain the compound ( XXXXXV);
- Cx-Cy used in the present invention represents the range of the number of carbon atoms, where x and y are both integers, for example, C3-C8 cycloalkyl represents a cycloalkyl group with 3-8 carbon atoms, -C0 -C2 alkyl means an alkyl group having 0-2 carbon atoms, where -C0 alkyl means a chemical single bond.
- alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, for example, 1 to 18 carbon atoms, 1 to 12 carbon atoms , 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms linear and branched groups.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, and various branched chain isomers, etc.
- Alkyl groups can be optionally substituted or unsubstituted.
- alkenyl refers to a straight chain or branched hydrocarbon group containing at least 1 carbon-carbon double bond, which may include 2 to 20 carbon atoms, for example, 2 to 18 carbon atoms, 2 to 12 Straight-chain and branched-chain groups of 3 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. There may be 1-3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
- C2-C4 alkenyl refers to an alkenyl group having 2 to 4 carbon atoms. Including vinyl, propenyl, butenyl, buten-2-yl, 2-methylbutenyl. Alkenyl groups can be optionally substituted or unsubstituted.
- alkynyl refers to a straight chain or branched hydrocarbon group containing at least 1 carbon-carbon triple bond, which may include 2 to 20 carbon atoms, for example, 2 to 18 carbon atoms, 2 to Straight and branched chain groups of 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
- C2-C4 alkynyl refers to an alkynyl group having 2 to 4 carbon atoms. Non-limiting examples include ethynyl, propynyl, butynyl and butyn-2-yl, 3-methylbutynyl. Alkynyl groups can be optionally substituted or unsubstituted.
- cycloalkyl refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group, which includes 3 to 12 ring atoms, for example, 3 to 12, 3 to 10, 3 to 8 or 3 Up to 6 ring atoms, or can be a 3, 4, 5, or 6-membered ring.
- monocyclic cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cycloalkyl groups can be optionally substituted or unsubstituted.
- heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which includes 3 to 20 ring atoms, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8, or 3 to 6 ring atoms, of which one or more ring atoms are selected from nitrogen, oxygen or S(O)m (where m is an integer of 0 to 2) heteroatoms, but not including- The ring part of OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
- the heterocyclyl ring contains 3 to 10 ring atoms, more preferably contains 3 to 8 ring atoms, most preferably a 5-membered ring or a 6-membered ring
- 1 to 4 are heteroatoms
- more preferably 1 to 3 are heteroatoms
- most preferably 1 to 2 are heteroatoms.
- monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
- Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. The heterocyclic group may be optionally substituted or unsubstituted.
- heterocyclylene refers to a substituted or unsubstituted heterocyclic group having two terminal monovalent group cores, which is obtained by removing one hydrogen atom from each of the two terminal atoms. Produced; the heterocyclic group has the meaning described above.
- Non-limiting examples of “heterocyclylene” include pyrrolidinylene, piperidinylene, piperazinylene, morpholinylene, and the like.
- spiroheterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings, wherein one or more ring atoms are selected from nitrogen and oxygen. Or S(O)m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
- the spiro ring group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro ring group and a bispiro ring group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro ring group.
- Non-limiting examples of spirocyclic groups include The spirocyclic group may be optionally substituted or unsubstituted.
- spiroheterocyclylene refers to a substituted or unsubstituted spiroheterocyclic group having two terminal monovalent group cores, which removes one hydrogen from each of the two terminal atoms. Atom; the spiroheterocyclic group has the meaning described above.
- Non-limiting examples of “spiroheterocyclylene” include
- fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
- One or more rings can be Contain one or more double bonds, but no ring has a fully conjugated ⁇ -electron system, where one or more ring atoms are selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2). Atoms, the rest of the ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
- the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups, preferably bicyclic or tricyclic, more preferably 4-membered/5-membered, 5-membered/5-membered, 5-membered/6-membered Bicyclic fused heterocyclic group.
- fused heterocyclic groups include
- the heterocyclyl ring may be fused to an aryl, heteroaryl or cyclic ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples include:
- the fused heterocyclic group may be optionally substituted or unsubstituted.
- fused heterocyclylene refers to a substituted or unsubstituted fused heterocyclic group having two terminal monovalent group cores, which removes one hydrogen from each atom of the two terminal atoms. Atom; the fused heterocyclic group has the meaning described above.
- fused heterocyclylene include
- aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, a ring that shares adjacent pairs of carbon atoms) group, a polycyclic group with a conjugated ⁇ -electron system (that is, It has a ring) group with adjacent pairs of carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, most preferably phenyl.
- the aryl ring may be fused on a heteroaryl, heterocyclic or cyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include:
- Aryl groups can be substituted or unsubstituted.
- heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms include oxygen, sulfur, and nitrogen. Preferably it is 5 to 10 yuan.
- the heteroaryl group is 5-membered or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, Isoxazolyl, etc.
- the heteroaryl ring may be fused to an aryl, heterocyclic or cyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include:
- Heteroaryl groups can be optionally substituted or unsubstituted.
- halogen refers to fluorine, chlorine, bromine or iodine.
- cyano refers to -CN.
- nitro refers to an NO 2 group.
- hydroxyl refers to the -OH group.
- amino refers to the -NH 2 group.
- substitution of one or two hydrogens on an amino group by an alkyl group can form a mono- or dialkylamino group, and the alkyl group has the aforementioned meaning.
- carbonyl refers to Group. One side of the carbon on the carbonyl group is connected to an alkyl group to form an alkylcarbonyl group, and the alkyl group has the meaning described above.
- alkoxy refers to an alkyl group connected through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group.
- the alkyl group, heterocycloalkyl group and cycloalkyl group have the aforementioned meanings.
- heteroaryloxy refers to a heteroaryl group connected through an oxygen bridge, and the heteroaryl group has the aforementioned meaning.
- hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, and includes a hydroxyalkyl group, a hydroxycycloalkyl group, and a hydroxyheterocycloalkyl group.
- the alkyl group, heterocycloalkyl group and cycloalkyl group have the aforementioned meanings.
- haloalkyl refers to an alkyl substituent in which at least one hydrogen is replaced by a halogen group.
- Typical halogen groups include chlorine, fluorine, bromine and iodine.
- Examples of haloalkyl groups include fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, 1-bromoethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if a substituent is substituted with more than one halogen group, those halogen groups may be the same or different (unless otherwise stated).
- heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
- substituted refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
- the substituent includes, but is not limited to, the various groups described above.
- the compound claimed in the present invention includes not only the compound itself, but also isomers, prodrugs, stable isotope derivatives of the compound or a pharmaceutically acceptable salt thereof.
- the "pharmaceutical composition” of the present invention refers to a mixture containing one or more isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof and other chemical components of the compound of the present invention. Other components such as pharmaceutically acceptable pharmaceutically acceptable carriers, diluents and excipients.
- the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
- room temperature in the present invention refers to 15-30°C.
- stable isotope derivatives include: isotopically substituted derivatives obtained by substituting any hydrogen atom in formula I with 1-5 deuterium atoms, and any carbon atom in formula I with 1-3 carbon 14 atoms.
- the "pharmaceutically acceptable salt” of the present invention is discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and it is also discussed by medicinal chemists. It is obvious that the salt is basically non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
- the pharmaceutically acceptable salt of the present invention can be synthesized by general chemical methods.
- the salt can be prepared by reacting a free base or acid with an equivalent or excess acid (inorganic acid or organic acid) or base in a suitable solvent or solvent composition.
- prodrug in the present invention refers to the conversion of a compound into the original active compound after being metabolized in the body.
- prodrugs are inactive substances, or less active than the active parent compound, but can provide convenient operation, administration, or improved metabolic properties.
- the "isomers” in the present invention refer to tautomers, mesoisomers, racemates, enantiomers, diastereomers, and other compounds of the formula (I) of the present invention Mixture form and so on. All these isomers, including stereoisomers and geometric isomers, are included in the present invention.
- the geometric isomers include cis and trans isomers.
- the present invention includes any polymorphic form of the compound or salt thereof, as well as any hydrate or other solvate.
- the term "patient” generally refers to mammals, especially humans.
- tumor includes benign tumors and malignant tumors, such as cancer.
- cancer includes various tumors mediated by RET kinase, including but not limited to hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.
- the term "therapeutically effective amount” refers to an amount including the compound of the present invention that can effectively treat or prevent related diseases mediated by RET kinase.
- the structure of all the compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
- MS mass spectrometry
- Gradient elution condition 1 0: 95% solvent A1 and 5% solvent B1, 1-2: 5% solvent A1 and 95% solvent B1; 2.01-2.50: 95% solvent A1 and 5% solvent B1.
- the percentage is the volume percentage of a certain solvent in the total solvent volume.
- Solvent A1 0.01% formic acid aqueous solution;
- Solvent B1 0.01% formic acid in acetonitrile; the percentage is the volume percentage of the solute in the solution.
- the thin layer silica gel plate is Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- Column chromatography generally uses Yantai Huanghai 100-200 or 200-300 mesh silica gel as a carrier.
- Preparative liquid chromatography uses Waters SQD2 mass spectrometry guided high pressure liquid chromatography separator, XBridge-C18; 30X150mm preparative column, 5 ⁇ m;
- Method 1 Acetonitrile-water (0.2% formic acid), flow rate 25mL/min;
- Method 2 Acetonitrile-water (0.8% ammonium bicarbonate), flow rate 25mL/min;
- the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Bi De Pharmaceutical, Shanghai A Latin Chemical, Shanghai Myrell Chemical, Bailingwei Chemical, Anaiji Chemical and other companies.
- the solvents used in the reaction are all anhydrous solvents.
- commercially available tetrahydrofuran is used as anhydrous tetrahydrofuran
- sodium block is used as water remover
- benzophenone is used as indicator
- the solution is refluxed under argon protection. It is blue-purple, collected by distillation and stored at room temperature under argon protection.
- Other anhydrous solvents are purchased from Anaiji Chemical and Bailingwei Chemical. The transfer and use of all anhydrous solvents must be carried out under argon protection unless otherwise specified.
- the reactions are all carried out under an argon atmosphere or a nitrogen atmosphere.
- the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
- the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
- the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
- reaction temperature is room temperature, and the temperature range is 15°C-30°C.
- the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), and the developing agent system used in the reaction includes A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system.
- TLC thin-layer chromatography
- the volume ratio of the solvent is adjusted according to the polarity of the compound.
- the eluent system of column chromatography and the developing solvent system of thin layer chromatography used to purify the compound include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system.
- the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents.
- reaction solution was diluted with dichloromethane/methanol (10:1, 200mL), water (5mL) was added, stirred vigorously for 15 minutes, and then filtered.
- the filter cake was washed with dichloromethane (40mL ⁇ 3), and the organic phases were combined with water ( 20mL) and saturated brine (20mL) to wash. Dry with anhydrous sodium sulfate, filter to remove the desiccant, and desolvate under reduced pressure.
- the reaction solution was diluted with ethyl acetate (80 mL), and washed with water (10 mL ⁇ 3) and saturated brine (10 mL ⁇ 3).
- the organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure.
- the residue was purified with a preparative silica gel plate (petroleum ether/ethyl acetate 1:1) to obtain the target product ((3S, 4S)-1-(5-(7-chloro-1,6-naphthyridine-5-yl) ) Pyridin-2-yl)-3-hydroxypiperidin-4-yl) tert-butyl carbamate (60 mg, yellow solid), yield 61%;
- reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL), and the organic phase was washed with water (20 mL) and saturated brine (20 mL). Dry with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure.
- Example 183 Refer to the third step of Example 183 to synthesize the target product 2-chloro-N-((3S, 4S)-3-hydroxy-1-(5-(7-((1-methylpiperidine-4- (Yl)methoxy)-1,6-naphthyridine-5-yl)pyridin-2-yl)piperidin-4-yl)benzamide;
- reaction solution was cooled to room temperature and poured into water (40mL), extracted with ethyl acetate (50mL ⁇ 3), the organic phases were combined and washed with saturated brine (50mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure.
- Examples 224 to 255 refer to the synthesis of Example 223: where 2-(5-fluoropyridin-2-yl)acetic acid is substituted with a different acid:
- Example 258 For the synthesis of Example 258, refer to the operation steps of Example 257:
- Example 285 For the synthesis of Example 285, refer to the operation steps of Example 257:
- reaction solution was diluted with ethyl acetate (100 mL), and then washed with saturated brine (80 mL ⁇ 3).
- the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- Example 286 For the synthesis steps of Examples 321 to 322, refer to Example 286 for synthesis.
- Example 288 For the synthesis steps of Examples 323 to 324, refer to Example 288 for synthesis.
- Example 183 For the synthesis steps of Examples 325 to 365, refer to Example 183 for synthesis.
- reaction solution was concentrated, dichloromethane (20 mL) was added, and washed with 1M sodium hydroxide solution (5 mL, 5 mmol) and saturated brine (25 mL) in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- Example 366 For the synthesis steps of Examples 367 to 371, refer to Example 366 for synthesis.
- Example 372 For the synthesis of Example 372, refer to the procedure of Example 44.
- Example 461 For the synthesis of Example 461, refer to the synthesis steps of Example 223.
- HTRF Homogeneous time-resolved fluorescence
- the reaction buffer contains the following components: the kit comes with enzyme reaction buffer (1 ⁇ ), 5mM MgCl 2 , 1mM DTT; human recombinant RET protein (Cat. No.
- reaction buffer ng/ ⁇ l kinase solution
- substrate reaction solution includes 0.66 ⁇ M biotin-labeled tyrosine kinase substrate and 12 ⁇ M ATP diluted with reaction buffer
- detection buffer includes 0.1ng/ ⁇ l Eu3+ label diluted with reaction buffer
- the compound was dissolved and diluted to 25 ⁇ M in 100% DMSO, and then a 4-fold serial dilution was performed with DMSO to a minimum concentration of 1.5 nM, and each concentration point was diluted 40-fold with reaction buffer.
- the ratio of 665/620 is positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of RET kinase.
- the group without RET kinase protein was regarded as 100% inhibition, and the group with RET kinase protein but no compound was regarded as 0% inhibition.
- the percentage of compound inhibition of RET kinase activity can be calculated using the following formula:
- the IC 50 value of the compound is calculated from 8 concentration points using the XLfit (ID Business Solutions Ltd., UK) software through the following formula:
- Y is the percentage of inhibition
- X is the logarithm of the concentration of the compound to be tested
- Bottom is the maximum percentage of inhibition
- Top is the minimum percentage of inhibition
- slope factor is the slope coefficient of the curve.
- the in vitro activity of RET M918T was determined by detecting the phosphorylation level of the substrate in the kinase reaction.
- the reaction buffer contains the following components: the kit comes with enzyme reaction buffer (1 ⁇ ), 5mM MgCl 2 , 1mM DTT; human recombinant RET M918T protein (Cat. No. PV6217) was purchased from Thermo Fish and diluted with reaction buffer.
- substrate reaction solution includes 0.9 ⁇ M biotin-labeled tyrosine kinase substrate and 18 ⁇ M ATP diluted with reaction buffer; detection buffer includes 0.1ng/ ⁇ l Eu with reaction buffer 3+ labeled cage antibody and 56.25nM streptavidin labeled XL665.
- the compound was dissolved and diluted to 10 ⁇ M in 100% DMSO, and then a 4-fold serial dilution was performed with DMSO to the lowest concentration of 0.61 nM, and each concentration point was diluted 40-fold with reaction buffer.
- the ratio of 665/620 is positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of RET M918T kinase.
- the group without RET M918T kinase protein was regarded as 100% inhibition, and the group with RET M918T kinase protein but no compound was regarded as 0% inhibition.
- the compound's inhibitory percentage of RET M918T activity can be calculated with the following formula:
- Inhibition percentage 100-100*(signal value at a specific concentration of the test compound-negative control signal value)/(positive control signal value-negative control signal value).
- the IC 50 value of the compound is calculated from 8 concentration points using the XLfit (ID Business Solutions Ltd., UK) software through the following formula:
- Y is the percentage of inhibition
- X is the logarithm of the concentration of the compound to be tested
- Bottom is the maximum percentage of inhibition
- Top is the minimum percentage of inhibition
- slope factor is the slope coefficient of the curve.
- HTRF Homogeneous time-resolved fluorescence
- the reaction buffer contains the following components: the kit comes with enzyme reaction buffer (1 ⁇ ), 5mM MgCl 2 , 1mM DTT and 0.08% Tween-20; human recombinant RET V804M protein (Cat. No.
- the reaction buffer is diluted to 0.15ng/ ⁇ l kinase solution;
- the substrate reaction solution includes 0.9 ⁇ M biotin-labeled tyrosine kinase substrate and 8 ⁇ M ATP diluted with the reaction buffer;
- the detection buffer includes the reaction buffer diluted into 0.1ng/ ⁇ l Eu 3+ labeled cage antibody and 56.25nM streptavidin labeled XL665.
- the compound was dissolved and diluted to 25 ⁇ M in 100% DMSO, and then a 4-fold serial dilution was performed with DMSO to a minimum concentration of 1.5 nM, and each concentration point was diluted 40-fold with reaction buffer.
- the ratio of 665/620 is positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of RET V804M kinase.
- the group without RET V804M kinase protein was regarded as 100% inhibition, and the group with RET V804M kinase protein but no compound was regarded as 0% inhibition.
- the compound's inhibitory percentage of RET V804M activity can be calculated with the following formula:
- Inhibition percentage 100-100*(signal value at a specific concentration of the test compound-negative control signal value)/(positive control signal value-negative control signal value).
- the IC 50 value of the compound is calculated from 8 concentration points using the XLfit (ID Business Solutions Ltd., UK) software through the following formula:
- Y is the percentage of inhibition
- X is the logarithm of the concentration of the compound to be tested
- Bottom is the maximum percentage of inhibition
- Top is the minimum percentage of inhibition
- slope factor is the slope coefficient of the curve.
- the in vitro activity of RET V804L was determined by detecting the phosphorylation level of the substrate in the kinase reaction.
- the reaction buffer contains the following components: the kit comes with enzyme reaction buffer (1 ⁇ ), 5mM MgCl 2 , 1mM DTT and 0.05% Tween-20; human recombinant RET V804L protein (Cat. No.
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Abstract
本发明涉及化合物、含有其的药物组合物以及它们的制备方法,和其作为转染期间重排(RET,Rearranged during transfection)激酶抑制剂的用途。所述化合物为式I所示的化合物,或其药学上可接受的盐、前药、异构体和稳定同位素衍生物。本发明还涉及所述化合物用于治疗或预防由RET激酶介导的相关疾病例如肿瘤的用途以及应用其治疗所述疾病的方法。
Description
本发明涉及化合物、含有其的药物组合物和其作为转染期间重排(RET,Rearranged during transfection)激酶抑制剂的用途。更具体说,本发明提供了新的作为RET激酶抑制剂的化合物、含有这种化合物的药物组合物和应用所述化合物治疗或预防由RET激酶介导的相关疾病的方法,所述相关疾病例如肿瘤。本发明还涉及制备下文所描述的化合物的方法。
RET(Rearranged during transfection)基因编码膜受体酪氨酸激酶RET蛋白,属于钙粘素超家族,在神经嵴来源和泌尿生殖系统的细胞中表达,并在神经嵴发育过程中发挥至关重要的作用。RET激酶通过与四个神经胶质细胞源性的神经营养因子(GDNF)家族受体α(GFRα)蛋白之一结合以形成复合体,该复合体使RET激酶同源二聚化、磷酸化并激活其酪氨酸激酶活性,激活Ras/MAPK、PI3K/Akt、JNK、p38和PLCg通路信号级联反应(Mulligan,L.M.Nature Reviews Cancer,2014,14,173-186)。
RET基因的致癌、激活突变(主要是细胞遗传水平的重排或融合)可以在不依赖配体结合的情况下放大信号级联反应,同时还可激活其他信号级联(如STAT3和STAT1)反应,促进肿瘤发生。RET是一个癌症驱动基因,突变会导致RET信号通路的过度活跃,引起不受控的细胞增长,进而引发肿瘤的形成。
RET蛋白变异类型主要包括与KIF5B、TRIM33、CCDC6和NCOA4等基因的融合突变,以及M918T等位点的点突变,人们常见的RET突变主要发生在甲状腺癌、非小细胞肺癌等多种癌症类型里,虽然其在非小细胞肺癌中的发病率只有2%,但是我国的患者基数非常大,临床治疗中这类患者并不少见,而RET融合在年轻患者中更为常见,特别是年轻的非吸烟肺腺癌患者,发生率高达7%-17%。
在既往的RET阳性患者的治疗中,靶向药物往往会选择卡博替尼或凡德他尼,这两种药物作为多靶点的酪氨酸激酶抑制剂,对于RET 的选择性并不强。对卡博替尼在RET治疗上曾做过26例小样本的研究,主要终点ORR为28%,PFS的中位时间是5.5个月,而治疗中有19例患者因为不良反应而调整了剂量,毒性反应非常明显。开发选择性RET激酶抑制剂有可能降低由脱靶点引起的不良反应,提高治疗效果。目前,已开发的选择性RET激酶抑制剂主要有Blu-667(US20170121312A1,Subbiah,V.;Gainor,J.F.;et al.Cancer Discovery.2018,8(7),836-849.)和Loxo-292(WO2018071454A1,WO2018071447A1,WO2017011776A1,Subbiah,V.;Busaidy,N.L.;et al.Annal Oncolology,2018,29(8),1869-1876.)。仍需要新的能够降低由脱靶点引起的不良反应,并提高治疗效果的选择性RET激酶抑制剂。
发明内容
本发明的目的在于提供一种可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐:
其中:
X
1为CR
1或N;优选为CH或N;
X
2为CH或N;
条件是X
1、X
2中至多有1个为N;
Y
1为CR
2或N;优选为CH或N;最优选为N;
Y
2为CR
3或N;优选为CH或N;最优选为CH;
Y
3为CR
4或N;优选为CH或N;
Y
4为CR
5或N;优选为CH或N;最优选为CH;
条件是Y
1、Y
2、Y
3和Y
4中至多有2个为N;
优选下列条件之一:Y
1-Y
4都不为N;仅Y
1或Y
2为N;Y
1和Y
2都为N;或Y
1和Y
3都为N;
进一步优选下列条件之一:仅Y
1或Y
2为N;或Y
1和Y
3都为N;最优选下列条件之一:Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3
为N,Y
2和Y
4为CH;
R
1-R
5各自独立地选自氢、卤素、氰基、C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、-OR
6、-NR
7R
8、-OC(O)NR
7R
8、-C(O)OR
6、-C(O)NR
7R
8、-NR
9C(O)R
6、-NR
9C(O)NR
7R
8、-S(O)
mR
6、-NR
9S(O)
mR
6、-SR
6、-S(O)
mNR
7R
8或-NR
9S(O)
mNR
7R
8,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基或炔基任选被一个或多个选自卤素、氰基、C3-C8环烷基、4-8元杂环基、-OR
10、-NR
11R
12,-OC(O)NR
11R
12、-C(O)OR
10、-C(O)NR
11R
12、-NR
11C(O)R
10、-NR
13C(O)NR
11R
12、-S(O)
mR
10、-NR
13S(O)
mR
10、-SR
10、-S(O)
mNR
11R
12或-NR
13S(O)
mNR
11R
12的取代基所取代;优选地,R
1-R
5各自独立地选自氢、卤素、氰基、C1-C6烷基、-OR
6或-NR
7R
8;进一步优选地,R
1-R
5各自独立地选自氢、卤素或C1-C4烷基;最优选地,R
1-R
5都为氢;
A选自氢、卤素、氰基或C1-C8烷基;优选地,A选自氢、卤素、氰基或C1-C6烷基;进一步优选地,A选自氢、氰基或C1-C4烷基;最优选地,A为氢;
R
14选自氢、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基、炔基任选被一个或多个选自卤素、氰基、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基的取代基所取代;优选地,R
14选自氢、C1-C6烷基、C3-C8环烷基或4-8元杂环基,其中所述烷基、环烷基、杂环基任选被一个或多个选自卤素、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基的取代基所取代;进一步优选地,R
14选自C1-C4烷基、C3-C6环烷基或4-6元杂环基,其中所述烷基、环烷基、杂环基任选被一个或多个选自卤素、羟基、任选被C1-C4烷基取代的4-6元杂环基的取代基所取代;最优选地,R
14为任选被1-甲 基哌啶-4-基取代的C1-C4烷基;
Ar
1选自含有1-3个环上杂原子的5或6元杂芳基,其中所述杂原子各自独立地选自N、O、S;优选地,Ar
1选自含有两个环上N原子的5或6元杂芳基;进一步优选地,Ar
1选自含有两个环上N原子的5元杂芳基;最优选地,Ar
1为
Ar
1任选可被一个或多个取代基所取代,所述取代基各自独立地选自卤素、氰基、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR
6、-NR
7R
8、-OC(O)NR
7R
8、-C(O)OR
6、-C(O)R
6、-C(O)NR
7R
8、-NR
9C(O)R
6、-NR
9C(O)NR
7R
8、-S(O)
mR
6、-NR
9S(O)
mR
6、-SR
6、-S(O)
mNR
7R
8或-NR
9S(O)
mNR
7R
8,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基、炔基任选被一个或多个选自卤素、氰基、C3-C8环烷基、4-8元杂环基、-OR
10、-NR
11R
12,-OC(O)NR
11R
12、-C(O)OR
10、-C(O)NR
11R
12、-NR
11C(O)R
10、-NR
13C(O)NR
11R
12、-S(O)
mR
10、-NR
13S(O)
mR
10、-SR
10、-S(O)
mNR
11R
12、-NR
13S(O)
mNR
11R
12的取代基所取代;
R
15选自氢、C1-C8烷基、羟基C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基或杂芳基;优选地,R
15选自氢、C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基或4-8元杂环基;进一步优选地,R
15选自氢、C1-C4烷基、羟基C1-C4烷基、C3-C6环烷基或含有1-2个选自N、O或S的杂原子的4-6元杂环基;最优选地,R
15为C1-C4烷基;
D选自含有1-3个选自N、O的杂原子的4-8元亚杂环基、6-8元亚稠杂环基或7-11元亚螺杂环基;优选地,D选自含有1-2个N的4~6元亚杂环基或含有1-2个N的6~8元亚稠杂环基;最优选地,D选自:
D任选被一个选自卤素、氰基、羟基、氨基或C1-C8烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C8烷基)氨基、N-(C1-C8烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C8烷基取代的4-8元杂环基;优选地,D任选被一个选自卤素、氰基、羟基、氨基或C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C6烷基)氨基、N-(C1-C6烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C6烷基取代的4-6元杂环基;进一步优选地,D任选被一个选自羟基、氨基或C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:羟基、单或二(C1-C4烷基)氨基、N-(C1-C4烷基)-N-(C1-C4烷基羰基)氨基、任选被(C1-C4烷基)羰基或C1-C6烷基取代的4-6元杂环基;最优选地,D任选被一个选自羟基、氨基或C1-C4烷基的取代基取代,所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;其中对于
若取代基为羟基,则在其3-位取代;若取代基为羟基以外的其它取代基,则在其4-位取代;对于
取代基为羟基或氨基,在其4-位取代;
E选自氨基、NHC(O)R
X、-C(O)R
y、
-OR
6、-NR
7R
8、-OC(O)NR
7R
8、-C(O)OR
6、-C(O)NR
7R
8、-NR
9C(O)NR
7R
8、-S(O)
mR
6、-NR
9S(O)
mR
6、-SR
6、-S(O)
mNR
7R
8、-NR
9S(O)
mNR
7R
8、或-CH
2-Ar
2;优选地,E选自氨基、杂芳基氧基、-NHC(O)R
X、-SO
2(C1-C8)烷基、-C(O)R
y、
或-CH
2-Ar
2;进一步优选地,E选自氨基、吡啶氧基、-NHC(O)R
X、SO
2(C1-C6)烷基、-C(O)R
y、
或-CH
2-Ar
2;
最优选地,当D为
时,E选自氨基、-NHC(O)R
X或-SO
2(C1-C4)烷基;当D为
时,E为吡啶-2-氧基;当D为
时,E选自-C(O)R
y、
-SO
2(C1-C4)烷基、或-CH
2-Ar
2;
R
X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;优选地,R
X选自C1-C6烷氧基、任选被取代的6元芳基、任选被取代的含有1或2个选自N、O的杂原子的5-6元杂芳基、任选被取代的C1-C6烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C6烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C6烷氧基或C3-C6环烷基;最优选地,R
X选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6 元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
R
y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;优选地,R
y选自任选被取代的氨基、C1-C6烷基、含有1或2个选自N、O、S的杂原子的4-6元杂环基、或C3-C6环烷基,所述取代基选自任选被芳基取代的C1-C6烷基;最优选地,R
y选自任选被C1-C4烷基或苄基取代的氨基、C1-C4烷基、含有1或2个选自N、O的杂原子的4-6元杂环基或C3-C6环烷基;
Ar
2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基或C1-C8烷氧基;优选地,Ar
2选自任选被单或二取代的5-6元芳基或杂芳基,所述取代基选自卤素、C1-C6烷氧基;最优选地,Ar
2选自任选被单或二取代的苯基、任选被单或二取代的吡啶基,所述取代基选自卤素、C1-C4烷氧基;
R
m、R
n各自独立地选自氢、羟基、C1-C8烷基或羟基C1-C8烷基,或R
m、R
n与其连接的碳原子一起形成C3-C8环烷基;优选地,R
m、R
n各自独立地选自氢、羟基、C1-C6烷基或羟基C1-C6烷基,或R
m、R
n与其连接的碳原子一起形成C3-C6环烷基;最优选地,R
m、R
n各自独立地选自氢、羟基或羟基C1-C4烷基,或R
m、R
n与其连接的碳原子一起形成环丙基;
R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13各自独立地选自氢、卤素、羟基、氨基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、4-8元杂环基、杂芳基、芳基、C2-C8烯基或C2-C8炔基;
r选自0、1、2或3;优选地,r选自0、1或2;
m选自1或2。
优选地,本发明提供一种如前文所述的可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐,其中
X
1为CR
1或N;
X
2为CH或N;
条件是X
1、X
2中至多有1个为N;
Y
1为CR
2或N;
Y
2为CR
3或N;
Y
3为CR
4或N;
Y
4为CR
5或N;
且满足下列条件之一:Y
1-Y
4都不为N;仅Y
1或Y
2为N;Y
1和Y
2都为N;或Y
1和Y
3都为N;
R
1-R
5各自独立地选自氢、卤素、氰基、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR
6、-NR
7R
8、-OC(O)NR
7R
8、-C(O)OR
6、-C(O)NR
7R
8、
-NR
9C(O)R
6、-NR
9C(O)NR
7R
8、-S(O)
mR
6、-NR
9S(O)
mR
6、-SR
6、-S(O)
mNR
7R
8或-NR
9S(O)
mNR
7R
8;
A选自氢、卤素、氰基或C1-C6烷基;
B选自氢、卤素、-OR
14或任选被取代的Ar
1;
R
14选自氢、C1-C6烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基、炔基任选被一个或多个选自下列的取代基所取代:卤素、氰基、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基;
Ar
1选自含有1-3个环上杂原子的5或6元杂芳基,其中所述杂原子各自独立地选自N、O、S;
Ar
1任选可被一个或多个取代基所取代,所述取代基各自独立地选自卤素、氰基、C1-C8烷基、C3-C8环烷基、杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR
6、-NR
7R
8、-OC(O)NR
7R
8、-C(O)OR
6、-C(O)R
6、-C(O)NR
7R
8、-NR
9C(O)R
6、-NR
9C(O)NR
7R
8、-S(O)
mR
6、-NR
9S(O)
mR
6、-SR
6、-S(O)
mNR
7R
8或-NR
9S(O)
mNR
7R
8;
D任选被一个选自卤素、氰基、羟基、氨基、或C1-C8烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C8烷基)氨基、N-(C1-C8烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C8烷基取代的4-8元杂环基;
E选自氨基、NHC(O)R
X、-C(O)R
y、
-OR
6、-NR
7R
8、-OC(O)NR
7R
8、-C(O)OR
6、-C(O)NR
7R
8、-NR
9C(O)NR
7R
8、-S(O)
mR
6、-NR
9S(O)
mR
6、-SR
6、-S(O)
mNR
7R
8、-NR
9S(O)
mNR
7R
8、或-CH
2-Ar
2;
R
X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;
R
y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;
Ar
2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基或C1-C8烷氧基;
R
m、R
n各自独立地选自氢、羟基、C1-C8烷基、羟基C1-C8烷基,或R
m、R
n与其连接的碳原子一起形成C3-C8环烷基;
R
6、R
7、R
8、R
9各自独立地选自氢、卤素、羟基、氨基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、4-8元杂环基、杂芳基、芳基、C2-C8烯基或C2-C8炔基;
m为1或2;
r为0、1、2或3。
进一步优选地,本发明提供一种如前文所述的可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐,其中
X
1为CR
1或N;
X
2为CH或N;
条件是X
1、X
2中至多有1个为N;
Y
1为CR
2或N;
Y
2为CR
3或N;
Y
3为CR
4或N;
Y
4为CR
5或N;
且满足下列条件之一:Y
1-Y
4都不为N;仅Y
1或Y
2为N;Y
1和Y
2都为N;或Y
1和Y
3都为N;
R
1-R
5各自独立地选自氢、卤素、氰基、C1-C6烷基、-OR
6或-NR
7R
8;
A选自氢、卤素、氰基或C1-C6烷基;
B选自氢、卤素、-OR
14或任选被取代的Ar
1;
R
14选自氢、C1-C6烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基、炔基任选被一个或多个选自下列的取代基所取代:卤素、氰基、羟基、C3-C8环烷基、或任选被C1-C6烷基取代的4-8元杂环基;
Ar
1选自含有两个环上N原子的5或6元杂芳基;
Ar
1任选可被一个或多个取代基所取代,所述取代基各自独立地选自卤素、氰基、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR
6、-NR
7R
8、-OC(O)NR
7R
8、-C(O)OR
6、-C(O)R
6、-C(O)NR
7R
8、-NR
9C(O)R
6、-NR
9C(O)NR
7R
8、-S(O)
mR
6、-NR
9S(O)
mR
6、-SR
6、-S(O)
mNR
7R
8或-NR
9S(O)
mNR
7R
8;
D任选被一个选自卤素、氰基、羟基、氨基、C1-C8烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C8烷基)氨基、N-(C1-C8烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C8烷基取代的4-8元杂环基;
R
X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、 任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;
R
y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;
Ar
2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基、C1-C8烷氧基;
R
m、R
n各自独立地选自氢、羟基、C1-C8烷基、羟基C1-C8烷基,或R
m、R
n与其连接的碳原子一起形成C3-C8环烷基;
R
6、R
7、R
8、R
9各自独立地选自氢、卤素、羟基、氨基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、4-8元杂环基、杂芳基、芳基、C2-C8烯基或C2-C8炔基;
m为1或2;
r为0、1、2或3。
更进一步优选地,本发明提供一种如前文所述的可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐,其中
X
1为CR
1或N;
X
2为CH或N;
条件是X
1、X
2中至多有1个为N;
Y
1为CR
2或N;
Y
2为CR
3或N;
Y
3为CR
4或N;
Y
4为CR
5或N;
且满足下列条件之一:Y
1-Y
4都不为N;仅Y
1或Y
2为N;或Y
1和Y
3都为N;
R
1-R
5各自独立地选自氢、卤素或C1-C4烷基;
A选自氢、氰基或C1-C4烷基;
B选自氢、卤素、-OR
14或任选被取代的Ar
1;
R
14选自氢、C1-C6烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基或杂芳基、 烯基、炔基任选被一个或多个选自下列的取代基所取代:卤素、氰基、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基;
Ar
1选自含有两个环上N原子的5元杂芳基;
Ar
1任选可被一个或多个取代基所取代,所述取代基各自独立地选自卤素、氰基、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR
6、-NR
7R
8、-OC(O)NR
7R
8、-C(O)OR
6、-C(O)R
6、-C(O)NR
7R
8、-NR
9C(O)R
6、-NR
9C(O)NR
7R
8、-S(O)
mR
6、-NR
9S(O)
mR
6、-SR
6、-S(O)
mNR
7R
8、-NR
9S(O)
mNR
7R
8;
D任选被一个选自卤素、氰基、羟基、氨基、C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C6烷基)氨基、N-(C1-C6烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C6烷基取代的4-6元杂环基;
R
X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;
R
y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;
Ar
2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基、C1-C8烷氧基;
R
m、R
n各自独立地选自氢、羟基、C1-C8烷基、羟基C1-C8烷基,或R
m、R
n与其连接的碳原子一起形成C3-C8环烷基;
R
6、R
7、R
8、R
9各自独立地选自氢、卤素、羟基、氨基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、4-8元杂环基、杂芳基、芳基、C2-C8烯基或C2-C8炔基;
m为1或2;
r为0、1、2或3。
再进一步优选地,本发明提供一种如前文所述的可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐,其中
X
1为CH或N;
X
2为CH或N;
条件是X
1、X
2中至多有1个为N;
Y
1为CH或N;
Y
2为CH或N;
Y
3为CH或N;
Y
4为CH或N;
且满足下列条件之一:Y
1、Y
2、Y
3和Y
4都为CH;仅Y
1或Y
2为N;或Y
1和Y
3都为N;
A为氢;
R
14选自氢、C1-C6烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基或炔基任选被一个或多个选自下列的取代基所取代:卤素、氰基、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基;
R
15选自氢、C1-C8烷基、羟基C1-C8烷基、C3-C8环烷基、含有1-2个选自N、O、S的杂原子的4-8元杂环基、芳基或杂芳基;
D选自:
D任选被一个选自卤素、氰基、羟基、氨基或C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C6烷基)氨基、N-(C1-C6烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C6烷基取代的4-6元杂环基;
R
X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;
R
y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;
Ar
2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基或C1-C8烷氧基;
R
m、R
n各自独立地选自氢、羟基、C1-C8烷基、羟基C1-C8烷基,或R
m、R
n与其连接的碳原子一起形成C3-C8环烷基;
r为0、1、2或3。
又进一步优选地,本发明提供一种如前文所述的可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同 位素衍生物或其药学上可接受的盐,其中
X
1为CH或N;
X
2为CH或N;
条件是X
1、X
2中至多有1个为N;
Y
1为CH或N;
Y
2为CH或N;
Y
3为CH或N;
Y
4为CH或N;
且满足下列条件之一:Y
1、Y
2、Y
3和Y
4都为CH;仅Y
1或Y
2为N;或Y
1和Y
3都为N;
A为氢;
R
14选自氢、C1-C6烷基、C3-C8环烷基或4-8元杂环基,其中所述烷基、环烷基、杂环基任选被一个或多个选自下列的取代基所取代:卤素、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基;
R
15选自氢、C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、或含有1-2个选自N、O、S的杂原子的4-8元杂环基;
D选自:
D任选被一个选自羟基、氨基或C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:单或二(C1-C6烷基)氨基、N-(C1-C6烷基)-N-(C1-C4烷基)羰基氨基、任选被C1-C6烷基、乙酰基取代的4-6元杂环基;
R
X选自C1-C6烷氧基、任选被取代的6元芳基、任选被取代的含有1或2个选自N、O的杂原子的5-6元杂芳基、任选被取代的C1-C6烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C6烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C6烷氧基或C3-C6环烷基;
R
y选自任选被取代的氨基、C1-C6烷基、含有1或2个选自N、O、S的杂原子的4-6元杂环基、或C3-C6环烷基,所述取代基选自任选被芳基取代的C1-C6烷基;
Ar
2选自任选被单或二取代的5-6元芳基或杂芳基,所述取代基选自卤素或C1-C6烷氧基;
R
m、R
n各自独立地选自氢、羟基、C1-C6烷基或羟基C1-C6烷基,或R
m、R
n与其连接的碳原子一起形成C3-C6环烷基;
r为0、1、2或3。
又进一步优选地,本发明提供一种如前文所述的可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐,其中
X
1为CH或N;
X
2为CH或N;
条件是X
1、X
2中至多有1个为N;
Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3为N,Y
2和Y
4为CH;
A为氢;
R
14选自C1-C4烷基、C3-C6环烷基或4-6元杂环基,其中所述烷基、环烷基或杂环基任选被一个或多个选自下列的取代基所取代:卤素、羟基、任选被C1-C4烷基取代的4-6元杂环基;
R
15选自氢、C1-C4烷基、羟基C1-C4烷基、C3-C6环烷基或含有 1-2个各自独立地选自N、O或S的杂原子的4-6元杂环基;
D选自:
D任选被一个选自羟基、氨基或C1-C4烷基的取代基所取代,所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;
R
X选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
R
y选自任选被C1-C4烷基或苄基取代的氨基、C1-C4烷基、含有1或2个选自N、O的杂原子的4-6元杂环基或C3-C6环烷基;
Ar
2选自任选被单或二取代的苯基、任选被单或二取代的吡啶基,所述取代基选自卤素或C1-C4烷氧基;
R
m、R
n各自独立地选自氢、羟基、羟基C1-C4烷基,或R
m、R
n与其连接的碳原子一起形成环丙基;
r为0、1或2。
又进一步优选地,本发明提供一种如前文所述的可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同 位素衍生物或其药学上可接受的盐,其中
X
1为CH或N;
X
2为CH或N;
条件是X
1、X
2中至多有1个为N;
Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3为N,Y
2和Y
4为CH;
A为氢;
R
14选自任选被1-甲基哌啶-4-基取代的C1-C4烷基;
R
15为C1-C4烷基;
D选自
D任选被一个选自羟基、氨基或C1-C4烷基的取代基取代,所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;
R
X选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
R
y选自任选被C1-C4烷基或苄基取代的氨基、C1-C4烷基、含有1或2个选自N、O的杂原子的4-6元杂环基或C3-C6环烷基;
Ar
2选自任选被单或二取代的苯基、任选被单或二取代的吡啶基,所述取代基选自卤素、C1-C4烷氧基;
R
m、R
n各自独立地选自氢、羟基、羟基C1-C4烷基,或R
m、R
n与其连接的碳原子一起形成环丙基;
r为0、1或2。
又更进一步优选地,本发明提供一种如前文所述的可用作选择性RET激酶抑制剂的如式(I)所示的化合物、其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐,其中所述化合物为:
本发明进一步涉及一种药物组合物,所述药物组合物包括本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐及药学上可接受的载体、稀释剂、赋形剂,以及任选地进一步包含一种或多种其它RET激酶抑制剂。
本发明还涉及根据本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐在制备用作RET激酶抑制剂的药物中的用途。
本发明还涉及根据本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐在制备药物中的用途,其中所述药物用于治疗或者预防由RET激酶介导的疾病,例如癌症,尤其是恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明还涉及根据本发明所述的药物组合物在制备药物中的用途,其中所述药物用于治疗或者预防由RET激酶介导的疾病,例如癌症,尤其是恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明还涉及一种治疗或者预防RET激酶介导的疾病(例如肿瘤, 尤其是恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤)的方法,其包括给予有需要的患者治疗有效量的本发明任意一个实施方案中所述的化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐,或本发明所述的药物组合物。
本发明的另一方面涉及本发明任意一个实施方案中所述的化合物、或其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐,其用于治疗或者预防RET激酶介导的疾病,例如肿瘤,尤其是恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明的另一方面涉及一种药物组合物,所述药物组合物包括本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐及药学上可接受的载体、稀释剂、赋形剂,其用于治疗或者预防RET激酶介导的疾病,例如肿瘤,尤其是恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明的另一方面涉及作为治疗和/或预防RET激酶介导的疾病(例如肿瘤等)的本发明任意一个实施方案中所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、其混合物形式、及其药学可接受的盐。所述肿瘤尤其是恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明的另一方面涉及作为治疗和/或预防RET激酶介导的疾病(例如肿瘤等)的药物组合物,所述药物组合物包括本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、稳定的同位素衍生物或其药学上可接受的盐及药学上可接受的载体、稀释剂、赋形剂,以及任选地进一步包含一种或多种其它RET激酶抑制剂。
根据本发明,所述药物可以是任何药物剂型,包括但不限于片剂、胶囊剂、溶液剂、冻干制剂、注射剂。
本发明的药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。这种单位可根据治疗的病症、给药方法和患者的年龄、体重和状况包含例如0.5毫克至1克,优选1毫克至700毫克,特别优选5毫克至300毫克的本发明的化合物,或药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。优选剂量单位制剂是包含如上指示的日剂量或分剂量或其相应分数的活性成分的那些。 此外,可以使用制药领域中公知的方法制备这种类型的药物制剂。
本发明药物制剂可适于通过任何所需的合适方法给药,例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、阴道或肠道外(包括皮下、肌内、静脉内或皮内)方法给药。可以使用制药领域中已知的所有方法通过例如将活性成分与一种或多种赋形剂或一种或多种辅助剂合并来制备这样的制剂。
制备方法
本发明还提供制备所述化合物的方法。本发明的化合物可以通过本领域公知的各种方法制备。例如,本发明的化合物可以如方案1-10中所示合成。
方案1
R
16选自C1-C4烷基;
P
1和P
2各自独立地选自卤素,例如氯、溴、碘等;
第一步:
化合物(I)在选自1,4-二氧六环、四氢呋喃或水等的溶剂中,加入碱(例如碳酸氢钠)和R
16OCOCl,在室温或油浴加热下(20~50℃)进行反应,得到化合物(II);
第二步:
在惰性气体(如氮气或氩气)氛围下,在无水溶剂(如无水甲苯) 中,加入化合物(II)、R
16OH、叠氮磷酸二苯酯和碱(如无水三乙胺),油浴加热,保持温度为70~90℃进行Curtius重排反应,得到化合物(III);
第三步:
在惰性气体(如氮气或氩气)氛围下,在无水溶剂(如无水甲苯)中,加入化合物(IV)、R
16OH、叠氮磷酸二苯酯和碱(如无水三乙胺),油浴加热,保持温度为60~80℃进行Curtius重排反应,得到化合物(III);
第四步:
在溶剂(如三氟乙酸等)中加入化合物(III)和碱(如六亚甲基四胺),油浴加热,保持温度为80~100℃进行闭环反应,得到化合物(V);
第五步:
将化合物(V)溶于溶剂(如乙醇与水)中,加入碱(例如氢氧化钾),油浴加热,在温度为70~90℃搅拌1~3小时,再加入氧化剂(例如铁氰化钾)在相同温度下继续搅拌2~6小时进行水解及氧化反应,得到化合物(VI);
第六步:
将化合物(VI)溶于5%~15%的稀盐酸中,冰浴下缓慢加入亚硝酸钠水溶液,油浴加热,保持温度为40~50℃搅拌1~3小时,再滴加卤代盐(如碘化钾等)的水溶液,继续在40~50℃搅拌1~3小时,进行胺基重氮化及卤代反应,得到化合物(IX);
第七步:
将化合物(VII)、二异丙基氨基锂与N,N-二甲基甲酰胺加入溶剂(如四氢呋喃等)中,在-78℃下进行甲酰化反应,得到化合物(VIII);
第八步:
将化合物(VIII)、碳酸钾、醋酸甲眯加入溶剂(如无水乙腈等)中,油浴加热,在100~120℃进行取代关环反应,得到化合物(IX)。
方案2
P
1、P
2、P
3各自独立地选自卤素,例如氯、溴、碘等;
Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3为N,Y
2和Y
4为CH;
PG
1选自叔丁氧羰基;
R
17选自氢、羟基;
R
18选自氢、氨基或C1-C4烷基,所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;
R
19选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
R
20、R
21各自独立地选自氢、C1-C4的烷基;
第一步:
将起始原料(IX)(P
1为氯,P
2为溴或碘)、N-取代吡唑硼酸酯(或硼酸)溶于溶剂(二氧六环与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钠或碳酸钾作碱,在氮气或氩气保护下,油浴加热,在温度为70~100℃搅拌2~12小时,进行Suzuki偶联反应,得到化合物(X);
第二步:
将起始原料(X),硼酸酯(或硼酸)(XI)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为90~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XIV);
第三步:
频哪醇硼酸酯的制备:将起始原料(X)、联硼酸频那醇酯溶于溶剂(如:二氧六环)中,使用钯络合物如1,1’-双(二苯基膦基)二茂铁二氯化钯作为催化剂,或使用三(二亚苄基丙酮)二钯作为催化剂,再加入膦配体如三环己基膦,用醋酸钾作碱,在氮气或氩气保护下,油浴加热,在温度为60~100℃搅拌2~12小时,得到化合物(XII);
第四步:
将起始原料(XII)、杂环芳基卤代物(XIII)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为90~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XIV);
第五步:
PG
1的脱保护,例如叔丁氧羰基的脱保护反应使用三氟乙酸或盐酸作为酸;在二氯甲烷或二氧六环等溶剂中,反应在0~25℃条件下进行;反应得到化合物(XV);
第六步:
将起始原料(XV)与相应的酰氯溶于溶剂(如:四氢呋喃,二氯甲烷等)中,加入碱如三乙胺等,室温搅拌20分钟~18小时缩合;或者将起始原料(XV)与相应的羧酸溶于溶剂(四氢呋喃,二氯甲烷或N,N-二甲基甲酰胺等)中,加入缩合剂如2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐等,加入碱如三乙胺等,室温搅拌20分钟~18小 时缩合;可得化合物(XVI);
第七步:
将起始原料(XV)与相应的异氰酸酯溶于溶剂(四氢呋喃,二氯甲烷或N,N-二甲基甲酰胺等)中,室温搅拌20分钟~18小时;或者将起始原料(XV)与N,N′-羰基二咪唑或N,N′-羰基二(1,2,4-三氮唑)等溶于溶剂(四氢呋喃,二氯甲烷或N,N-二甲基甲酰胺等)中,室温或油浴加热(20~70℃)搅拌20分钟,加相应的胺,室温或油浴加热(20~70℃)搅拌20分钟~18小时缩合;可得化合物(XVII);
第八步:
将起始原料(IX)(P
1为溴或碘,P
2为氯)、硼酸酯(或硼酸)(XI)溶于溶剂(二氧六环与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钠或碳酸钾作碱,在氮气或氩气保护下,油浴加热,在温度为50~100℃搅拌2~12小时,进行Suzuki偶联反应,得到化合物(XVIII);
第九步:
将起始原料(XVIII)、N-取代吡唑硼酸酯(或硼酸)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为90~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XIV)。
方案3:
第一步:
将8-氨基喹啉(XIX)溶解在二氯甲烷中,依次加入三乙胺和苯甲酰氯,加完后25℃下反应1小时得到N-(喹啉-8-基)苯甲酰胺(XX);
第二步:
将N-(喹啉-8-基)苯甲酰胺(XX)加入到水中,分批加入N-溴代丁二酰亚胺,加完后25℃下反应15小时。得到N-(5-溴喹啉-8-基)苯甲酰胺(XXI);
第三步:
将N-(5-溴喹啉-8-基)苯甲酰胺(XXI)溶解在乙醇中,在25℃下搅拌加入1M氢氧化钠的乙醇溶液,在85℃下搅拌15小时,得到5-溴-8-氨基喹啉(XXII);
第四步:
将5-溴-8-氨基喹啉(XXII)溶解在乙腈中,加入N-氯代丁二酰亚胺,在80℃下搅拌6小时,得到5-溴-7-氯-8-氨基喹啉(XXIII);
第五步:
将5-溴-7-氯-8-氨基喹啉(XXIII)加入到水中,然后0℃下滴加浓硫酸,大部分固体消失,溶液变为橙红色时滴加4M亚硝酸钠水溶液,在0℃下搅拌0.5小时,最后将此混合物滴加到次磷酸中,在65℃下搅拌4小时,混合物倒入饱和氢氧化钠水溶液(3L)中,得到5-溴-7-氯喹啉(XXIV)。
方案4
P
3选自卤素,例如氯、溴、碘等;
Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3为N,Y
2和Y
4为CH;
PG
1选自叔丁氧羰基;
R
15选自C1-C4烷基;
R
17选自氢、羟基;
R
18选自氨基或C1-C4烷基,其中所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;
R
19选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
第一步:
将起始原料(XXIV)、硼酸酯(或硼酸)(XI)溶于溶剂(二氧六环与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钠或碳酸钾作碱,在氮气或氩气保护下,油浴加热,在温度为50~100℃搅拌2~ 12小时,进行Suzuki偶联反应,得到化合物(XXV);
第二步:
将起始原料(XXV)、N-取代吡唑硼酸酯(或硼酸)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为90~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XXVI);
第三步:
叔丁氧羰基的脱保护反应使用三氟乙酸或盐酸作为酸;在二氯甲烷或二氧六环等溶剂中进行PG
1的脱保护,,反应在0~25℃条件下进行,得到化合物(XXVII);
第四步:
将起始原料(XXVII)与相应的酰氯溶于溶剂(如:四氢呋喃,二氯甲烷等)中,加入碱如三乙胺等,室温搅拌20分钟~18小时缩合;或者将起始原料(XXVII)与相应的羧酸溶于溶剂(四氢呋喃,二氯甲烷或N,N-二甲基甲酰胺等)中,加入缩合剂如2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐等,加入碱如三乙胺等,室温搅拌20分钟~18小时缩合;可得化合物(XXVIII);
第五步:
将起始原料(XXIV)与联硼酸频那醇酯溶解在四氢呋喃中,加入醋酸钾和1,1’-双(二苯基膦基)二茂铁二氯化钯,体系用氮气鼓泡10分钟,氮气保护下60℃搅拌2小时,直接旋蒸得到7-氯-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)喹啉(XXIX),粗品用于下一步无需纯化;
第六步:
将起始原料7-氯-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)喹啉(XXIX),杂环芳基卤代物(XIII)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为90~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XXV)。
方案5
P
3选自卤素,例如氯、溴、碘等;
Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3为N,Y
2和Y
4为CH;
PG
1选自叔丁氧羰基;
R
17选自氢、羟基;
R
18选自氨基或C1-C4烷基,其中所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;
R
19选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的 杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
第一步:
将2-氯-4-乙氧基-6-氟苯甲醛(XXX)溶解在二甲基亚砜中,搅拌下加入碳酸钾和乙酸甲脒,在110℃下搅拌6小时,得到5-氯-7-乙氧基喹唑啉(XXXI);
第二步:
将起始原料5-氯-7-乙氧基喹唑啉(XXXI),硼酸酯(或硼酸)(XI)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为90~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XXXIII);
第三步:
将起始原料5-氯-7-乙氧基喹唑啉(XXXI)、联硼酸频那醇酯溶于溶剂(如二氧六环)中,使用钯络合物如1,1’-双(二苯基膦基)二茂铁二氯化钯作为催化剂,或使用三(二亚苄基丙酮)二钯作为催化剂,再加入膦配体如三环己基膦,用醋酸钾作碱,在氮气或氩气保护下,油浴加热,在温度为60~100℃搅拌2~12小时,得到化合物(XXXII);
第四步:
将起始原料(XXXII)、杂环芳基卤代物(XIII)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为90~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XXXIII);
第五步:
PG
1的脱保护,例如叔丁氧羰基的脱保护反应使用三氟乙酸或盐酸作为酸;在二氯甲烷或二氧六环等溶剂中,反应在0~25℃条件下进行;反应得到化合物(XXXIV);
第六步:
将起始原料(XXXIV)与相应的羧酸溶于溶剂(四氢呋喃,二氯甲烷或N,N-二甲基甲酰胺等)中,加入缩合剂如2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐等,加入碱如三乙胺等,室温搅拌 20分钟~18小时缩合;可得化合物(XXXV)。
方案6
Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3为N,Y
2和Y
4为CH;
PG
1选自叔丁氧羰基;
R
17选自氢、羟基;
R
18选自氨基或C1-C4烷基,其中所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;
R
19选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
第一步:将起始原料5,7-二氯-1,6-二氮杂萘(合成参考:PCT Int.Appl.,2011134971)(XXXVI),硼酸酯(或硼酸)(XI)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂或者三(二亚苄基丙酮)二钯作为催化剂,三环己基膦作为配体,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为80~90℃搅拌12~16小时,进行Suzuki偶联反应,得到化合物(XXXVII);
第二步:
将起始原料(XXXVII),N-甲基吡唑硼酸酯(或硼酸)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作 为催化剂,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为120~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XXXVIII);
第三步:
PG
1的脱保护,例如叔丁氧羰基的脱保护反应使用氯化氢二氧六环溶液或氯化氢乙酸乙酯溶液作为酸;在甲醇、乙酸乙酯或二氧六环等溶剂中,反应在0~25℃条件下进行;
第四步:
将起始原料(XXXIX)与相应的羧酸溶于溶剂(四氢呋喃,二氯甲烷或N,N-二甲基甲酰胺等)中,加入缩合剂如2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐等,加入碱如三乙胺等,室温搅拌20分钟~18小时缩合;可得化合物(XXXX)。
方案7
Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3为N,Y
2和Y
4为CH;
PG
1选自叔丁氧羰基;
R
14选自C1-C4烷基或任选被1-甲基哌啶-4-基取代的C1-C4烷基;
R
17选自氢、羟基;
R
18选自氨基或C1-C4烷基,其中所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;
R
19选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
第一步:
将起始原料XXXVII(R
14为乙基)溶于使用钠与乙醇现制的乙醇钠乙醇溶液中,油浴加热,在温度为100℃搅拌约16小时,得到化合物(XXXXI);或
将起始原料XXXVII、1-甲基-4-哌啶甲醇溶解在1,4-二氧六环中,使用金属络合物如三(二亚苄基丙酮)二钯作为催化剂,碳酸铯作碱,反应液用氮气鼓泡十分钟,氮气保护下110℃微波加热搅拌1小时,得到化合物(XXXXI);
第二步:
PG
1的脱保护,例如叔丁氧羰基的脱保护反应使用氯化氢乙酸乙酯溶液作为酸;在乙酸乙酯等溶剂中,反应在0~25℃条件下进行;
第三步:
将起始原料(XXXXII)与相应的羧酸溶于溶剂(四氢呋喃,二氯甲烷或N,N-二甲基甲酰胺等)中,加入缩合剂如2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐等,加入碱如三乙胺等,室温搅拌20分钟~18小时缩合;可得化合物(XXXXIII)。
方案8
Y
1为N,Y
2、Y
3和Y
4都为CH;或Y
1和Y
3为N,Y
2和Y
4为CH;
PG
1选自叔丁氧羰基;
R
19选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;
R
22选自任选被单或二取代的苯基、任选被单或二取代的吡啶基,所述取代基选自卤素、C1-C4烷氧基;
R
23选自C1-C4烷基;
第一步:
将起始原料5,7-二氯-1,6-二氮杂萘(合成参考:PCT Int.Appl.,2011134971)(XXXVI)、硼酸酯(或硼酸)(XXXXIV)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂或者三(二亚苄基丙酮)二钯作为催化剂,三环己基膦作为配体,用碳酸钾或磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为80~90℃搅拌12~16小时,进行Suzuki偶联反应,得到化合物(XXXXV);
第二步:
将起始原料(XXXXV)、N-甲基吡唑硼酸酯(或硼酸)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用磷酸钾作碱,在氮气或氩气保护下,油浴或微波加热,在温度为120~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XXXXVI);
第三步:
PG
1的脱保护,例如叔丁氧羰基的脱保护反应使用氯化氢二氧六环溶液或氯化氢乙酸乙酯溶液作为酸;在甲醇、乙酸乙酯或二氧六环等溶剂中,反应在0~25℃条件下进行,可得化合物(XXXXVII);
第四步:
将起始原料(XXXXVII)与相应醛或者酮溶于溶剂(甲醇,乙醇或1,2-二氯乙烷等)中,加入还原剂如三乙酰氧基硼氢化钠等,20~50℃下室温或油浴加热搅拌12~48小时,可得化合物(XXXXVIII)。
第五步:
将起始原料(XXXXVII)与相应的羧酸溶于溶剂(四氢呋喃,二氯甲烷或N,N-二甲基甲酰胺等)中,加入缩合剂如2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐等,加入碱如三乙胺等,室温搅拌20分钟~18小时缩合;可得化合物(XXXXIX)。
第六步:
将起始原料(XXXXVII)与相应的羧酸溶于溶剂(N,N-二甲基甲酰胺等)中,加入烷基磺酰氯R
23S(O)
2Cl,加入碱如三乙胺等,室温搅拌15分钟~18小时;可得化合物(XXXXX)。
方案9
R
23选自C1-C4烷基;
第一步:
将起始原料5,7-二氯-1,6-二氮杂萘(合成参考:PCT Int.Appl.,2011134971)(XXXVI)、硼酸酯(或硼酸)(XXXXXI)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂或者三(二亚苄基丙酮)二钯作为催化剂,三环己基膦作为配体,用碳酸钾或磷酸钾作碱,氮气或氩气保护下,在80~90℃搅拌12~16小时,进行Suzuki偶联反应,得到化合物(XXXXXII);
第二步:
将起始原料(XXXXXII)、N-甲基吡唑硼酸酯(或硼酸)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用磷酸钾作碱,氮气或氩气保护下,在120~140℃搅拌1~12小时,进行Suzuki偶联反应,得到化合物(XXXXXIII)。
方案10
R
17选自氢、羟基或氨基;
第一步:
将起始原料(XXXXXIV)溶于N,N-二甲基甲酰胺中,加入钠氢,室温搅拌半小时,然后加入2-氟吡啶,在80~90℃搅拌4~16小时,得到化合物(XXXXXV);
第二步:
将起始原料(XXXXXV)、5-溴-2-氟吡啶和N,N-二异丙基乙胺溶于二甲基亚砜中,在90~110℃搅拌10~20小时,得到化合物(XXXXXVI);
第三步:
将起始原料(XXXXXVI)、联硼酸频那醇酯、醋酸钾和1,1′-双二苯基膦基二茂铁二氯化钯在氮气保护下溶于二氧六环中,在80~100℃搅拌4~10小时,所得的混合物冷却到室温,氮气保护下加入5,7-二氯-1,6-二氮杂萘(合成参考:PCT Int.Appl.,2011134971)(XXXVI)、钯络合物如四(三苯基膦)钯作为催化剂或者三(二亚苄基丙酮)二钯作为催化剂,三环己基膦作为配体、用碳酸钾或磷酸钾作碱,再添加水,在80~90℃搅拌12~20小时,进行Suzuki偶联反应,得到化合物(XXXXXVII);
第四步:
将起始原料(XXXXXVII)、N-甲基吡唑硼酸酯(或硼酸)溶于溶剂(二氧六环或N,N-二甲基甲酰胺与水)中,使用钯络合物如四(三苯基膦)钯作为催化剂,用磷酸钾作碱,在氮气或氩气保护下,在130~150℃搅拌2~12小时,进行Suzuki偶联反应,得到化合物(XXXXXVIII)。
定义
除非有相反陈述,否则下列用在说明书和权利要求书中的术语具有下述含义。
在本发明中使用的表示方式“Cx-Cy”表示碳原子数的范围,其中x和y均为整数,例如C3-C8环烷基表示具有3-8个碳原子的环烷基,-C0-C2烷基表示具有0-2个碳原子的烷基,其中-C0烷基是指化学单键。
在本发明中,术语“烷基”指饱和的脂族烃基团,包括1至20个碳原子的直链和支链基团,例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、及其各种支链异构体等。烷基可以是任选取代的或未取代的。
在本发明中,术语“烯基”指含有至少1个碳碳双键的直链、支链烃基,其可包括2至20个碳原子,例如可以是2至18个碳原子、2至12个碳原子、2至8个碳原子、2至6个碳原子或2至4个碳原子的直链和支链基团。其中可以存在1-3个碳碳双键,优选存在1个碳碳双键。术语“C2-C4烯基”是指具有2-4个碳原子的烯基。包括乙烯基、丙烯基、丁烯基、丁烯-2-基、2-甲基丁烯基。烯基可以是任选取代的或未取代的。
在本发明中,术语“炔基”是指含有至少1个碳碳三键的直链、支链烃基,其可包括2至20个碳原子,例如可以是2至18个碳原子、2至12个碳原子、2至8个碳原子、2至6个碳原子或2至4个碳原子的直链和支链基团。其中可以存在1-3个碳碳三键,优选存在1个碳碳 三键。术语“C2-C4炔基”是指具有2-4个碳原子的炔基。非限制性实例包括乙炔基、丙炔基、丁炔基和丁炔-2-基、3-甲基丁炔基。炔基可以是任选取代的或未取代的。
在本发明中,术语“环烷基”指饱和单环或多环环状烃基,其包括3至12个环原子,例如可以是3至12个、3至10个、3至8个或3至6个环原子,或者可以是3、4、5、6元环。单环环基的非限制性实例包含环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。环烷基可以是任选取代的或未取代的。
在本发明中,术语“杂环基”指饱和或部分不饱和单环或多环环状烃基,其包括3至20个环原子,例如可以是3至16个、3至12个、3至10个、3至8个或3至6个环原子,其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包括3至12个环原子,其中1~4个是杂原子,更优选杂环基环包含3至10个环原子、更优选包括3至8个环原子,最优选5元环或6元环,其中1~4个是杂原子,更优选1~3个是杂原子,最优选1~2个是杂原子。单环杂环基的非限制性实例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。杂环基可以是任选取代的或未取代的。
在本发明中,术语“亚杂环基”指具有两个端部单价基团核心的取代或未取代的杂环基,其是从两个端部原子的每个原子上除去一个氢原子所产生的;所述杂环基具有前文所述的含义。“亚杂环基”的非限制性实例包含亚吡咯烷基、亚哌啶基、亚哌嗪基、亚吗啉基等。
在本发明中,术语“螺杂环基”指5至20元,单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺环基和双螺环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环基。螺环基的非限制性实例包含
螺环基可以是任选取代的或未取代的。
在本发明中,术语“亚螺杂环基”指具有两个端部单价基团核心的取代或未取代的螺杂环基,其是从两个端部原子的每个原子上除去一个氢原子所产生的;所述螺杂环基具有前文所述的含义。“亚螺杂环基”的非限制性实例包含
在本发明中,术语“稠杂环基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为4元/5元、5元/5元、5元/6元双环稠杂环基。稠杂环基的非限制性实例包含
所述杂环基环可以稠合于芳基、杂芳基或环基环上,其中与母体结构连接在一起的环为杂环基,非限制性实例包含:
等。稠杂环基可以是任选取代的或未取代的。
在本发明中,术语“亚稠杂环基”指具有两个端部单价基团核心的取代或未取代的稠杂环基,其是从两个端部原子的每个原子上除去一 个氢原子所产生的;所述稠杂环基具有前文所述的含义。“亚稠杂环基”的非限制性实例包含
在本发明中,术语“芳基”指6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团,优选为6至10元,例如苯基和萘基,最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环基环上,其中与母体结构连接在一起的环为芳基环,非限制性实例包含:
芳基可以是取代的或未取代的。
在本发明中,术语“杂芳基”指包含1至4个杂原子,5至14个环原子的杂芳族体系,其中杂原子包括氧、硫和氮。优选为5至10元。更优选杂芳基是5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基、噁唑基、异噁唑基等,所述杂芳基环可以稠合于芳基、杂环基或环基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实例包含:
杂芳基可以是任选取代的或未取代的。
在本发明中,术语“卤素”指氟、氯、溴或碘。
在本发明中,术语“氰基”指-CN。
在本发明中,术语“硝基”是指NO
2基团。
在本发明中,术语“羟基”指-OH基团。
在本发明中,术语“氨基”是指-NH
2基团。氨基上的一或二个氢被烷基取代可形成单或二烷基氨基,所述烷基具有前文所述的含义。
在本发明中,术语“烷氧基”指通过氧桥连接的烷基,包含烷基氧基、环烷基氧基和杂环烷基氧基。所述烷基、杂环烷基和环烷基具有前文所述的含义。
在本发明中,术语“杂芳基氧基”指通过氧桥连接的杂芳基,所述杂芳基具有前文所述的含义。
在本发明中,术语“羟基烷基”指被羟基取代的烷基,包含羟基烷基、羟基环烷基和羟基杂环烷基。所述烷基、杂环烷基和环烷基具有前文所述的含义。
在本发明中,术语“卤代烷基”是指至少一个氢被卤素基团代替的烷基取代基。典型的卤素基团包括氯、氟、溴和碘。卤代烷基的例子包括氟甲基、氟乙基、氯甲基、氯乙基、1-溴乙基、二氟甲基、三氟甲基和1,1,1-三氟乙基。应该认识到,如果取代基被一个以上的卤素基团取代,则那些卤素基团可以相同或不同(除非另有说明)。
在本发明中,“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
在本发明中,“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
所述取代基包括但不限于前文所述的各种基团。
本发明要求保护的化合物不仅包括所述化合物本身,还包括所述化合物的异构体、前药、稳定的同位素衍生物或其药学上可接受的盐。
本发明所述“药物组合物”表示含有一种或多种本发明所述化合物异构体、前药、稳定的同位素衍生物或其药学上可接受的盐及其他化学组分的混合物。其他组分例如药学上可接受的药学可接受的载体、稀释剂和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
当在说明书中使用时,术语“包含”包括“由...组成”。
本发明所述“室温”是指15-30℃。
本发明所述“稳定的同位素衍生物”包括:式I中任意的氢原子被1-5个氘原子取代得到的同位素取代衍生物、式I中任意的碳原子被1-3个碳14原子取代得到的同位素取代衍生物或式I中任意的氧原子被1-3个氧18原子取代得到的同位素取代衍生物。
本发明所述“药学上可接受的盐”在Berge,et al.,“Pharmaceutically acceptable salts”,J.Pharm.Sci.,66,1-19(1977)中有讨论,并对药物化学家来说是显而易见,所述的盐是基本上无毒性的,并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄等。
本发明药学上可接受的盐可通过一般的化学方法合成。
一般情况下,盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱在合适的溶剂或溶剂组合物中反应制得。
本发明所述“前药”是指化合物在体内代谢后转换成原始活性化合物。代表性地讲,前药为非活性物质,或者比活性母体化合物活性小,但可以提供方便的操作、给药或者改善代谢特性。
本发明所述“异构体”是指本发明的式(I)化合物的互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、其混合物形式等。所有这些异构体,包括立体异构体、几何异构体均包含在本发明中。所述几何异构体包括顺反异构体。
本发明包括所述化合物或其盐的任何多晶型物以及任何水合物或其它溶剂合物。
在本发明中,术语“患者”通常指哺乳动物,尤其是人。
在本发明中,术语“肿瘤”包括良性肿瘤和恶性肿瘤,例如癌症。
在本发明中,术语“癌症”包括RET激酶介导的的各种肿瘤,包括但不限于恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤。
在本发明中,术语“治疗有效量”是指包括可有效治疗或预防由RET激酶介导的相关疾病的本发明化合物的量。
实施例
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明所有化合物的结构可通过核磁共振(
1H NMR)和/或质谱检测(MS)鉴定。
1H NMR化学位移(δ)以PPM(parts per million,百万分之几)记录。NMR通过Bruker AVANCE III-400MHz光谱仪进行。合适的溶剂选自氘代氯仿(CDCl
3)、氘代甲醇(CD
3OD)、氘代二甲亚砜(DMSO-d
6)等,四甲基硅烷作为内标(TMS)。
低分辨率质谱(MS)由Agilent 1260 HPLC/6120质谱仪测定,使用Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm。
梯度洗脱条件一:0:95%溶剂A1和5%溶剂B1,1-2:5%溶剂A1和95%溶剂B1;2.01-2.50:95%溶剂A1和5%溶剂B1。百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A1:0.01%甲酸水溶液;溶剂B1:0.01%甲酸的乙腈溶液;百分数为溶质占溶液的体积百分数。
薄层硅胶板是烟台黄海HSGF254或青岛GF254硅胶板。柱层析一般使用烟台黄海100-200或200-300目硅胶作为载体。
制备液相色谱(prep-HPLC)使用Waters SQD2质谱导向高压液相色谱分离仪,XBridge-C18;30X150mm制备柱,5μm;
方法一:乙腈-水(0.2%甲酸),流速25mL/分钟;方法二:乙腈-水(0.8%碳酸氢铵),流速25mL/分钟;
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、上海毕得医药、上海阿拉丁化学、上海迈瑞尔化学、百灵威化学、安耐吉化学等公司。
实施例中如无特殊说明,反应所用溶剂均为无水溶剂,其中无水四氢呋喃使用市售四氢呋喃,以钠块为除水剂,以二苯甲酮作为指示剂,氩气保护下回流至溶液呈蓝紫色,蒸馏收集,氩气保护下室温储存,其他无水溶剂购自安耐吉化学及百灵威化学,所有无水溶剂的转 移和使用如无特殊说明,均需在氩气保护下进行。
实施例中如无特殊说明,反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空,充入氢气,反复操作3次。
实施例中如无特殊说明,反应的温度为室温,温度范围是15℃-30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂的体系有A:二氯甲烷和甲醇体系;B:石油醚和乙酸乙酯体系。溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括A:二氯甲烷和甲醇体系;B:石油醚和乙酸乙酯体系。溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
实施例23
2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
第一步
((3S,4S)-1-(5-溴吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯
将化合物2-氟-5-溴吡啶(1.08g,5.00mmol),((3S,4S)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(合成参考:WO 2004058144A2)(1.18g,5.00mmol)和N,N-二异丙基乙胺(1.29g,10.00mmol)溶于二甲基亚砜(10mL)中,加热至90℃反应过夜。冷却后反应液用乙酸乙酯(100mL)稀释,有机相用水(100mL)及饱和食盐水(100mL)洗涤,无 水硫酸钠干燥,有机相减压浓缩,残余物硅胶柱分离纯化(乙酸乙酯/石油醚=2∶3)得到目标产物(3S,4S)-1-(5-溴吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(1.40g,黄色固体)。产率:75.4%。MS m/z(ESI):372&374[M+1];
第二步
((3S,4S)-1-(5-(7-氯喹啉-5-基)吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯
将化合物((3S,4S)-1-(5-溴吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(0.15g,0.54mmol)、7-氯-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉(合成参考:WO 2017032840A1)(0.15g,0.54mmol)、四(三苯基膦)钯(20mg,0.05mmol)、碳酸钾(75mg,0.54mmol)溶于二氧六环(6mL)和水(1mL)中,氮气氛条件下,油浴80℃搅拌2小时。反应液加水(20mL)稀释,用乙酸乙酯(50mL)萃取,有机相用水(10mL)及饱和食盐水(10mL)洗涤。无水硫酸钠干燥,过滤,减压脱溶,残余物硅胶柱色谱分离(二氯甲烷∶甲醇=100∶0~9∶1)得到目标产物((3S,4S)-1-(5-(7-氯喹啉-5-基)吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(0.11g,黄色液体),产率:90%。MS m/z(ESI):455[M+1];
第三步
(3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将化合物((3S,4S)-1-(5-(7-氯喹啉-5-基)吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(0.11g,0.24mmol)、1-甲基-1H-吡唑-4-硼酸频那醇酯(0.10g,0.48mmol)、四(三苯基膦)钯(20mg,0.02mmol)、磷酸钾(0.10g,0.48mmol溶于二氧六环(4mL)和水(1mL)中,氮气氛条件下,油浴120℃搅拌过夜。反应液加水(20mL)稀释,用乙酸乙酯(50mL)萃取,有机相用水(10mL)及饱和食盐水(10mL)洗涤。无水硫酸钠干燥,过滤,减压脱溶,残余物硅胶柱色谱分离(二氯甲烷∶甲醇=100∶0~20∶1)得到目标产物(3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-叔丁酯基)氨基甲酸酯(0.12g,黄色固体),产率:99%;
MS m/z(ESI):501[M+1];
1H NMR(400MHz,CDCl
3)δ8.88(d,J=4.0Hz,1H),8.28(d,J=2.0Hz,1H),8.18-8.16(m,2H),7.93(s,1H),7.79(s,1H),7.61(d,J=2.0Hz,1H),7.60-7.58(m,1H),7.31-7.29(m,1H),6.84(d,J=8.8Hz,1H),4.90-4.88(m,1H),4.50-4.43(m,2H),3.98(s,3H),3.63-3.57(m,2H),3.49-3.47(m,2H),3.00-2.87(m,1H),2.14-2.10(m,1H),1.47(s,9H);
第四步
(3S,4S)-4-氨基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-3-醇
将化合物(3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(0.11g,0.22mmol)溶于盐酸的二氧六环(4mL,16mmol,4M)中,室温条件下搅拌30分钟。反应液减压脱溶,以饱和碳酸氢钠(3mL)水溶液中和,乙酸乙酯(10mL)萃取,有机相用饱和食盐水洗(4mL×3)。无水硫酸钠干燥,过滤,减压脱溶,得到目标产物(3S,4S)-4-氨基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-3-醇(70mg,黄色固体),产率:80%。MS m/z(ESI):401[M+1];
第五步
2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
将化合物邻氯苯甲酸(4mg,0.02mmol)、三乙胺(5mg,0.05mmol)和2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(7mg,0.02mmol)溶于N,N-二甲基甲酰胺(1mL)中,室温搅拌5分钟。加入(3S,4S)-4-氨基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-3-醇(5mg,0.01mmol),继续室温搅拌10分钟。反应液以饱和氢氧化钠溶液(2mL)洗涤,乙酸乙酯(10mL)萃取,有机相用水(20mL)及饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压脱溶,得到目标产物2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺(2.7mg,白色固体),产率:42%;
MS m/z(ESI):539&541[M+1];
1H NMR(400MHz,CDCl
3)δ8.90-8.89(m,1H),8.32(d,J=2.0Hz,1H),8.18(s,1H),7.93(s,1H),7.80(s,1H),7.77-7.75(m,1H), 7.66-7.64(m,1H),7.60(d,J=1.6Hz,1H),7.53(d,J=8.4Hz,1H),7.45-7.35(m,3H),7.33-7.30(m,1H),6.89(d,J=8.8Hz,1H),6.42(d,J=6.4Hz,1H),4.20-4.15(m,1H),4.00(s,3H),3.73-2.99(m,5H),2.05-2.00(m,2H)。
实施例44
2-氯-N-(4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)-6-氟苯甲酰胺
第一步
1-(5-溴吡啶-2-基)-4-((叔丁氧基羰基)氨基)哌啶-4-羧酸甲酯
将化合物2-氟-5-溴吡啶(0.61g,3.49mmol)、4-((叔丁氧基羰基)氨基)哌啶-4-羧酸甲酯(0.90g,3.49mmol)、碳酸钾(1.60g,13.94mmol)和二甲基亚砜(15mL)混合,100℃搅拌16小时。冷却至室温,此混合物缓慢倒入水(40mL)中,用乙酸乙酯萃取(50mL×3),有机相用水(50mL×3)和饱和食盐水(50mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压干燥得到1-(5-溴吡啶-2-基)-4-((叔丁氧基羰基)氨基)哌啶-4-羧酸甲酯(1.10g,粗品)。直接用于下一步。MS m/z(ESI):414&416[M+1];
第二步
(1-(5-溴吡啶-2-基)-4-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯
将化合物1-(5-溴吡啶-2-基)-4-((叔丁氧基羰基)氨基)哌啶-4-羧酸甲酯(0.25g,0.60mmol)溶于四氢呋喃(3mL)中,室温下加入硼氢化锂的四氢呋喃溶液(2mL,2M),混合物于室温下搅拌反应16小时。反应液中加入水(20mL)淬灭,用乙酸乙酯萃取(20mL×3),有机相用水(20mL×3)和饱和食盐水(20mL×3)洗涤。以无 水硫酸钠干燥,过滤除去干燥剂,滤液减压脱溶,残余物用硅胶层析柱纯化(石油醚∶乙酸乙酯=100∶0~4∶6)得目标产物(1-(5-溴吡啶-2-基)-4-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯(0.14g,白色固体),产率:56%。MS m/z(ESI):386&388[M+1];
第三步
(1-(5-溴吡啶-2-基)-4-甲酰基哌啶-4-基)氨基甲酸叔丁酯
将化合物(1-(5-溴吡啶-2-基)-4-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯(0.93g,2.59mmol)溶于二氯甲烷(10mL)中,分批加入戴斯-马丁试剂(1.65g,3.89mmol),室温搅拌4小时。反应液以饱和亚硫酸钠(5mL)溶液洗涤,二氯甲烷(20mL)萃取,有机相用水(20mL)和饱和食盐水(20mL)洗涤。无水硫酸钠干燥,过滤,减压脱溶,得到目标产物(1-(5-溴吡啶-2-基)-4-甲酰基哌啶-4-基)氨基甲酸叔丁酯(0.68g,白色固体),产率:68%;
MS m/z(ESI):384&386[M+1];
1H NMR(400MHz,CDCl
3)δ9.52(s,1H),8.18(d,J=2.0Hz,1H),7.55-7.52(m,1H),6.58(d,J=8.8Hz,1H),4.92(s,1H),3.94-3.88(m,2H),3.36-3.33(m,2H),2.04-1.98(m,2H),1.87-1.84(m,2H),1.45(s,9H);
第四步
(1-(5-溴吡啶-2-基)-4-((4-乙基哌嗪-1-基)甲基)哌啶-4-基)氨基甲酸叔丁酯
将化合物(1-(5-溴吡啶-2-基)-4-甲酰基哌啶-4-基)氨基甲酸叔丁酯(0.60g,1.60mmol)和2-乙基哌嗪(0.34g,3.00mmol)溶于四氢呋喃(15mL)中,向其中加入钛酸四乙酯(0.94g,4.16mmol),室温搅拌30分钟后,加入醋酸硼氢化钠(0.85g,4.00mmol),于50℃反应3小时。反应液以二氯甲烷/甲醇(10∶1,200mL)稀释后,加入水(5mL),剧烈搅拌15分钟后过滤,滤饼以二氯甲烷(40mL×3)洗涤,合并有机相,用水(20mL)和饱和食盐水(20mL)洗涤。以无水硫酸钠干燥,过滤除去干燥剂,减压脱溶。残余物用硅胶柱层析纯化(二氯甲烷∶甲醇=20∶1)得到目标产物(1-(5-溴吡啶-2-基)-4-((4-乙基哌嗪-1-基)甲基)哌啶-4-基)氨基甲酸叔丁酯(0.53g,黄色油状),产率:70%。MS m/z(ESI):482&484[M+1];
第五步
(1-(5-(7-氯喹啉-5-基)哌啶-2-基)-4-((4-乙基哌嗪-1-基)甲基)哌啶-4-基)氨基甲酸叔丁酯
将7-氯-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)喹啉(0.17g,0.60mmol)、(1-(5-溴吡啶-2-基)-4-((4-乙基哌嗪-1-基)甲基)哌啶-4-基)氨基甲酸叔丁酯(0.20g,0.41mmol)和二氧六环(10mL)、水(2mL)混合,氩气保护下加入碳酸钾(0.17g,1.23mmol)和四(三苯基膦)钯(47mg,0.041mmol),氩气置换三次,氩气保护下80℃搅拌5小时。冷却至室温,减压脱溶,残余物加入水(20mL),以乙酸乙酯(15mL×3)萃取,有机相用饱和食盐水(20mL×3)洗涤。无水硫酸钠干燥,过滤除去干燥剂,减压脱溶得粗品,通过快速硅胶柱层析纯化(二氯甲烷∶甲醇=100∶0~15∶1)得到目标产物(1-(5-(7-氯喹啉-5-基)哌啶-2-基)-4-((4-乙基哌嗪-1-基)甲基)哌啶-4-基)氨基甲酸叔丁酯(0.10g,黄色固体),产率:43%。MS m/z(ESI):565&567[M+1];
第六步
(4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将化合物(1-(5-(7-氯喹啉-5-基)哌啶-2-基)-4-((4-乙基哌嗪-1-基)甲基)哌啶-4-基)氨基甲酸叔丁酯(0.10g,0.18mmol)、1-甲基-1H-吡唑-4-硼酸频那醇酯(75mg,0.36mmol)和二氧六环(6mL)和水(1mL)混合加入35mL封管,氩气保护下加入碳酸钾(75mg,0.54mmol)和四(三苯基膦)钯(21mg,0.018mmol),氩气置换三次,氩气保护下140℃搅拌3小时。冷却至室温,减压脱溶,残余物加入水(20mL),以乙酸乙酯(15mL×3)萃取,有机相用饱和食盐水(20mL×2)洗涤。无水硫酸钠干燥,过滤除去干燥剂,减压脱溶得粗品,通过硅胶制备板纯化(二氯甲烷/甲醇=12∶1)得到目标产物(4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(50mg,黄色固体),产率:45%。MS m/z(ESI):611[M+1];
第七步
4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-胺
将化合物(4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基) 喹啉-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(50mg,0.082mmol)和氯化氢甲醇溶液(6mL,24mmol,4M)混合,室温下搅拌1小时。减压脱溶,残余物加入碳酸氢钠饱和溶液(10mL),以二氯甲烷(10mL×4)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤除去干燥剂,减压脱溶得目标产物4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-胺(35mg,黄色固体),产物不经纯化直接用于下一步反应。MS m/z(ESI):511[M+1];
第八步
2-氯-N-(4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)-6-氟苯甲酰胺
将化合物4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-胺(6.0mg,0.012mmol)、2-氯-6-氟苯甲酸(2.6mg,0.015mmol)、2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(6.8mg,0.018mmol)、三乙胺(3mg,0.03mmol)和N,N-二甲基甲酰胺(2mL)混合,室温下搅拌1小时。加水(20mL)稀释,以二氯甲烷(20mL×4)萃取,有机相用饱和食盐水(20mL×2)洗涤。无水硫酸钠干燥,过滤除去干燥剂,残余物由制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O25%-50%)得到目标产物2-氯-N-(4-((4-乙基哌嗪-1-基)甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)喹啉-5-基)吡啶-2-基)哌啶-4-基)-6-氟苯甲酰胺(2.2mg,白色固体),产率:28%;
MS m/z(ESI):667&669[M+1];
1H NMR(400MHz,CDCl
3)δ8.92-8.90(m,1H),8.32(d,J=2.4Hz,1H),8.27(s,1H),8.26-8.18(m,2H),7.94(s,1H),7.82(s,1H),7.67-7.59(m,2H),7.38-7.30(m,2H),7.09-7.06(m,1H),6.85(d,J=8.8Hz,1H),6.08(s,1H),4.34-4.18(m,2H),4.00(s,3H),3.40-3.27(m,2H),3.17-3.01(m,10H),2.98(s,2H),2.54-2.41(m,2H),1.82-1.69(m,2H),1.40-1.31(m,3H)。
实施例142
2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
第一步
((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯
将化合物5,7-二氯-1,6-二氮杂萘(合成参考:PCT Int.Appl.,2011134971)(45mg,0.23mmol),(6-((3S,4S)-4-氨基甲酸叔丁酯-3-羟基哌啶-1-基)吡啶-3-基)硼酸(粗品)和碳酸钾(89mg,0.65mmol)加入1,4-二氧六环(5mL)和水(1mL)中,氮气保护下加入四(三苯基膦)钯(25mg,0.022mmol),在90℃下反应12小时。反应液用乙酸乙酯(80mL)稀释,用水(10mL×3)及饱和食盐水(10mL×3)洗涤。有机相用无水硫酸钠干燥,过滤除去干燥剂,减压脱溶。残余物用制备硅胶板纯化(石油醚/乙酸乙酯1∶1)得到目标产物((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(60mg,黄色固体),产率61%;
MS m/z(ESI):456&458[M+1];
1H NMR(400MHz,CDCl
3)δ9.07(dd,J=4.2,1.6Hz,1H),8.50-8.46(m,2H),7.96-7.88(m,2H),7.70-7.61(m,1H),6.85(d,J=8.8Hz,1H),4.78(d,J=6.4Hz,1H),4.59-4.42(m,2H),3.66-3.59(m,1H),3.56-3.42(m,1H),3.02-2.88(m,2H),2.10-2.05(m,2H),1.47(s,9H);
第二步
((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将化合物(((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(25mg,0.055mmol),1-甲基-1H-吡唑-4-硼酸频那醇酯(29mg,0.137mmol)和磷酸钾(33mg,0.165mmol)溶于二氧六环(2mL)和水(0.5mL)中,氮气保护下加入四(三苯基膦)钯(7mg,0.006mmol),此混合物在140℃下微波反应1.5小时。 反应液以二氯甲烷/甲醇(20∶1,50mL)稀释,以饱和食盐水(5mL×3)洗涤,有机相以无水硫酸钠干燥,过滤除去干燥剂,减压脱溶。残余物用制备硅胶板纯化(二氯甲烷/甲醇25∶1)得到目标产物((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(15mg,黄色固体)。产率:54%。MS m/z(ESI):502[M+1];
第三步
(3S,4S)-4-氨基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-3-醇
将化合物((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(15mg,0.030mmol)溶于乙酸乙酯(2mL)中,室温加入盐酸乙酸乙酯溶液(8mL,16mml,2M)。常温搅拌反应0.5小时。反应液减压脱溶,残余物以二氯甲烷/甲醇(10∶1)溶解,以三乙胺调节pH至8-9左右。混合物旋蒸脱溶后,得黄色固体粗品,直接用于下一步反应。MS m/z(ESI):402[M+1];
第四步
2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
将化合物(3S,4S)-4-氨基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-3-醇(粗品,0.030mmol),2-氯苯甲酸(7mg,0.045mmol)和三乙胺(6mg,0.06mmol)溶于二氯甲烷(2mL)中,室温加入2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(17mg,0.045mmol),于室温下搅拌反应0.5小时。反应液加入水(20mL)稀释,用二氯甲烷(20mL×2)萃取,合并有机相用饱和食盐水(20mL×2)洗涤。用无水硫酸钠干燥,过滤,减压脱溶,残余物用制备硅胶板纯化(二氯甲烷/甲醇30∶1)得到目标产物2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺(10mg,黄色固体)。产率:62%;
MS m/z(ESI):540&542[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.00(m,1H),8.57(d,J=3.2Hz,1H),8.43(d,J=8.2Hz,1H),8.12(s,1H),8.08(s,1H),7.98-7.95(m,2H),7.75-7.73(m,1H),7.42-7.35(m,3H),6.91(d,J=8.8Hz,1H),6.64 (d,J=6.8Hz,1H),4.65-4.53(m,2H),4.27-4.25(m,1H),4.17-4.15(m,1H),3.99(s,3H),3.77-3.71(m,1H),3.30-3.24(m,1H),2.96-2.90(m,1H),2.32-2.27(m,1H)。
实施例143到167的合成步骤参考实施例142最后一步:其中用不同的酸代替2-氯苯甲酸:
实施例168
2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-4-基)苯甲酰胺
第一步
(6-((3S,4S)-4-((叔丁氧基羰基)氨基)-3-羟基哌啶-1-基)吡嗪-3-基)硼酸
将(3S,4S)-1-(5-溴吡嗪-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(合成参考实施例23的第一步)(0.52g,1.40mmol),联硼酸频那醇酯(0.71g,2.80mmol),溶解在1,4-二氧六环(20mL)中,加入三(二亚苄基丙酮)二钯(0.14g,0.15mmol)、三环己基膦(84mg,0.30mmol)和醋酸钾(0.41g,4.20mmol),反应液用氮气鼓泡十分钟,氮气保护下95℃加热搅拌2小时。反应液旋干得到粗产品(6-((3S,4S)-4-((叔丁氧 基羰基)氨基)-3-羟基哌啶-1-基)吡嗪-3-基)硼酸(1.20g,粗品),直接用于下一步,无需纯化。MS m/z(ESI):339[M+1];
第二步
((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡嗪-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯
将(6-((3S,4S)-4-((叔丁氧基羰基)氨基)-3-羟基吡嗪-1-基)吡啶-3-基)硼酸(1.20g,粗品),5,7-二氯-1,6-二氮杂萘(合成参考:PCT Int.Appl.,2011134971)(0.30g,1.50mmol),溶解在1,4-二氧六环(5mL)和水(1mL)中,加入三(二亚苄基丙酮)二钯(92mg,0.10mmol)、三环己基膦(56mg,0.20mmol)和碳酸钾(0.62g,4.50mmol),反应液用氮气鼓泡十分钟,氮气保护下90℃加热搅拌14小时。冷却至室温,用二氯甲烷(100mL)稀释,有机相用水(20mL×3)和饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,减压脱溶,粗品用硅胶柱纯化(石油醚∶乙酸乙酯=1∶1)得到((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡嗪-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(0.28g,黄色固体),收率43.7%;
MS m/z(ESI):457&459[M+1];
1H NMR(400MHz,CDCl
3)δ9.39(d,J=8.8Hz,1H),9.06-9.04(m,1H),9.00(s,1H),8.26(s,1H),8.19-8.16(m,1H),7.94(s,1H),4.76-4.74(m,1H),4.58-4.52(m,2H),3.55-3.48(m,1H),3.06-2.80(m,2H),2.12-2.07(m,1H),1.57-1.51(m,1H),1.47(s,9H);
第三步
((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-4-基)氨基甲酸叔丁酯
将((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡嗪-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(0.28g,0.62mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(0.26g,1.24mmol),溶解在N,N-二甲基乙酰胺(5mL)和水(1mL),反应液用氮气鼓泡十分钟,在氮气保护下120℃加热搅拌4小时。反应液冷却至室温,用二氯甲烷(100mL)稀释,有机相用水(20mL)和饱和食盐水(20mL)洗涤。用无水硫酸钠干燥,过滤,减压脱溶,所得粗品用硅胶柱纯化(二氯甲烷∶甲醇=40∶1)得到目标产物((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4- 基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-4-基)氨基甲酸叔丁酯(100mg,黄色固体),收率32.7%;
MS m/z(ESI):503[M+1];
1H NMR(400MHz,CDCl
3)δ9.28(d,J=8.8Hz,1H),9.13(s,1H),8.99-8.97(m,1H),8.27(s,1H),8.14(s,1H),8.09(s,1H),7.98(s,1H),7.44-7.40(m,1H),4.89-4.87(m,1H),4.57-4.53(m,2H),3.97(s,3H),3.54-3.51(m,1H),3.09-2.94(m,2H),2.15-2.11(m,1H),1.59-1.51(m,1H),1.47(s,9H);
第四步
(3S,4S)-4-氨基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-3-醇盐酸盐
将((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-4-基)氨基甲酸叔丁酯(0.10g,0.20mmol)溶解在盐酸二氧六环溶液中(5mL,20mmol,4M),室温搅拌1小时。反应液旋干得到粗产品(3S,4S)-4-氨基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-3-醇盐酸盐(110mg,粗品),直接用于下一步,无需纯化。MS m/z(ESI):403[M+1];
第五步
2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-4-基)苯甲酰胺
将化合物(3S,4S)-4-氨基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-3-醇盐酸盐(粗品,0.004mmol),2-氯苯甲酸(1mg,0.006mmol)和三乙胺(1mg,0.008mmol)溶于二氯甲烷(1mL)中,室温加入2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(2.3mg,0.006mmol),于室温下搅拌反应0.5小时。反应液加入水(5mL)稀释,二氯甲烷(10mL×2)萃取,有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,减压脱溶,残余物用制备硅胶板纯化(二氯甲烷/甲醇25∶1)得到目标产物2-氯-N-((3S,4S)-3-羟基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡嗪-2-基)哌啶-4-基)苯甲酰胺(1.2mg,黄色固体)。产率:50%;
MS m/z(ESI):541&543[M+1];
1H NMR(400MHz,CDCl
3)δ9.31(d,J=7.8Hz,1H),9.10(d,J= 1.2Hz,1H),9.01-9.00(m,1H),8.32(s,1H),8.14(s,1H),8.09(s,1H),8.00(s,1H),7.79-7.73(m,1H),7.45-7.36(m,3H),6.45(d,J=6.8Hz,1H),4.68-4.56(m,2H),4.30-4.17(m,1H),4.00(s,3H),3.81-3.68(m,1H),3.18-3.06(m,2H),2.29-2.26(m,1H),2.01-1.98(m,1H)。
实施例169到181的合成步骤参考实施例27最后一步:其中用不同的酸代替2-氯苯甲酸:
实施例183
2-氯-N-(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
第一步
(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将(1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(合成参考实施例168的第三步)(38mg,0.09mmol),1- 甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(37mg,0.18mmol)溶解N,N-二甲基甲酰胺(4mL)中,依次加入四(三苯基膦)钯(10mg,0.009mmol)和磷酸钾(57mg,0.27mmol),氮气保护下加热至140℃反应6小时。反应液降至室温后倒入水中(20mL),用乙酸乙酯萃取(25mL×3)萃取,有机相合并后用饱和食盐水洗涤(25mL×3),无水硫酸钠干燥,过滤浓缩,薄层色谱提纯(二氯甲烷∶甲醇=15∶1)得到目标化合物(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(37mg,白色固体),收率84.7%;
MS m/z(ESI):486[M+1];
1H NMR(400MHz,CDCl
3)δ9.00(s,1H),8.57(m,1H),8.44-8.42(m,1H),8.12(s,1H),8.07(s,1H),7.96-7.95(m,2H),7.38-7.35(m,1H),6.83(d,J=8.8Hz,1H),4.53-4.52(m,1H),4.37-4.35(m,2H),3.99(s,3H),3.77-3.76(m,1H),3.14-3.08(m,2H),2.10-2.05(m,4H),1.47(s,9H);
第二步
(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基盐酸盐
(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(10mg,0.02mmol)溶解在甲醇(3mL)中,加入盐酸二氧六环溶液(3mL,12mmol,4M),室温反应30分钟。反应液浓缩,得到目标化合物粗品(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5基)吡啶-2-基)哌啶-4-基)氨基盐酸盐(粗品,10mg,黄色固体),直接投下一步。MS m/z(ESI):386[M+1];
第三步
2-氯-N-(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
将邻氯苯甲酸(6mg,0.04mmol),2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(16mg,0.04mmol),三乙胺(0.1mL)溶解在二氯甲烷(5mL)中,加入(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基盐酸盐(10mg,0.02mmol),室温搅拌反应1小时。加入二氯甲烷(20mL)稀释,有机相用饱和食盐水(25mL)洗涤,有机相用无水硫酸钠干燥,过滤浓缩,薄层色谱提纯 (二氯甲烷∶甲醇=15∶1)得到2-氯-N-(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺(8.0mg,黄色固体),收率76.5%;
MS m/z(ESI):524&526[M+1];
1H NMR(400MHz,CDCl
3)δ9.01-9.00(m,1H),8.59-8.58(m,1H),8.43(d,J=8.4Hz,1H),8.12(s,1H),8.07(s,1H),7.98-7.95(m,2H),7.69-7.66(m,1H),7.41-7.32(m,4H),6.87(d,J=8.8Hz,1H),6.22(d,J=8.0Hz,1H),4.43-4.34(m,3H),3.99(s,3H),3.27-3.21(m,2H),2.23-2.21(m,2H),1.67-1.62(m,2H)。
实施例184到203的合成步骤参考实施例183最后一步:其中用不同的酸代替2-氯苯甲酸:
实施例205
2-氯-N-((3S,4S)-3-羟基-1-(5-(7-((1-甲基哌啶-4-基)甲氧基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
第一步
((3S,4S)-3-羟基-1-(5-(7-((1-甲基哌啶-4-基)甲氧基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(46mg,0.10mmol),1-甲基-4-哌啶甲醇(65mg,0.05mmol),溶解在1,4-二氧六环(1.5mL)中,加入三(二亚苄基丙酮)二钯(9.2mg,0.01mmol),碳酸铯(98mg,0.30mmol),反应液用氮气鼓泡十分钟,在氮气保护下110℃微波加热搅拌1小时。加二氯甲烷(20mL)稀释,用饱和食盐水(20mL×2)洗涤。有机相用无水硫酸钠干燥,过滤,滤液减压脱溶。残余物用硅胶柱纯化(二氯甲烷∶甲醇=15∶1)得到目标产物((3S,4S)-3-羟基-1-(5-(7-((1-甲基哌啶-4-基)甲氧基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(8mg,黄色固体),收率20.2%;
MS m/z(ESI):549[M+1];
1H NMR(400MHz,CDCl
3)δ8.95(d,J=2.8Hz,1H),8.50(d,J=2.0Hz,1H),8.41(d,J=8.8Hz,1H),8.34(s,1H),7.91-7.88(m,1H),7.30-7.27(m,1H),7.20(s,1H),6.86(d,J=8.8Hz,1H),4.78-4.48(m, 3H),4.33(d,J=6.0Hz,2H),3.66-3.51(m,4H),3.02-2.89(m,2H),2.76-2.70(m,5H),2.13-2.04(m,4H),1.92-1.84(m,2H),1.47(s,9H);
第二步
(3S,4S)-4-氨基-1-(5-(7-((1-甲基哌啶-4-基)甲氧基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-3-醇
将((3S,4S)-3-羟基-1-(5-(7-((1-甲基哌啶-4-基)甲氧基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(8mg,0.02mmol)溶解在盐酸二氧六环溶液中(1mL,4mmol,4M),室温搅拌1小时。反应液加入三乙胺中和,旋干得到粗产品(3S,4S)-4-氨基-1-(5-(7-((1-甲基哌啶-4-基)甲氧基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-3-醇(10mg,粗品),直接用于下一步,无需纯化。MS m/z(ESI):449[M+1];
第三步
2-氯-N-((3S,4S)-3-羟基-1-(5-(7-((1-甲基哌啶-4-基)甲氧基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
参照实施例183的第三步操作步骤合成得到目标产物2-氯-N-((3S,4S)-3-羟基-1-(5-(7-((1-甲基哌啶-4-基)甲氧基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺;
MS m/z(ESI):587&589[M+1];
1H NMR(400MHz,CD
3OD)δ8.95-8.93(m,1H),8.53-8.49(m,2H),7.97-7.94(m,1H),7.46-7.36(m,5H),7.16(s,1H),7.04(d,J=8.8Hz,1H),4.65-4.58(m,1H),4.42-4.39(m,3H),4.11-4.05(m,1H),3.67-3.62(m,1H),3.54-3.48(m,2H),3.21-3.13(m,1H),3.07-2.97(m,2H),2.86(s,3H),2.17-2.10(m,4H),1.75-1.61(m,4H)。
实施例206到211的合成步骤参考实施例205最后一步:其中用不同的酸代替2-氯苯甲酸:
实施例212
2-氯-N-(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
第一步
(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸乙酯
向无水乙醇(5mL)中加入金属钠(0.23g,10mmol),室温搅拌20分钟,加入(1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(20mg,0.046mmol),升温至80℃反应2小时,大量原料剩余,继续升温至100℃,反应16小时,粗品(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸乙酯反应液直接投料下 一步。MS m/z(ESI):408[M+1];
第二步
(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)胺
向粗品(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸乙酯(粗品,0.046mmol)乙醇(5mL)溶液中加入水(3mL),氢氧化钠(5mg,0.09mmol),升温至120℃反应5小时。反应液旋干,加入乙酸乙酯(50mL),用饱和食盐水(25mL)洗涤,用无水硫酸钠干燥,过滤,滤液浓缩得到(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)胺(粗品,20mg),直接投料下一步。MS m/z(ESI):350[M+1];
第三步
2-氯-N-(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺
将邻氯苯甲酸(18mg,0.12mmol),2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(34mg,0.09mmol),三乙胺(10mg,0.10mmol)溶解在二氯甲烷(5mL)中,加入(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)胺(粗品,20mg,0.06mmol),室温搅拌反应1小时。加入二氯甲烷(20mL)稀释,有机相用饱和食盐水(25mL)洗涤,无水硫酸钠干燥,过滤浓缩,残余物制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O25%-50%)得到目标产物2-氯-N-(1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)苯甲酰胺(2.5mg,黄色固体),三步总收率8.5%;
MS m/z(ESI):488&490[M+1];
1H NMR(400MHz,CDCl
3)δ8.96(s,1H),8.54(d,J=2.0Hz,1H),8.44(d,J=8.4Hz,1H),7.97-7.94(m,1H),7.69-7.67(m,1H),7.40-7.33(m,4H),7.25-7.21(m,1H),6.86(d,J=9.2Hz,1H),6.16(d,J=7.6Hz,1H),4.49-4.39(m,5H),3.27-3.21(m,2H),2.24-2.22(m,2H),1.65-1.62(m,2H),1.27-1.23(m,3H)。
实施例213
2-氯-N-((3S,4S)-1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)-3-羟基哌啶-4-基)苯甲酰胺
第一步
((3S,4S)-1-(5-(7-乙氧基-1,6-二氮杂萘-5-基))吡啶-2-基)-3-羟基哌啶-4-基)胺
向无水乙醇(5mL)中加入金属钠(0.23g,10mmol),室温搅拌20分钟,加入((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基))吡啶-2-基)-3-羟基哌啶-4-基)氨基甲酸叔丁酯(合成参考实施例142的第一步)(20mg,0.046mmol),升温至90℃反应16小时。减压浓缩,残留物中加入乙酸乙酯(20mL)和水(20mL),用乙酸乙酯萃取(20mL×2),用饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,减压脱溶,得到((3S,4S)-1-(5-(7-乙氧基-1,6-二氮杂萘-5-基))吡啶-2-基)-3-羟基哌啶-4-基)胺(crude,20mg),反应液直接投料下一步。MS m/z(ESI):366[M+1];
第二步
2-氯-N-((3S,4S)-1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)-3-羟基哌啶-4-基)苯甲酰胺
将邻氯苯甲酸(10mg,0.055mmol),2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(42mg,0.11mmol),三乙胺(0.1mL)溶解在二氯甲烷(3mL)中,加入((3S,4S)-1-(5-(7-乙氧基-1,6-二氮杂萘-5-基))吡啶-2-基)-3-羟基哌啶-4-基)胺(粗品,20mg),在室温搅拌反应30分钟。加入二氯甲烷(20mL)稀释,用氢氧化锂水溶液(10mL,1M)和饱和食盐水(20mL×2)洗涤。用无水硫酸钠干燥,过滤,减压脱溶,残余物制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O 20%-50%)得到目标产物2-氯-N-((3S,4S)-1-(5-(7-乙氧基-1,6-二氮杂萘-5-基)吡啶-2-基)-3-羟基哌啶-4-基)苯甲酰胺(2.0mg,黄色固体),两步总收率9.9%;
MS m/z(ESI):504&506[M+1];
1H NMR(400MHz,CDCl
3)δ8.95-8.94(m,1H),8.54(d,J=2.0Hz,1H),8.39(d,J=8.8Hz,1H),7.96-7.93(m,1H),7.77-7.75(m,1H),7.43-7.35(m,3H),7.25-7.23(m,1H),6.88(d,J=9.2Hz,1H),6.40(d,J=6.4Hz,1H),4.64-4.61(m,1H),4.56-4.50(m,1H),4.49-4.43(m,2H),4.19-4.15(m,1H),4.06-4.04(m,1H),3.73-3.66(m,1H),3.10-2.99(m,2H),2.23-2.21(m,1H),1.72-1.65(m,1H),1.50-1.45(m,3H)。
实施例214
5-(6-(4-(3-氟苯甲基)哌嗪-1-基)吡啶-3-基)-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘甲酸盐
第一步
4-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-1-哌嗪-1-甲酸叔丁酯
将(1-(5-(4,4,5,5-四甲基-4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)-1-哌嗪-1-基)甲酸叔丁酯(0.17g,0.45mmol),5,7-二氯-1,6-二氮杂萘(60mg,0.3mmol)溶解二氧六环(6mL)中,依次加入四(三苯基膦)钯(35mg,0.03mmol)和碳酸钾(0.12g,0.90mmol),在氮气保护下加热至85℃反应16小时。反应液降至室温后过滤,滤液浓缩后加入二氯甲烷(50mL)稀释,饱和食盐水洗涤(50mL),无水硫酸钠干燥,过滤,减压脱溶,硅胶制备版纯化(石油醚∶乙酸乙酯=1∶1.5)得到目标化合物4-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-1-哌嗪-1-甲酸叔丁酯(110mg,黄色固体),收率86.0%。MS m/z(ESI):427&429[M+1];
1H NMR(400MHz,CDCl
3)δ9.08-9.06(m,1H),8.51-8.48(m,2H),7.98-7.95(m,1H),7.92(s,1H),7.48-7.45(m,1H),6.82(d,J=8.4Hz,1H),3.70-3.68(m,4H),3.60-3.56(m,4H),1.49(s,9H);
第二步
4-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-1-哌嗪-1-甲酸叔丁酯
将4-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-1-哌嗪-1-甲酸叔丁酯(0.11g,0.26mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(0.11g,0.52mmol)溶解N,N-二甲基乙酰胺(4mL)中,依次加入四(三苯基膦)钯(30mg,0.026mmol)和磷酸钾(0.17g,0.78mmol),氮气保护下加热至140℃反应6小时。反应液降至室温后倒入水中(40mL),用乙酸乙酯萃取(50mL×3),有机相合并后用饱和食盐水洗涤(50mL×3),无水硫酸钠干燥,过滤,减压脱溶,硅胶制备版纯化(二氯甲烷∶甲醇=15∶1)得到目标化合物4-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-1-哌嗪-1-甲酸叔丁酯(0.12g,黄色固体),收率97.8%;
MS m/z(ESI):472[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.01(m,1H),8.59(d,J=2.4Hz,1H),8.43-8.41(m,1H),8.12(s,1H),8.07(s,1H),8.00-7.96(m,2H),7.39-7.36(m,1H),6.82(d,J=8.8Hz,1H),3.98(s,3H),3.91-3.68(m,4H),3.61-3.59(m,4H),1.51(s,9H);
第三步
(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基盐酸盐
4-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-1-哌嗪-1-甲酸叔丁酯(0.12g,0.25mmol)溶解在甲醇(5mL)中,加入盐酸二氧六环溶液(5mL,20mmol,4M),在室温反应1.5小时。反应液浓缩后得到目标化合物粗品(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5基)吡啶-2-基)哌啶-4-基)氨基盐酸盐(粗品,黄色固体),直接投下一步。MS m/z(ESI):372[M+1];
第四步
5-(6-(4-(3-氟苯甲基)哌嗪-1-基)吡啶-3-基)-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘甲酸盐
将(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5基)吡啶-2-基)哌啶-4-基)氨基盐酸盐(粗品,0.07mmol)溶解在甲醇(10mL)中,加入三乙胺(10mg,0.10mmol),搅拌10分钟,浓缩后加入甲醇(10mL)溶解,依次加入间氟苯甲醛(16mg,0.11mmol),醋酸硼氢化钠(47mg,0.21mmol),加完后室温反应48小时。反应液浓缩后加入二氯 甲烷(25mL)溶解,饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,减压脱溶,残余物制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O 25%-50%)得到目标产物5-(6-(4-(3-氟苯甲基)哌嗪-1-基)吡啶-3-基)-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘甲酸盐(15mg,黄色固体),收率50.6%;
MS m/z(ESI):480[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.01(m,1H),8.58(d,J=2.0Hz,1H),8.45-8.43(m,1H),8.27(s,1H),8.13(s,1H),8.07(s,1H),7.98-7.96(m,2H),7.41-7.38(m,1H),7.36-7.30(m,1H),7.18-7.13(m,2H),7.04-7.02(m,1H),6.82(d,J=8.8Hz,1H),3.99(s,3H),3.79-3.77(m,4H),3.72(m,2H),2.74(t,J=4.8Hz,4H)。
实施例215到222的合成参照实施例214的合成步骤:
实施例223
2-(5-氟吡啶-2-基)-1-(4-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮
将化合物7-(1-甲基-1H-吡唑-4-基)-5-(6-(哌嗪-1-基)吡啶-3-基)-1,6-二氮杂萘盐酸盐(20mg,0.05mmol)和三乙胺(10mg,0.10mmol)溶于二氯甲烷(2mL)中,并加入2-(5-氟吡啶-2-基)乙酸(8mg,0.05mmol)、2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(23mg,0.06mmol),用10mL水淬灭,分出有机相,水相用二氯甲烷(10mL×2)萃取,合并有机相用饱和食盐水(20mL×2)洗涤。将有机相用无水硫酸钠干燥,过滤除去干燥剂,减压脱溶。残余物由制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O((0.1%TFA)25%-55%)得到目标产物2-(5-氟吡啶-2-基)-1-(4-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(5mg,黄色固体)。产率:19%;
MS m/z(ESI):509[M+1];
1H NMR(400MHz,DMSO-d
6)δ9.06-9.05(m,1H),8.56-8.54(m,1H),8.50-8.49(m,1H),8.45(s,1H),8.43-8.41(m,1H),8.18(s,1H),8.06(s,1H),8.03-8.00(m,1H),7.72-7.67(m,1H),7.56-7.53(m,1H),7.43-7.40(m,1H),7.06(d,J=8.8Hz,1H),3.99(s,2H),3.92(s,3H),3.75-3.58(m,8H)。
实施例224到255的合成步骤参考实施例223合成:其中用不同的酸取代2-(5-氟吡啶-2-基)乙酸:
实施例256
5-(6-(4-(乙基磺酰)哌嗪-1-基)吡啶-3-基)-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘
将化合物7-(1-甲基-1H-吡唑-4-基)-5-(6-(哌嗪-1-基)吡啶-3-基)-1,6-二氮杂萘盐酸盐(合成参考实施例214的第三步)(20mg,0.054mmol)溶解在N,N-二甲基甲酰胺(2mL)中,依次加入三乙胺(16mg,0.162mmol)和乙基磺酰氯(9mg,0.064mmol),加完后在25℃下磁力搅拌15分钟。加水(10mL)淬灭,混合物用二氯甲烷(10mL×2)萃取,合并有机相用饱和食盐水(10mL)洗涤。将有机相用无水硫酸钠干燥,过滤除去干燥剂,减压脱溶。残余物用制备型高效液相色谱纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O(0.5%NH
4OH)15%-35%)得到目标产物5-(6-(4-(乙基磺酰)哌嗪-1-基)吡啶-3-基)-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘(11.4mg,黄色固体),产率:46%;
MS m/z(ESI):464[M+1];
1H NMR(400MHz,CDCl
3)δ9.03-8.99(m,1H),8.60(d,J=2.1Hz,1H),8.42(d,J=8.0Hz,1H),8.13(s,1H),8.07(s,1H),8.00-7.90(m,2H),7.45-7.40(m,1H),6.85(d,J=8.7Hz,1H),3.99(s,3H),3.85-3.74(m,4H),3.50-3.41(m,4H),3.02-2.95(m,2H),1.47-1.40(m,3H)。
实施例257
N-苯甲基-4-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌嗪-1-甲酰胺
将苄胺(11mg,0.10mmol)和三乙胺(25mg,0.25mmol)溶解在二氯甲烷(5mL),加入氯甲酸苯酯(16mg,0.10mmol)室温搅拌10分钟,然后加入7-(1-甲基-1H-吡唑-4-基)-5-(6-(哌嗪-1-基)吡啶-3-基)-1,6-二氮杂萘盐酸盐(合成参考实施例214的第三步)(20mg,0.05mmol)。升温至60℃反应5小时。减压脱溶,残余物溶于乙酸乙酯(20mL),用饱和食盐水洗(20mL),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O(0.5%NH
4OH)15%-35%)得到目标产物N-苯甲基-4-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌嗪-1-甲酰胺(7mg,黄色固体),产率:28.2%;
MS m/z(ESI):505[M+1];
1H NMR(400MHz,CDCl
3)δ9.04-8.97(m,1H),8.57(s,1H),8.42(d,J=8.0Hz,1H),8.11(d,J=12.0Hz,2H),8.01-7.95(m,2H),7.44-7.25(m,6H),6.83(d,J=8.0Hz,1H),4.46(s,2H),3.99(s,3H),3.80-3.72(m,4H),3.63-3.59(m,4H)。
实施例258的合成参照实施例257的操作步骤:
实施例259到283的合成步骤参考实施例223的合成。
实施例284
3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷-6-基)(哌啶-4-基)甲酮盐酸盐
第一步
4-(3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷-6-羰基)哌啶-1-甲酸叔丁酯
将化合物1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-胺(15mg,0.04mmol)溶于二氯甲烷(2mL)中,并加1-(叔丁氧基羰基)哌啶-4-甲酸(12mg,0.05mmol)、2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(19mg,0.05mmol)、N,N-二异丙基乙胺(11mg,0.08mmol),在室温搅拌0.5小时。加二氯甲烷(20mL)稀释,用水(20mL×2)和饱和食盐水(20mL×2)洗。有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残余物由制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,CH
3CN/H
2O((0.1%TFA)15%-30%)得到目标产物4-(3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷-6-羰基)哌啶-1-甲酸叔丁酯(8.6mg,黄色固体)。产率:36%。MS m/z(ESI):595[M+1];
第二步
3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷-6-基)(哌啶-4-基)甲酮盐酸盐
将化合物4-(3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷-6-羰基)哌啶-1-甲酸叔丁酯(8.6mg,0.01mmol)溶于盐酸的1,4-二氧六环溶液(2mL,8.00mmol,4M)中,并在常温下反应1小时。反应液直接浓缩,得到目标产物3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷-6-基)(哌啶-4-基)甲酮盐酸盐(5.4mg,黄色固体)。产率:78%;
MS m/z(ESI):495[M+1];
1H NMR(400MHz,CD
3OD)δ9.38-9.37(m,1H),9.33-9.29(m,1H),8.65-8.52(m,3H),8.31(s,1H),8.21(s,1H),8.12-8.08(m,1H),7.62-7.56(m,1H),4.74-4.68(m,1H),4.27-4.22(m,1H),4.03(s,3H),3.46-3.44(m,2H),3.10-3.04(m,4H),2.71-2.67(m,1H),2.17-2.14(m,4H),1.93-1.89(m,4H);
实施例285的合成参照实施例257的操作步骤:
实施例286
6-(3-氯苯甲基)-3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷
将化合物3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷(粗品,0.17mmol)溶于1,2-二氯乙烷(2mL)中,并加入3-氯苯甲醛(29mg,0.20mmol)和醋酸硼氢化钠(72mg,0.34mmol),在常温下反应8小时。加入饱和氯化铵溶液淬灭反应,分出有机相,水相用二氯甲烷(10mL×2)萃取。合并有机相用饱和食盐水(10mL)洗,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物由制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,CH
3CN/H
2O((0.1%TFA)25%-55%)得到目标产物6-(3-氯苯甲基)-3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷(3mg,黄色固体)。产率:3%;
MS m/z(ESI):508&510[M+1];
1H NMR(400MHz,CD
3OD)δ8.93-8.92(m,1H),8.48-8.47(m,1H),8.24(s,1H),8.09(s,1H),8.01-7.98(m,1H),7.91(s,1H),7.49-7.46(m,1H),7.36(s,1H),7.30-7.19(m,3H),7.05-7.02(m,1H),6.87(d,J=8.8Hz,1H),4.03-3.98(m,1H),3.90(s,3H),3.87-3.84(m,2H),3.72-3.66(m,3H),2.11-2.07(m,1H),1.71-1.69(m,1H),1.52-1.49(m,2H)。
实施例287的合成参照实施例286的操作步骤:
实施例288
2-(5-氟吡啶-2-基)-1-(3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙烷-1-酮
第一步
3-(5-溴吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
将化合物5-溴-2-氟吡啶(4.9g,28.2mmol)、3,8-二氮杂双环[3.2.1]辛烷-8-甲酸酸叔丁酯(2.00g,9.40mmol)和N,N-二异丙基乙胺(3.60g,28.20mmol)加入二甲基亚砜(5mL),升温至100℃反应过夜。冷却至室温,用乙酸乙酯(50mL)稀释,水(50mL×3)和饱和食盐水(50mL)洗。有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱分离纯化(10~20%乙酸乙酯/石油醚)得到目标产物3-(5-溴吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(3.10g,白色固体),产率:89.5%;
MS m/z(ESI):368&370[M+1];
1H NMR(400MHz,CDCl
3)δ8.18(d,J=4.0Hz,1H),7.52(dd,J=8.0,4.0Hz,1H),6.49(d,J=8.0Hz,1H),4.46-4.52(m,2H),3.88-3.58(m,2H),3.26-3.03(m,2H),2.041.76(m,4H),1.45(s,9H);
第二步
3-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛 烷-8-甲酸叔丁酯
将化合物3-(5-溴吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(3.10g,8.40mmol)、联硼酸频那醇酯(3.20g,12.60mmol)、醋酸钾(1.70g,16.80mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(0.61g,0.80mmol)加入二氧六环(30mL),抽真空氮气置换三次,升温至90℃反应4小时。冷却至室温后加入5,7-二氯-1,6-二氮杂萘(1.70g,8.40mmol)、四(三苯基膦)钯(0.97g,0.80mmol)、无水碳酸钾(2.30g,16.60mmol)和水(6mL),升温至85℃氮气氛围下反应过夜。减压浓缩,将残余物溶于乙酸乙酯(100mL)后水(100mL)和饱和食盐水(100mL)洗。有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残余物用硅胶柱分离纯化(20~70%乙酸乙酯/石油醚)得到目标产物3-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1.90g,黄色固体)。产率:49.8%;
MS m/z(ESI):452&454[M+1];
1H NMR(400MHz,CDCl
3)δ9.08(d,J=4.0Hz,1H),8.56-8.46(m,2H),7.93(s,1H),7.72-7.63(m,1H),7.59-7.52(m,1H),6.84-6.76(m,1H)4.45-4.42(m,2H),4.23-3.96(m,2H),3.27(s,2H),2.00-1.98(m,2H),1.85-1.75(m,2H),1.50(s,9H);
第三步
3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯
将化合物3-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1.90g,4.20mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(1.70g,8.40mmol)、磷酸钾(1.80g,8.40mmol)和四三苯基膦钯(0.49g,0.40mmol)加入N,N-二甲酰基乙酰胺(8mL)与水(2mL)的混合溶液,抽真空氮气置换三次,升温至140℃反应4小时。冷却至室温后,反应液用乙酸乙酯(100mL)稀释,然后饱和食盐水洗(80mL×3)。有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残余物用硅胶柱分离纯化(20~100%乙酸乙酯/石油醚)得到目标产物3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1.40g,黄色固体)。产率:66.8%;
MS m/z(ESI):498[M+1];
1H NMR(400MHz,CDCl
3)δ9.05-9.00(m,1H),8.62-8.58(m,1H),8.12(s,1H),8.08(s,1H),8.00(s,1H),7.72-7.63(m,1H),7.59-7.52(m,2H),6.84-6.76(m,1H),4.44(s,2H),4.28-4.06(m,2H),3.99(s,3H),3.27(s,2H),2.04-1.98(m,2H),1.86-1.78(m,2H),1.50(s,9H);
第四步
5-(6-(3,8-二氮杂双环[3.2.1]辛-3-基)吡啶-3-基)-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘盐酸盐
将化合物3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1.40g,2.80mmol)溶于氯化氢的1,4-二氧六环溶液(5mL,20.00mmol,4M),室温搅拌1小时。减压浓缩得5-(6-(3,8-二氮杂双环[3.2.1]辛-3-基)吡啶-3-基)-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘盐酸盐(1.20g,黄色固体),粗品。MS m/z(ESI):398[M+1];
第五步
2-(5-氟吡啶-2-基)-1-(3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙烷-1-酮
将化合物5-(6-(3,8-二氮杂二环[3.2.1]辛烷-3-基)吡啶-3-基)-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘盐酸盐(17mg,0.04mmol)溶于二氯甲烷(2mL)中,并加2-(5-氟吡啶-2-基)乙酸(8mg,0.05mmol)、2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(19mg,0.05mmol)、N,N-二异丙基乙胺(11mg,0.08mmol),室温搅拌0.5小时。加二氯甲烷(20mL)稀释,饱和食盐水(20mL×2)洗,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残余物由制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,CH
3CN/H2O((0.1%TFA)20%-40%)得到目标产物2-(5-氟吡啶-2-基)-1-(3-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙烷-1-酮(6mg,黄色固体)。产率:28%;
MS m/z(ESI):535[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.01(m,1H),8.58-8.57(m,1H),8.42-8.40(m,2H),8.12(s,1H),8.06(s,1H),7.96-7.94(m,2H),7.47-7.35(m,3H),6.76(d,J=8.4Hz,1H),4.90(s,1H),4.67(s,1H), 4.25-4.22(m,1H),4.05-3.90(m,3H),3.99(s,3H),3.21-3.18(m,1H),3.01-2.98(m,1H),1.96-1.81(m,4H)。
实施例289到320的合成步骤参考实施例288合成:其中用不同的酸取代2-(5-氟吡啶-2-基)乙酸:
实施例321到322的合成步骤参考实施例286合成。
实施例323到324的合成步骤参考实施例288合成。
实施例325到365的合成步骤参考实施例183合成。
实施例366
3-氯-N-(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)-2-氨基甲酰基吡啶
第一步
(4-(羟甲基)-1-(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将(1-(5-溴-2-基)-4-(羟甲基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(合成参考实施例44的第二步)(1.00g,2.6mmol)和联硼酸频那醇酯(0.99g,3.9mmol)溶解在二氧六环(30mL)中,依次加入双(三苯基膦)二氯化钯(0.19g,0.26mmol),醋酸钾(0.51g,5.2mmol),氮气保护下加热至90℃反应8小时。反应液降至室温后,粗品的二氧六环溶液直接投料下一步。MS m/z(ESI):434[M+1];
第二步
(1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯
向(4-(羟甲基)-1-(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(1.14g,2.6mmol)的二氧六环(30mL)溶液中,依次加入5,7-二氯-1,6-二氮杂萘(0.52g,2.6mmol),四(三苯基膦)钯(0.30g,0.26mmol),碳酸钾(0.90g,6.5mmol)和水(6mL)。氮气保护下加热至85℃反应16小时。反应液降至室温后加入乙酸乙酯(50mL)和水(20mL)稀释,分离有机相,水相用乙酸乙酯萃取(50mL×2)。合并有机相用饱和食盐水洗涤(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩。残余物用柱层析纯化(乙酸乙酯)得到目标化合物(1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯(0.65g,黄色固体),收率53.2%。MS m/z(ESI):470&472[M+1];
第三步
(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将(1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(羟甲基)哌啶-4-基)氨基甲酸叔丁酯(0.65g,1.39mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(0.58g,2.8mmol)溶解N,N-二甲基乙酰胺(10mL)中,依次加入四(三苯基膦)钯(0.16g,0.14mmol),磷酸钾(0.89g,4.17mmol)和水(2mL)。在氮气保护下加热至140℃反应4小时。反应液降至室温后倒入水中(50mL),用乙酸乙酯(50mL×3)萃取。有机相合并后用饱和食盐水洗涤(50mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩。残余物用柱层析纯化(石油醚∶乙酸乙酯=1∶3)得到目标化合物(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(0.42g,白色固体),收率58.8%;
MS m/z(ESI):516[M+1];
1H NMR(400MHz,CDCl
3)δ8.98-8.97(m,1H),8.56(d,J=2.4Hz,1H),8.41(d,J=8.0Hz,1H),8.12(s,1H),8.09(s,1H),7.93-7.92(m,2H),7.37-7.33(m,1H),6.83(d,J=8.8Hz,1H),4.98(s,1H),4.06-4.01(m,2H),3.97(s,3H),3.77(s,2H),3.40-3.35(m,2H),2.14-2.10(m,2H),1.83-1.76(m,2H),1.45(s,9H);
第四步
4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-胺
(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(0.28g,0.54mmol)溶解在甲醇(3mL)中,加入盐酸二氧六环溶液(3mL,12.00mmol,4M),在室温下反应3小时。反应液浓缩,加入二氯甲烷(15mL),三乙胺调节pH至8-9,再次浓缩得到目标化合物粗品4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-胺(粗品,0.45g,黄色固体),直接投下一步。MS m/z(ESI):416[M+1];
第五步
3-氯-N-(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)-2-氨基甲酰基吡啶
将3-氯邻吡啶甲酸(10mg,0.06mmol),2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(27mg,0.072mmol),三乙胺(20mg,0.20mmol)溶解在N,N-二甲基甲酰胺(4mL)中,室温搅拌10分钟,加入4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-胺(粗品,80mg,0.096mmol),室温搅拌反应2小时。反应液浓缩,加入二氯甲烷(20mL),依次用1M氢氧化钠溶液(5mL,5mmol)和饱和食盐水(25mL)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残余物用高效液相色谱制备提纯得到目标化合物3-氯-N-(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)-2-氨基甲酰基吡啶(28mg,黄色固体),收率52.6%;
MS m/z(ESI):555[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.01(m,1H),8.59(d,J=2.4Hz,1H),8.47-8.44(m,2H),8.17(s,1H),8.12(s,1H),8.08(s,1H),7.99-7.96(m,2H),7.86-7.83(m,1H),7.42-7.38(m,2H),6.88(d,J=8.8Hz,1H),4.16-4.12(m,2H),3.99(s,3H),3.94(s,2H),3.51-3.46(m,2H),2.35-2.31(m,2H),1.95-1.89(m,2H)。
实施例367到371的合成步骤参考实施例366合成。
实施例372的合成参照实施例44的操作步骤。
实施例373
3-氟-N-(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-基)-2-氨基甲酰基吡啶
第一步
(6-(4-((叔丁氧基羰基)氨基)-4-(甲氧羰基)哌啶-1-基)吡啶-3-基)硼酸
将化合物1-(5-溴吡啶-2-基)-4-((叔丁氧基羰基)氨基)哌啶-4-羧酸甲酯(合成参考实施例44的第一步)(4.60g,11.14mmol)加入到1,4-二氧六环(50mL)中,分批加入联硼酸频那醇酯(4.24g,16.71mmol),[1,1′-双(二苯基膦)二茂铁]二氯化钯(1.22g,1.67mmol)和乙酸钾(3.27g,33.41mmol)。加完后置换氩气三次,在90℃下磁力搅拌并冷凝回流3小时。冷却至室温,减压脱溶得到目标产物(6-(4-((叔-丁氧基羰基)氨基)-4-(甲氧羰基)哌啶-1-基)吡啶-3-基)硼酸(粗品),此混合物不经纯化直接用于下一步反应。MS m/z(ESI):380[M+1];
第二步
4-((叔丁氧基羰基)氨基)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-羧酸甲酯
将化合物(6-(4-((叔-丁氧基羰基)氨基)-4-(甲氧羰基)哌啶-1-基)吡 啶-3-基)硼酸(粗品,11.14mmol),5,7-二氯-1,6-二氮杂萘(2.65g,13.37mmol),四(三苯基膦)钯(1.92g,1.67mmol),无水碳酸钾(3.07g,22.28mmol),1,4-二氧六环(50mL)和水(5mL)混合加入到250mL单口瓶中,置换氩气三次,在120℃下磁力搅拌并冷凝回流16小时。冷却至室温后,加入100mL水淬灭,用乙酸乙酯(100mL×3)萃取,合并有机相并用饱和食盐水(100mL×2)洗,无水硫酸钠干燥,过滤除去干燥剂,滤液减压脱溶,残余物通过色谱硅胶柱纯化(石油醚/乙酸乙酯=100∶1~7∶3)得到目标产物4-((叔丁氧基羰基)氨基)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-羧酸甲酯(3.20g,黄色油状)。产率:58%;
MS m/z(ESI):498&500[M+1];
1H NMR(400MHz,CDCl
3)δ9.08-9.06(m,1H),8.53-8.47(m,2H),7.95(m,1H),7.91(s,1H),7.18(s,1H),6.84(d,J=8.9Hz,1H),4.85(s,1H),4.14-4.12(m,4H),3.76(s,3H),3.44-3.42(m,2H),2.21-3.19(m,2H),1.46(s,9H);
第三步
4-((叔丁氧基羰基)氨基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-羧酸甲酯
将化合物4-((叔-丁氧基羰基)氨基)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-羧酸甲酯(3.20g,6.43mmol),1-甲基-4-吡唑硼酸频那醇酯(1.6g,7.71mmol),四(三苯基膦)钯(1.11g,0.96mmol),无水碳酸钾(1.77g,12.85mmol),N,N-二甲基乙酰胺(50mL)混合加入到250mL单口瓶中,置换氩气三次,在120℃下磁力搅拌并冷凝回流8小时。冷却至室温后,加入100mL水淬灭,用乙酸乙酯(100mL×3)萃取,合并有机相并用饱和食盐水(100mL×2)洗,无水硫酸钠干燥,过滤除去干燥剂,滤液减压脱溶,残余物通过色谱硅胶柱纯化(二氯甲烷/甲醇=100∶1~9∶1)得到目标产物4-((叔丁氧基羰基)氨基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-羧酸甲酯(2.77g,黄色油状)。产率:79%;
MS m/z(ESI):544[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.00(m,1H),8.58(d,J=2.3Hz,1H),8.43(d,J=8.5Hz,1H),8.12(s,1H),8.08(s,1H),7.98-7.96(m, 2H),7.38-7.36(m,1H),6.86(d,J=8.8Hz,1H),4.91(s,1H),4.18-4.09(m,2H),3.99(s,3H),3.76(s,3H),3.55-3.34(m,4H),2.26-2.18(m,2H),1.46(s,9H);
第四步
(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将化合物4-((叔丁氧基羰基)氨基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-羧酸甲酯(1.00g,1.842mmol)加入到四氢呋喃(10mL)中,然后0℃下分批缓慢加入四氢铝锂(70mg,1.841mmol),在0℃下磁力搅拌0.5小时后。加入水(30mL)淬灭,用乙酸乙酯(30mL×3)萃取,合并有机相并用饱和食盐水(100mL×2)洗,无水硫酸钠干燥,过滤除去干燥剂。滤液减压脱溶,残余物通过色谱硅胶柱纯化(二氯甲烷/甲醇=100∶1~9∶1)得到目标产物(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(0.70g,黄色固体)。产率:74%;
MS m/z(ESI):516[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.00(m,1H),8.59(d,J=2.2Hz,1H),8.43(d,J=8.4Hz,1H),8.16-8.05(m,2H),8.00-7.87(m,2H),7.39-7.32(m,1H),6.86(d,J=8.8Hz,1H),4.68(s,1H),4.03-4.01(m,2H),3.99(s,3H),3.78(s,2H),3.49-3.36(m,2H),2.12-1.99(m,2H),1.86-1.75(m,2H),1.46(s,9H);
第五步
(4-甲酰基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将化合物(4-(羟甲基)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(0.70g,1.359mmol)加入到二氯甲烷(10mL)中,然后加入戴斯马丁氧化剂(69mg,1.631mmol),在室温下下磁力搅拌1小时后。加入饱和亚硫酸钠水溶液(15mL)淬灭,再向其中加入碳酸氢钠饱和水溶液(35mL),用乙酸乙酯(50mL×3)萃取。合并有机相并用饱和食盐水(100mL×2)洗,无水硫酸钠干燥,过滤除去干燥剂,滤液减压脱溶得到目标产物(4- 甲酰基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(0.60g,黄色油状)。产率:86%;
MS m/z(ESI):514[M+1];
1H NMR(400MHz,CDCl
3)δ9.56(s,1H),9.03-8.98(m,1H),8.59-8.57(m,1H),8.43(d,J=8.4Hz,1H),8.11-8.09(m,2H),8.00-7.95(m,2H),7.39-7.33(m,1H),6.86(d,J=8.9Hz,1H),4.66(s,1H),4.20-4.06(m,2H),3.99(s,3H),3.21-3.18(m,2H),2.14-2.02(m,2H),1.97-1.85(m,2H),1.43(s,9H);
第六步
(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-基)氨基甲酸叔丁酯
将化合物(4-甲酰基-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(0.12g,1.167mmol)溶解在1,2-二氯乙烷(10mL)中,依次加入吗啡啉(0.15g,1.400mmol),氯化锌(0.79g,5.835mmol)和氰基硼氢化钠(0.15g,2.334mmol),室温下搅拌3小时。加水(30mL)淬灭,用二氯甲烷(30mL×3)萃取,合并有机相并用饱和食盐水(100mL×2)洗,无水硫酸钠干燥,过滤除去干燥剂。滤液减压脱溶,残余物通过色谱硅胶柱纯化(二氯甲烷/甲醇=100∶1~9∶1)得到目标产物(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-基)氨基甲酸叔丁酯(0.30g,黄色油状)。产率:44%;
MS m/z(ESI):585[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.00(m,1H),8.58(d,J=2.2Hz,1H),8.44(d,J=8.0Hz,1H),8.11-8.09(m,2H),7.99-7.92(m,2H),7.39-7.27(m,1H),6.84(d,J=8.8Hz,1H),4.61(s,1H),4.13-4.11(m,4H),3.99(s,3H),3.70-3.68(m,4H),3.25-3.23(m,,4H),2.86-2.84(m,2H),2.60-2.55(m,4H),1.45(s,9H);
第七步
1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-胺盐酸盐
将化合物(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-基)氨基甲酸叔丁酯(15mg,0.03mmol) 溶于二氯甲烷(1mL)和甲醇(0.5mL)中,室温下加入盐酸二氧六环(1mL,4.00mmol,4M),在25℃下搅拌反应30分钟。反应液减压脱溶得到粗品1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-胺盐酸盐,直接进行下一步反应。MS m/z(ESI):485[M+1];
第八步
3-氟-N-(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-基)-2-氨基甲酰基吡啶
将化合物1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-胺盐酸盐(粗品,0.03mmol),3-氟吡啶-2-羧酸(7mg,0.036mmol)和三乙胺(10mg,0.09mmol)溶于N,N-二甲基甲酰胺(2mL)中,室温加入2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(18mg,0.045mmol),在25℃下磁力搅拌1小时。加水(20mL)淬灭,用二氯甲烷(30mL×3)萃取。合并有机相用饱和食盐水(30mL)洗,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物经过制备型高效液相色谱制备得到目标产物3-氟-N-(1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-((吗啉-4-基)甲基)哌啶-4-基)-2-氨基甲酰基吡啶(6.8mg,黄色固体)。产率:38%;
MS m/z(ESI):608[M+1];
1H NMR(400MHz,CDCl
3)δ9.03-9.01(m,1H),8.59(d,J=2.2Hz,1H),8.47-8.39(m,2H),8.14-8.05(m,2H),7.96(s,2H),7.61-7.55(m,1H),7.52(s,1H),7.39-7.37(m,1H),6.87(d,J=8.8Hz,1H),4.29(s,2H),3.99(s,3H),3.78-3.76(m,4H),3.32-3.30(m,2H),3.12-3.10(m,2H),2.85-2.83(m,4H),2.64-2.62(m,2H),1.84-1.82(m,2H)。
实施例374到412的合成步骤参考实施例373的合成。
实施例446
7-(1-甲基-1H-吡唑-4-基)-5-(6-(4-(甲砜基)哌啶-1-基)吡啶-3- 基)-1,6-二氮杂萘
第一步
5-溴-2-(4-(甲砜基)哌啶-1-基)吡啶
将化合物5-溴-2-氟吡啶(0.89g,5.06mmol)、4-(甲砜基)哌啶(0.75g,4.60mmol)、碳酸钾(1.27g,9.20mmol)溶于二甲基亚砜(10mL)中,在80℃下反应8小时,将反应液倒入水(50mL)中并用乙酸乙酯(30mL×3)萃取。合并有机相用水(50mL×3)和饱和食盐水(50mL×3)洗,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过色谱硅胶柱纯化(石油醚/乙酸乙酯=100∶1~3∶1)得到目标产物5-溴-2-(4-(甲砜基)哌啶-1-基)吡啶(0.62g,黄色固体)。产率:42%;
MS m/z(ESI):319&321[M+1];
1H NMR(400MHz,CDCl
3)δ8.19(d,J=2.4Hz,1H),7.56-7.53(m,1H),6.59(d,J=9.0Hz,1H),4.46-4.44(m,2H),3.12-3.02(m,1H),2.93-2.86(m,2H),2.85(s,3H),2.24-2.20(m,2H),1.90-1.79(m,2H);
第二步
(6-(4-(甲砜基)哌啶-1-基)吡啶-3-基)硼酸
将化合物5-溴-2-(4-(甲砜基)哌啶-1-基)吡啶(0.62g,1.94mmol),联硼酸频那醇酯(0.99g,3.89mmol),醋酸钾(0.38g,3.88mmol),[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(15mg,0.02mmol)和1,4-二氧六环(20mL)加入到一个100mL的单口瓶中,加完后用氩气置换三次气体并让该反应在90℃下反应4小时。由此得到的目标产物(6-(4-(甲砜基)哌啶-1-基)吡啶-3-基)硼酸粗品(1.94mmol)反应液直接用于下一步无需后处理。MS m/z(ESI):285[M+1];
第三步
7-氯-5-(6-(4-(甲砜基)哌啶-1-基)吡啶-3-基)-1,6-二氮杂萘
将化合物(6-(4-(甲砜基)哌啶-1-基)吡啶-3-基)硼酸(粗品,1.94mmol)反应液,5,7-二氯-1,6-二氮杂萘(0.42g,2.13mmol)、碳酸钾(0.53g,3.88mmol),四(三苯基膦)钯(23mg,0.02mmol)和水(4mL)加入到一个100mL的单口瓶中,加完后用氩气置换三次气体并让该反应在100℃下反应6小时。冷却至室温,加水(50mL)稀释,用乙酸乙酯(50mL×3)萃取。合并有机相并用食盐水(50mL×2)洗,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过色谱硅胶柱纯化(二氯甲烷/甲醇=100∶1~25∶1)得到目标产物7-氯-5-(6-(4-(甲砜基)哌啶-1-基)吡啶-3-基)-1,6-二氮杂萘(0.40g,黄色固体)。产率:51%。MS m/z(ESI):403&405[M+1];
第四步
7-(1-甲基-1H-吡唑-4-基)-5-(6-(4-(甲砜基)哌啶-1-基)吡啶-3-基)-1,6-二氮杂萘
将化合物7-氯-5-(6-(4-(甲砜基)哌啶-1-基)吡啶-3-基)-1,6-二氮杂萘(20mg,0.05mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(13mg,0.06mmol)、磷酸钾(22mg,0.10mmol),四(三苯基膦)钯(12mg,0.01mmol)和N,N-二甲基乙酰胺(10mL)/水(2mL)混合,用氩气置换三次并让该反应在120℃下反应2小时。加水(50mL)稀释,用乙酸乙酯(50mL×3)萃取。有机相用水(50mL×3)和饱和食盐水(50mL×3)洗,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物由制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O((0.1%TFA)15%-40%)得到目标产物7-(1-甲基-1H-吡唑-4-基)-5-(6-(4-(甲砜基)哌啶-1-基)吡啶-3-基)-1,6-二氮杂萘(6.80mg,黄色固体)。产率:31%;
MS m/z(ESI):449[M+1];
1H NMR(400MHz,CDCl
3)δ9.02-9.01(m,1H),8.59-8.58(m,1H),8.43(d,J=8.4Hz,1H),8.12(s,1H),8.08(s,1H),7.99-7.97(m,1H),7.97(s,1H),7.40-7.37(m,1H),6.87(d,J=8.8Hz,1H),4.69-4.67(m,2H),3.99(s,3H),3.21-3.13(m,1H),3.07-3.00(m,2H),2.89(s,3H),2.29-2.26(m,2H),1.98-1.90(m,2H)。
实施例447到448的合成步骤参考实施例446的合成。
实施例449
(3S,4S)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶-2-氧基)吡咯烷-3-胺
第一步
(3S,4S)-3-(1,3-二氧代异吲哚啉-2-基)-4-羟基吡咯烷-1-甲酸叔丁酯
将(3S,4S)-3-氨基-4-羟基吡咯烷-1-甲酸叔丁酯(0.25g,1.20mmol)、邻苯二甲酸酐(0.18g,1.20mmol)、三乙胺(0.36g,3.60mmol)和N,N-4-二甲氨基吡啶(12mg,0.10mmol)加入四氢呋喃(10mL),升温至70℃反应过夜。减压浓缩,将残余物溶于乙酸乙酯(50mL),用饱和食盐水洗(50mL),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残余物用硅胶柱纯化(30-50%乙酸乙酯/石油醚)得到目标产物(3S,4S)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶-2-氧基)吡咯烷-3-胺(0.15g,黄色固体)。产率:36.5%;
MS m/z(ESI):355[M+23];
1H NMR(400MHz,CDCl
3)δ7.88-7.83(m,2H),7.78-7.72(m,2H),5.08-4.94(m,1.5H),4.66-4.56(m,1.5H),4.02-3.80(m,3H),2.23-2.21(m,1H),1.47(s,9H);
第二步
2-(((3S,4S)-1-(叔丁氧基羰基)-4-(吡啶-2-基氧基)吡咯烷-3-基)氨基甲酰基)苯甲酸
将(3S,4S)-3-氨基-4-羟基吡咯烷-1-甲酸叔丁酯(0.15g,0.45mmol)溶于无水N,N-二甲基乙酰胺(2mL),加入钠氢(60%分散在矿物油中,54mg,1.35mmol)。室温下搅拌半小时,然后加入2-氟吡啶(0.13g,1.35mmol),升温至80℃反应4小时。冷却至室温后,将反应也倒入水中(20mL),水相用乙酸乙酯萃取(15mL×3)。有机相合并后用饱和食盐水(30mL×2)洗,无水硫酸钠干燥,过滤,滤液减压浓缩得到目标产物2-(((3S,4S)-1-(叔丁氧基羰基)-4-(吡啶-2-基氧基)吡咯烷-3-基)氨基甲酰基)苯甲酸(0.20g,黑色油状物)。粗品。MS m/z(ESI):428[M+1];
第三步
2-((3S,4S)-4-(吡啶-2-基氧基)吡咯烷-3-基)异二氢吲哚-1,3-二酮盐酸盐
将2-(((3S,4S)-1-(叔丁氧基羰基)-4-(吡啶-2-基氧基)吡咯烷-3-基)氨基甲酰基)苯甲酸(0.20g,0.45mmol)溶于氯化氢的甲醇溶液(5mL,20.00mmol,4M),室温下搅拌1小时。减压浓缩到目标产物2-((3S,4S)-4-(吡啶-2-基氧基)吡咯烷-3-基)异二氢吲哚-1,3-二酮盐酸盐(粗品,0.45mmol)。粗品。MS m/z(ESI):310[M+1];
第四步
2-((3S,4S)-1-(5-溴吡啶-2-基)-4-(吡啶-2-基氧基)吡咯烷-3-基)异二氢吲哚-1,3-二酮
将2-((3S,4S)-4-(吡啶-2-基氧基)吡咯烷-3-基)异二氢吲哚-1,3-二酮盐酸盐(粗品,0.45mmol)、5-溴-2-氟吡啶(0.24g,1.35mmol)和N,N-二异丙基乙胺(0.35g,2.70mmol)溶于二甲基亚砜(1mL),升温至100℃搅拌过夜。冷却至室温后将反应液倒入水中(20mL),水相用乙酸乙酯萃取(20mL×2)。有机相合并用水(30mL×2)和饱和食盐水(30mL×2)洗,无水硫酸钠干燥,过滤,滤液减压 脱溶。残余物硅胶柱分离纯化到目标产物2-((3S,4S)-1-(5-溴吡啶-2-基)-4-(吡啶-2-基氧基)吡咯烷-3-基)异二氢吲哚-1,3-二酮(65mg,白色固体)。产率:31.1%;
MS m/z(ESI):465&467[M+1];
1H NMR(400MHz,CDCl
3)δ8.24-8.14(m,1H),7.90-7.68(m,4H),7.62-7.46(m,2H),6.85-6.68(m,2H),6.40-6.30(m,1H),6.19-6.08(m,1H),5.22-5.12(m,1H),4.38-4.28(m,1H),4.14-3.84(m,2H),3.69-3.58(m,1H),3.52-3.41(m,1H);
第五步
2-(((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶-2-氧基)吡咯烷-3-基)氨基甲酰)苯甲酸
将化合物2-((3S,4S)-1-(5-溴吡啶-2-基)-4-(吡啶-2-基氧基)吡咯烷-3-基)异二氢吲哚-1,3-二酮(65mg,0.14mmol),联硼酸频那醇酯(53mg,0.21mmol),醋酸钾(28mg,0.28mmol),1,1′-双二苯基膦基二茂铁二氯化钯(7mg,0.10mmol)加入二氧六环(5mL),抽真空氮气置换三次,升温至90℃反应4小时。冷却至室温后加入5,7-二氯-1,6-二氮杂萘(28mg,0.14mmol)、四三苯基膦钯(12mg,0.01mmol)、无水碳酸钾(38mg,0.28mmol)和水(1mL)。升温至85℃在氮气氛围下反应过夜。冷却至室温后减压浓缩得到产物2-(((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶-2-氧基)吡咯烷-3-基)氨基甲酰)苯甲酸(0.20g)。粗产物。MS m/z(ESI):567&569[M+1];
第六步
2-(((3S,4S)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶-2-基氧基)吡咯烷-3-基)氨基甲酰基)苯甲酸
将化合物2-(((3S,4S)-1-(5-(7-氯-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶-2-氧基)吡咯烷-3-基)氨基甲酰)苯甲酸(0.20g,0.14mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(58mg,0.28mmol)、磷酸钾(59mg,0.28mmol)和四(三苯基膦)钯(12mg,0.01mmol)加入N,N-二甲酰基乙酰胺/水(4/1,2.5mL)的混合溶液,抽真空氮气置换三次,升温至140℃反应4小时。冷却至室温后,将反应液倒入水中(20mL)稀释,水相用二氯甲烷洗涤(20mL×2)。然后所得的水相减压浓缩得到产物2-(((3S,4S)-1-(5-(7-(1-甲基-1H-吡唑 -4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶-2-基氧基)吡咯烷-3-基)氨基甲酰基)苯甲酸(0.23g,黑色油状物)。粗品;MS m/z(ESI):613[M+1];
第七步
(3S,4S)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶吡啶-2-基氧基)吡咯烷-3-胺
将化合物2-(((3S,4S)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶-2-基氧基)吡咯烷-3-基)氨基甲酰基)苯甲酸(0.23g,0.14mmol)溶于盐酸水溶液(6mL,18.00mmol,3M),升温至50℃搅拌3小时。减压浓缩,残余物通过制备液相纯化(Agilent ZORBAX XDB-C18,4.6×50mm,3.5μm,ACN/H
2O(0.5%HCOOH)25%-40%)得(3S,4S)-1-(5-(7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-5-基)吡啶-2-基)-4-(吡啶吡啶-2-基氧基)吡咯烷-3-胺盐酸盐(1.8mg,黄色固体),产率:2.77%;
MS m/z(ESI):465[M+1];
1H NMR(400MHz,CDCl
3)δ9.04-8.98(m,1H),8.60-8.56(m,1H),8.44(d,J=8.0Hz,1H),8.20-8.16(m,1H),8.12(s,1H),8.07(s,1H),8.00-7.89(m,2H),7.63-7.56(m,1H),7.42-7.33(m,1H),6.94-6.88(m,1H),6.76(d,J=8.0Hz,1H),6.59(d,J=8.0Hz,1H),5.42-4.35(m,1H),4.24-4.14(m,1H),4.05-3.85(m,5H),3.77-3.69(m,1H),3.58-3.52(m,1H)。
实施例450到451的合成步骤参考实施例449的合成:
实施例461的合成参考实施例223合成步骤。
生物学实验
RET激酶的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对RET激酶活性的影响
实验方法概述如下:
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio,货号62TK0PEC),通过检测激酶反应中底物的磷酸化水平来测定RET激酶的体外活性。反应缓冲液包含以下组分:试剂盒自带酶反应缓冲液(1×)、5mM MgCl
2、1mM DTT;人源重组RET蛋白(货号11997) 购自义翘神州,用反应缓冲液稀释成0.1ng/μl的激酶溶液;底物反应溶液包括用反应缓冲液稀释成0.66μM生物素标记的酪氨酸激酶底物和12μM ATP;检测缓冲液包括用反应缓冲液稀释成0.1ng/μl Eu3+标记的笼状抗体-和41.25nM链霉亲和素标记的XL665。
将化合物在100%DMSO中溶解稀释至25μM,然后用DMSO进行4倍的系列稀释至最低浓度为1.5nM,每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning,货号4512)中添加4μL化合物溶液和2μL RET激酶溶液,混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液,将反应混合物在室温孵育60分钟。随后加入与反应等体积的10μL检测缓冲液,混合均匀并在室温条件下静置30分钟后,用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。665/620的比值与底物的磷酸化程度呈正相关性,从而检测出RET激酶的活性。该实验中,未加RET激酶蛋白组作为100%抑制,加RET激酶蛋白但是未加化合物组作为0%抑制。化合物对RET激酶活性抑制百分比可以用以下公式计算:
化合物IC
50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算:
Y=Bottom+(Top-Bottom)/(1+10^((logIC
50-X)*slope factor))
其中Y为抑制百分比,X为待测化合物浓度的对数值,Bottom为最大抑制百分比,Top为最小抑制百分比,slope factor为曲线斜率系数。
RET M918T的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对RET M918T活性的影响
实验方法概述如下:
使用HTRF激酶检测试剂盒(Cisbio,货号62TK0PEC),通过检测激酶反应中底物的磷酸化水平来测定RET M918T的体外活性。反应缓冲液包含以下组分:试剂盒自带酶反应缓冲液(1×)、5mM MgCl
2、1mM DTT;人源重组RET M918T蛋白(货号PV6217)购自Thermo Fish公司,用反应缓冲液稀释成0.35ng/μl的激酶溶液;底物反应溶液包括用反应缓冲液稀释成0.9μM生物素标记的酪氨酸激酶底物和18μM ATP;检测缓冲液包括用反应缓冲液稀释成0.1ng/μl Eu
3+标记的笼状 抗体和56.25nM链霉亲和素标记的XL665。
将化合物在100%DMSO中溶解稀释至10μM,然后用DMSO进行4倍的系列稀释至最低浓度为0.61nM,每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning,货号4512)中添加4μL化合物溶液和2μL RET M918T激酶溶液,混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液,将反应混合物在室温孵育40分钟。随后加入与反应等体积的10μL检测缓冲液,混合均匀并在室温条件下静置30分钟后,用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。665/620的比值与底物的磷酸化程度呈正相关性,从而检测出RET M918T激酶的活性。该实验中,未加RET M918T激酶蛋白组作为100%抑制,加RET M918T激酶蛋白但是未加化合物组作为0%抑制。化合物对RET M918T活性抑制百分比可以用以下公式计算:
抑制百分比=100-100*(待测化合物特定浓度下信号值-阴性对照信号值)/(阳性对照信号值-阴性对照信号值)。
化合物IC
50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算:
Y=Bottom+(Top-Bottom)/(1+10^((logIC
50-X)*slope factor))
其中Y为抑制百分比,X为待测化合物浓度的对数值,Bottom为最大抑制百分比,Top为最小抑制百分比,slope factor为曲线斜率系数。
RET V804M的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对RET V804M活性的影响
实验方法概述如下:
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio,货号62TK0PEC),通过检测激酶反应中底物的磷酸化水平来测定RET V804M的体外活性。反应缓冲液包含以下组分:试剂盒自带酶反应缓冲液(1×)、5mM MgCl
2、1mM DTT和0.08%Tween-20;人源重组RET V804M蛋白(货号PV6223)购自Thermo Fish,用反应缓冲液稀释成0.15ng/μl的激酶溶液;底物反应溶液包括用反应缓冲液稀释成0.9μM生物素标记的酪氨酸激酶底物和8μM ATP;检测缓冲液包括 用反应缓冲液稀释成0.1ng/μl Eu
3+标记的笼状抗体和56.25nM链霉亲和素标记的XL665。
将化合物在100%DMSO中溶解稀释至25μM,然后用DMSO进行4倍的系列稀释至最低浓度为1.5nM,每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning,货号4512)中添加4μL化合物溶液和2μL RET V804M激酶溶液,混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液,将反应混合物在室温孵育30分钟。随后加入与反应等体积的10μL检测缓冲液,混合均匀并在室温条件下静置30分钟后,用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。665/620的比值与底物的磷酸化程度呈正相关性,从而检测出RET V804M激酶的活性。该实验中,未加RET V804M激酶蛋白组作为100%抑制,加RET V804M激酶蛋白但是未加化合物组作为0%抑制。化合物对RET V804M活性抑制百分比可以用以下公式计算:
抑制百分比=100-100*(待测化合物特定浓度下信号值-阴性对照信号值)/(阳性对照信号值-阴性对照信号值)。
化合物IC
50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算:
Y=Bottom+(Top-Bottom)/(1+10^((logIC
50-X)*slope factor))
其中Y为抑制百分比,X为待测化合物浓度的对数值,Bottom为最大抑制百分比,Top为最小抑制百分比,slope factor为曲线斜率系数。
RET V804L的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对RET V804L活性的影响
实验方法概述如下:
使用HTRF激酶检测试剂盒(Cisbio,货号62TK0PEC),通过检测激酶反应中底物的磷酸化水平来测定RET V804L的体外活性。反应缓冲液包含以下组分:试剂盒自带酶反应缓冲液(1×)、5mM MgCl
2、1mM DTT和0.05%Tween-20;人源重组RET V804L蛋白(货号14-758)购自Merck,用反应缓冲液稀释成0.05ng/μl的激酶溶液;底物反应溶液包括用反应缓冲液稀释成1μM生物素标记的酪氨酸激酶底物和8μ M ATP;检测缓冲液包括用反应缓冲液稀释成0.1ng/μl Eu
3+标记的笼状抗体和62.5nM链霉亲和素标记的XL665。
将化合物在100%DMSO中溶解稀释至100μM,然后用DMSO进行4倍的系列稀释至最低浓度为6.1nM,每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning,货号4512)中添加4μL化合物溶液和2μL RET V804L激酶溶液,混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液,将反应混合物在室温孵育40分钟。随后加入与反应等体积的10μL检测缓冲液,混合均匀并在室温条件下静置30分钟后,用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。665/620的比值与底物的磷酸化程度呈正相关性,从而检测出RET V804L激酶的活性。该实验中,未加RET V804L激酶蛋白组作为100%抑制,加RET V804L激酶蛋白但是未加化合物组作为0%抑制。化合物对RET V804L活性抑制百分比可以用以下公式计算:
抑制百分比=100-100*(待测化合物特定浓度下信号值-阴性对照信号值)/(阳性对照信号值-阴性对照信号值)。
化合物IC
50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算:
Y=Bottom+(Top-Bottom)/(1+10^((logIC
50-X)*slope factor))
其中Y为抑制百分比,X为待测化合物浓度的对数值,Bottom为最大抑制百分比,Top为最小抑制百分比,slope factor为曲线斜率系数。
VEGFR2的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对VEGFR2活性的影响
实验方法概述如下:
使用HTRF激酶检测试剂盒(Cisbio,货号62TK0PEC),通过检测激酶反应中底物的磷酸化水平来测定VEGFR2的体外活性。反应缓冲液包含以下组分:试剂盒自带酶反应缓冲液(1×)、5mM MgCl
2、1mM DTT、1mM MnCl
2、0.01%BSA和0.05%Tween-20;人源重组VEGFR2蛋白(货号10012)购自义翘神州,用反应缓冲液稀释成0.3ng/μl的激酶溶液;底物反应溶液包括用反应缓冲液稀释成0.3μM生物素标记的酪氨酸激酶底物和3.5μM ATP;检测缓冲液包括用反应缓冲 液稀释成0.1ng/μl Eu
3+标记的笼状抗体和18.75nM链霉亲和素标记的XL665。
将化合物在100%DMSO中溶解稀释至1000μM,然后用DMSO进行4倍的系列稀释至最低浓度为0.06μM,每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning,货号4512)中添加4μL化合物溶液和2μL VEGFR2激酶溶液,混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液,将反应混合物在室温孵育40分钟。随后加入与反应等体积的10μL检测缓冲液,混合均匀并在室温条件下静置30分钟后,用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。665/620的比值与底物的磷酸化程度呈正相关性,从而检测出VEGFR2激酶的活性。该实验中,未加VEGFR2激酶蛋白组作为100%抑制,加VEGFR2激酶蛋白但是未加化合物组作为0%抑制。化合物对VEGFR2活性抑制百分比可以用以下公式计算:
抑制百分比=100-100*(待测化合物特定浓度下信号值-阴性对照信号值)/(阳性对照信号值-阴性对照信号值)
化合物IC
50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算:
Y=Bottom+(Top-Bottom)/(1+10^((logIC
50-X)*slope factor))
其中Y为抑制百分比,X为待测化合物浓度的对数值,Bottom为最大抑制百分比,Top为最小抑制百分比,slope factor为曲线斜率系数。
Ba/F3 KIF5B-RET细胞半数有效抑制浓度GI
50的测定
使用发光细胞活力测试实验评估本发明的化合物对Ba/F3 KIF5B-RET细胞增殖的影响。
实验方法概述如下:
使用CellTilter-Glo(CTG)检测试剂盒,通过采用一种独特的、稳定性荧光素酶检测有活力细胞代谢的指示剂ATP,试验中产生的发光信号和培养基中的有活力细胞数呈正比,从而检测Ba/F3 KIF5B-RET的细胞增殖状况。
Ba/F3 KIF5B-RET cell(南京科佰,CBP73195)培养在RPMI1640培养基(Thermofisher,12440053)中含10%FBS(GBICO,10099-141)和100units/ml青链霉素混合液(Thermofisher,15140122),培养的 细胞用0.25%胰酶(Thermofisher,25200056)消化吹散后种植于白色384孔板(Thermofisher,164610),每孔加含1000细胞的27μL培养基,然后将384孔板置于含5%CO
2的培养箱中37℃培养过夜。化合物在100%DMSO中溶解并稀释至5mM,之后用DMSO进行4倍的系列稀释至最低浓度为0.31μM,每个浓度点再使用RPMI1640培养基稀释50倍。如果化合物GI
50值非常低,可以降低化合物的起始浓度。每孔加入3μL稀释后的化合物,轻轻离心混匀。其中,不加细胞的培养基作为阴性对照(100%抑制),加0.2%DMSO组作为阳性对照(0%抑制)。该384孔板置于37℃,5%CO
2的培养箱中继续培养,72小时后取出于室温放置30分钟,CTG试剂也取出平衡至室温,每孔加30μLCTG试剂,置于摇床上轻轻摇动以确保细胞裂解充分,放置10分钟使冷光信号稳定,然后用EnVision(Perkin Elmer)读取冷光信号。另外为矫正细胞数,同时设置T
0对照,包括仅含培养基的空白对照和加细胞的对照,两者的差值设为T
0对照,在加药前通过加CTG试剂检测获得。
化合物对Ba/F3 KIF5B-RET细胞增殖抑制的百分比可以用以下公式计算:
抑制百分比=100-100*{[(signal
化合物-Signal
阴性对照)-T
0对照]/[(signal
阳性对
照-Signal
阴性对照)-T
0对照]}。
化合物GI
50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*slope factor))
其中Y为抑制百分比,Bottom为the bottom plateau of the curve(S型曲线的底部平台值),Top为the top plateau of the curve(S型曲线的顶部平台值),X为待测化合物浓度的对数值。
LC-2/ad细胞半数有效抑制浓度GI
50的测定
使用发光细胞活力测试实验评估本发明的化合物对LC-2/ad细胞增殖的影响。
实验方法概述如下:
使用CellTilter-Glo(CTG)检测试剂盒,通过采用一种独特的、稳定性荧光素酶检测有活力细胞代谢的指示剂ATP,试验中产生的发光信号和培养基中的有活力细胞数呈正比,从而检测LC-2/ad的细胞增殖 状况。
LC-2/ad cell(购自上海信裕生物公司)培养在RPMI1640∶F12(1∶1)完全培养基(Thermofisher,72400047,11765054)中含10%FBS(GBICO,10099-141)和100units/ml青链霉素混合液(Thermofisher,15140122),当细胞在培养容器中覆盖率达80-90%时,用0.25%胰酶(含EDTA)(Thermofisher,25200056)消化吹散后种植于白色384孔板(Thermofisher,164610),每孔加27μl IMDM完全培养基,其中含1000细胞,然后将384孔板置于含5%CO
2的培养箱中37℃培养过夜。化合物在100%DMSO中溶解并稀释至1mM,之后用DMSO进行4倍的系列稀释至最低浓度为0.061μM,每个浓度点再使用RPMI1640∶F12(1∶1)培养基稀释50倍。如果化合物GI
50值非常低,可以降低化合物的起始浓度。每孔加入3μl稀释后的化合物,轻轻离心混匀。其中,不加细胞的培养基作为阴性对照(100%抑制),加0.2%DMSO组作为阳性对照(0%抑制)。该384孔板置于37℃,5%CO
2的培养箱中继续培养,96小时后取出于室温放置30分钟,CTG试剂也取出平衡至室温,每孔加15μl CTG试剂,置于摇床上轻轻摇动5分钟以确保细胞裂解充分,放置10分钟使冷光信号稳定,然后用EnVision(Perkin Elmer)读取冷光信号。另外为矫正细胞数,同时设置T
0对照,包括仅含培养基的空白对照和加细胞的对照,两者的差值设为T
0对照,在加药前通过加CTG试剂检测获得。
化合物对LC-2/ad细胞增殖抑制的百分比可以用以下公式计算:
抑制百分比=100-100*{[(signal
化合物-Signal
阴性对照)-T
0对照]/[(signal
阳性对
照-Signal
阴性对照)-T
0对照]}。
化合物GI
50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*slope factor))
其中Y为抑制百分比,Bottom为the bottom plateau of the curve(S型曲线的底部平台值),Top为the top plateau of the curve(S型曲线的顶部平台值),X为待测化合物浓度的对数值。
TT细胞半数有效抑制浓度GI
50的测定
使用发光细胞活力测试实验评估本发明的化合物对TT细胞增殖的影响。
实验方法概述如下:
使用CellTilter-Glo(CTG)检测试剂盒,通过采用一种独特的、稳定性荧光素酶检测有活力细胞代谢的指示剂ATP,试验中产生的发光信号和培养基中的有活力细胞数呈正比,从而检测TT的细胞增殖状况。
TT cell(ATCC,CRL-1803)培养在F12K培养基(Thermofisher,21127022)中含10%FBS(GBICO,10099-141)和100units/ml青链霉素混合液(Thermofisher,15140122),培养的细胞用0.25%胰酶(Thermofisher,25200056)消化吹散后种植于白色384孔板(Thermofisher,164610),每孔加27μL含细胞的培养基,然后将384孔板置于含5%CO
2的培养箱中37℃培养过夜。化合物在100%DMSO中溶解并稀释至1mM,之后用DMSO进行4倍的系列稀释至最低浓度为0.061μM,每个浓度点再使用F12K培养基稀释50倍。如果化合物GI
50值非常低,可以降低化合物的起始浓度。每孔加入3μL稀释后的化合物,轻轻离心混匀。其中,不加细胞的培养基作为阴性对照(100%抑制),加0.2%DMSO组作为阳性对照(0%抑制)。该384孔板置于37℃,5%CO
2的培养箱中继续培养,96小时后取出于室温放置30分钟,CTG试剂也取出平衡至室温,每孔加30μL CTG试剂,置于摇床上轻轻摇动以确保细胞裂解充分,放置10分钟使冷光信号稳定,然后用EnVision(Perkin Elmer)读取冷光信号。另外为矫正细胞数,同时设置T
0对照,包括仅含培养基的空白对照和加细胞的对照,两者的差值设为T
0对照,在加药前通过加CTG试剂检测获得。
化合物对TT细胞增殖抑制的百分比可以用以下公式计算:
抑制百分比=100-100*{[(signal
化合物-Signal
阴性对照)-T
0对照]/[(signal
阳性对
照-Signal
阴性对照)-T
0对照]}
化合物GI
50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*slope factor))
其中Y为抑制百分比,Bottom为the bottom plateau of the curve(S型曲线的底部平台值),Top为the top plateau of the curve(S型曲线的顶部平台值),X为待测化合物浓度的对数值。
上述体外激酶检测实验的结果见下表1,细胞实验的结果见表2。
表1:体外激酶活性检测结果
表2:体外细胞活性检测结果
由上述实验结果可知,本发明的实施例化合物能够有效抑制RET激酶的活性,可以用于治疗RET激酶介导的疾病,例如癌症,尤其是恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤。部分化合物也能有效抑制Ba/F3_KIF5B-RET肿瘤细胞、LC-2/ad肿瘤细胞和TT肿瘤细胞增殖。
对于本领域技术人员来说,很明显,本公开不局限于上述说明性的实施例,并且在不背离本公开实质特性的条件下,其可以通过其它具体形式来具体实施。因此,期望在各方面都认为这些实施例是说明性的和非限制性的,应参照的是附加的权利要求,而不是上述实施例,且由此在权利要求的等效含义和范围内的所有变化都被包括在其中。
Claims (12)
- 根据式I的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:其中:X 1为CR 1或N;优选为CH或N;X 2为CH或N;条件是X 1、X 2中至多有1个为N;Y 1为CR 2或N;优选为CH或N;最优选为N;Y 2为CR 3或N;优选为CH或N;最优选为CH;Y 3为CR 4或N;优选为CH或N;Y 4为CR 5或N;优选为CH或N;最优选为CH;条件是Y 1、Y 2、Y 3和Y 4中至多有2个为N;优选下列条件之一:Y 1-Y 4都不为N;仅Y 1或Y 2为N;Y 1和Y 2都为N;或Y 1和Y 3都为N;进一步优选下列条件之一:仅Y 1或Y 2为N;或Y 1和Y 3都为N;最优选下列条件之一:Y 1为N,Y 2、Y 3和Y 4都为CH;或Y 1和Y 3为N,Y 2和Y 4为CH;R 1-R 5各自独立地选自氢、卤素、氰基、C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、-OR 6、-NR 7R 8、-OC(O)NR 7R 8、-C(O)OR 6、-C(O)NR 7R 8、-NR 9C(O)R 6、-NR 9C(O)NR 7R 8、-S(O) mR 6、-NR 9S(O) mR 6、-SR 6、-S(O) mNR 7R 8或-NR 9S(O) mNR 7R 8,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基或炔基任选被一个或多个选自卤素、氰基、C3-C8环烷基、4-8元杂环基、-OR 10、-NR 11R 12,-OC(O)NR 11R 12、-C(O)OR 10、-C(O)NR 11R 12、-NR 11C(O)R 10、-NR 13C(O)NR 11R 12、-S(O) mR 10、-NR 13S(O) mR 10、-SR 10、-S(O) mNR 11R 12 或-NR 13S(O) mNR 11R 12的取代基所取代;优选地,R 1-R 5各自独立地选自氢、卤素、氰基、C1-C6烷基、-OR 6或-NR 7R 8;进一步优选地,R 1-R 5各自独立地选自氢、卤素或C1-C4烷基;最优选地,R 1-R 5都为氢;A选自氢、卤素、氰基或C1-C8烷基;优选地,A选自氢、卤素、氰基或C1-C6烷基;进一步优选地,A选自氢、氰基或C1-C4烷基;最优选地,A为氢;R 14选自氢、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基、炔基任选被一个或多个选自卤素、氰基、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基的取代基所取代;优选地,R 14选自氢、C1-C6烷基、C3-C8环烷基或4-8元杂环基,其中所述烷基、环烷基、杂环基任选被一个或多个选自卤素、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基的取代基所取代;进一步优选地,R 14选自C1-C4烷基、C3-C6环烷基或4-6元杂环基,其中所述烷基、环烷基、杂环基任选被一个或多个选自卤素、羟基、任选被C1-C4烷基取代的4-6元杂环基的取代基所取代;最优选地,R 14为任选被1-甲基哌啶-4-基取代的C1-C4烷基;Ar 1选自含有1-3个环上杂原子的5或6元杂芳基,其中所述杂原子各自独立地选自N、O、S;优选地,Ar 1选自含有两个环上N原子的5或6元杂芳基;进一步优选地,Ar 1选自含有两个环上N原子的5元杂芳基;最优选地,Ar 1为Ar 1任选可被一个或多个取代基所取代,所述取代基各自独立地选自卤素、氰基、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR 6、-NR 7R 8、-OC(O)NR 7R 8、-C(O)OR 6、-C(O)R 6、-C(O)NR 7R 8、-NR 9C(O)R 6、-NR 9C(O)NR 7R 8、-S(O) mR 6、 -NR 9S(O) mR 6、-SR 6、-S(O) mNR 7R 8或-NR 9S(O) mNR 7R 8,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基、炔基任选被一个或多个选自卤素、氰基、C3-C8环烷基、4-8元杂环基、-OR 10、-NR 11R 12,-OC(O)NR 11R 12、-C(O)OR 10、-C(O)NR 11R 12、-NR 11C(O)R 10、-NR 13C(O)NR 11R 12、-S(O) mR 10、-NR 13S(O) mR 10、-SR 10、-S(O) mNR 11R 12、-NR 13S(O) mNR 11R 12的取代基所取代;R 15选自氢、C1-C8烷基、羟基C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基或杂芳基;优选地,R 15选自氢、C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基或4-8元杂环基;进一步优选地,R 15选自氢、C1-C4烷基、羟基C1-C4烷基、C3-C6环烷基或含有1-2个选自N、O或S的杂原子的4-6元杂环基;最优选地,R 15为C1-C4烷基;D选自含有1-3个选自N、O的杂原子的4-8元亚杂环基、6-8元亚稠杂环基或7-11元亚螺杂环基;优选地,D选自含有1-2个N的4~6元亚杂环基或含有1-2个N的6~8元亚稠杂环基;最优选地,D选自:且当X2为CH时,D不是 D任选被一个选自卤素、氰基、羟基、氨基或C1-C8烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C8烷基)氨基、N-(C1-C8烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C8烷基取代的4-8元杂环基;优选地,D任选被一个选自卤素、氰基、羟基、氨基或C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C6烷基)氨基、N-(C1-C6烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C6烷基取代的4-6元杂环基;进一步优选地,D任选被一个选自羟基、氨基或C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:羟基、单或二(C1-C4烷基)氨 基、N-(C1-C4烷基)-N-(C1-C4烷基羰基)氨基、任选被(C1-C4烷基)羰基或C1-C6烷基取代的4-6元杂环基;最优选地,D任选被一个选自羟基、氨基或C1-C4烷基的取代基取代,所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;其中对于 若取代基为羟基,则在其3-位取代;若取代基为羟基以外的其它取代基,则在其4-位取代;对于 取代基为羟基或氨基,在其4-位取代;E选自氨基、NHC(O)R X、-C(O)R y、 -OR 6、-NR 7R 8、-OC(O)NR 7R 8、-C(O)OR 6、-C(O)NR 7R 8、-NR 9C(O)NR 7R 8、-S(O) mR 6、-NR 9S(O) mR 6、-SR 6、-S(O) mNR 7R 8、-NR 9S(O) mNR 7R 8、或-CH 2-Ar 2;优选地,E选自氨基、杂芳基氧基、-NHC(O)R X、-SO 2(C1-C8)烷基、-C(O)R y、 或-CH 2-Ar 2;进一步优选地,E选自氨基、吡啶氧基、-NHC(O)R X、SO 2(C1-C6)烷基、-C(O)R y、 或-CH 2-Ar 2;最优选地,当D为 时,E选自氨基、-NHC(O)R X或-SO 2(C1-C4)烷基;当D为 时,E为吡啶-2-氧基;当D为 时,E选自-C(O)R y、 -SO 2(C1-C4)烷基、或-CH 2-Ar 2;R X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;优选地,R X选自C1-C6烷氧基、任选被取代的6元芳基、任选被取代的含有1或2个选自N、O的杂原子的5-6元杂芳基、任选被取代的C1-C6烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C6烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C6烷氧基或C3-C6环烷基;最优选地,R X选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;R y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;优选地,R y选自任选被取代的氨基、C1-C6烷基、含有1或2个选自N、O、S的杂原子的4-6元杂环基、或C3-C6环烷基,所述取代基选自任选被芳基取代的C1-C6烷基;最优选地,R y选自任选被C1-C4烷基或苄基取代的氨基、C1-C4烷基、含有1或2个选自N、O的杂原子的4-6元杂环基或C3-C6环烷基;Ar 2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基或C1-C8烷氧基;优选地,Ar 2选自任选被单或二取代的5-6元芳基或杂芳基,所述取代基选自卤素、C1-C6烷氧基;最优选地,Ar 2选 自任选被单或二取代的苯基、任选被单或二取代的吡啶基,所述取代基选自卤素、C1-C4烷氧基;R m、R n各自独立地选自氢、羟基、C1-C8烷基或羟基C1-C8烷基,或R m、R n与其连接的碳原子一起形成C3-C8环烷基;优选地,R m、R n各自独立地选自氢、羟基、C1-C6烷基或羟基C1-C6烷基,或R m、R n与其连接的碳原子一起形成C3-C6环烷基;最优选地,R m、R n各自独立地选自氢、羟基或羟基C1-C4烷基,或R m、R n与其连接的碳原子一起形成环丙基;R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13各自独立地选自氢、卤素、羟基、氨基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、4-8元杂环基、杂芳基、芳基、C2-C8烯基或C2-C8炔基;r选自0、1、2或3;优选地,r选自0、1或2;m选自1或2。
- 如权利要求1所述的式I化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其中X 1为CR 1或N;X 2为CH或N;条件是X 1、X 2中至多有1个为N;Y 1为CR 2或N;Y 2为CR 3或N;Y 3为CR 4或N;Y 4为CR 5或N;且满足下列条件之一:Y 1-Y 4都不为N;仅Y 1或Y 2为N;Y 1和Y 2都为N;或Y 1和Y 3都为N;R 1-R 5各自独立地选自氢、卤素、氰基、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR 6、-NR 7R 8、-OC(O)NR 7R 8、-C(O)OR 6、-C(O)NR 7R 8、-NR 9C(O)R 6、-NR 9C(O)NR 7R 8、-S(O) mR 6、-NR 9S(O) mR 6、-SR 6、-S(O) mNR 7R 8或-NR 9S(O) mNR 7R 8;A选自氢、卤素、氰基或C1-C6烷基;B选自氢、卤素、-OR 14或任选被取代的Ar 1;R 14选自氢、C1-C6烷基、C3-C8环烷基、4-8元杂环基、芳基、杂 芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基、炔基任选被一个或多个选自下列的取代基所取代:卤素、氰基、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基;Ar 1选自含有1-3个环上杂原子的5或6元杂芳基,其中所述杂原子各自独立地选自N、O、S;Ar 1任选可被一个或多个取代基所取代,所述取代基各自独立地选自卤素、氰基、C1-C8烷基、C3-C8环烷基、杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR 6、-NR 7R 8、-OC(O)NR 7R 8、-C(O)OR 6、-C(O)R 6、-C(O)NR 7R 8、-NR 9C(O)R 6、-NR 9C(O)NR 7R 8、-S(O) mR 6、-NR 9S(O) mR 6、-SR 6、-S(O) mNR 7R 8或-NR 9S(O) mNR 7R 8;D任选被一个选自卤素、氰基、羟基、氨基、或C1-C8烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C8烷基)氨基、N-(C1-C8烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C8烷基取代的4-8元杂环基;E选自氨基、NHC(O)R X、-C(O)R y、 -OR 6、-NR 7R 8、-OC(O)NR 7R 8、-C(O)OR 6、-C(O)NR 7R 8、-NR 9C(O)NR 7R 8、-S(O) mR 6、-NR 9S(O) mR 6、-SR 6、-S(O) mNR 7R 8、-NR 9S(O) mNR 7R 8、或-CH 2-Ar 2;R X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;R y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被 芳基或杂芳基取代的C1-C8烷基;Ar 2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基或C1-C8烷氧基;R m、R n各自独立地选自氢、羟基、C1-C8烷基、羟基C1-C8烷基,或R m、R n与其连接的碳原子一起形成C3-C8环烷基;R 6、R 7、R 8、R 9各自独立地选自氢、卤素、羟基、氨基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、4-8元杂环基、杂芳基、芳基、C2-C8烯基或C2-C8炔基;m为1或2;r为0、1、2或3。
- 如权利要求1所述的式I化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其中X 1为CR 1或N;X 2为CH或N;条件是X 1、X 2中至多有1个为N;Y 1为CR 2或N;Y 2为CR 3或N;Y 3为CR 4或N;Y 4为CR 5或N;且满足下列条件之一:Y 1-Y 4都不为N;仅Y 1或Y 2为N;Y 1和Y 2都为N;或Y 1和Y 3都为N;R 1-R 5各自独立地选自氢、卤素、氰基、C1-C6烷基、-OR 6或-NR 7R 8;A选自氢、卤素、氰基或C1-C6烷基;B选自氢、卤素、-OR 14或任选被取代的Ar 1;R 14选自氢、C1-C6烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基、炔基任选被一个或多个选自下列的取代基所取代:卤素、氰基、羟基、C3-C8环烷基、或任选被C1-C6烷基取代的4-8元杂环基;Ar 1选自含有两个环上N原子的5或6元杂芳基;Ar 1任选可被一个或多个取代基所取代,所述取代基各自独立地选自卤素、氰基、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR 6、-NR 7R 8、-OC(O)NR 7R 8、-C(O)OR 6、 -C(O)R 6、-C(O)NR 7R 8、-NR 9C(O)R 6、-NR 9C(O)NR 7R 8、-S(O) mR 6、-NR 9S(O) mR 6、-SR 6、-S(O) mNR 7R 8或-NR 9S(O) mNR 7R 8;D任选被一个选自卤素、氰基、羟基、氨基、C1-C8烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C8烷基)氨基、N-(C1-C8烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C8烷基取代的4-8元杂环基;R X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;R y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;Ar 2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基、C1-C8烷氧基;R m、R n各自独立地选自氢、羟基、C1-C8烷基、羟基C1-C8烷基,或R m、R n与其连接的碳原子一起形成C3-C8环烷基;R 6、R 7、R 8、R 9各自独立地选自氢、卤素、羟基、氨基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、4-8元杂环基、杂芳基、芳基、C2-C8烯基或C2-C8炔基;m为1或2;r为0、1、2或3。
- 如权利要求1所述的式I化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其中X 1为CR 1或N;X 2为CH或N;条件是X 1、X 2中至多有1个为N;Y 1为CR 2或N;Y 2为CR 3或N;Y 3为CR 4或N;Y 4为CR 5或N;且满足下列条件之一:Y 1-Y 4都不为N;仅Y 1或Y 2为N;或Y 1和Y 3都为N;R 1-R 5各自独立地选自氢、卤素或C1-C4烷基;A选自氢、氰基或C1-C4烷基;B选自氢、卤素、-OR 14或任选被取代的Ar 1;R 14选自氢、C1-C6烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基或杂芳基、烯基、炔基任选被一个或多个选自下列的取代基所取代:卤素、氰基、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基;Ar 1选自含有两个环上N原子的5元杂芳基;Ar 1任选可被一个或多个取代基所取代,所述取代基各自独立地选自卤素、氰基、C1-C8烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、C2-C8烯基、C2-C8炔基、-OR 6、-NR 7R 8、-OC(O)NR 7R 8、-C(O)OR 6、-C(O)R 6、-C(O)NR 7R 8、-NR 9C(O)R 6、-NR 9C(O)NR 7R 8、-S(O) mR 6、-NR 9S(O) mR 6、-SR 6、-S(O) mNR 7R 8、-NR 9S(O) mNR 7R 8;D任选被一个选自卤素、氰基、羟基、氨基、C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C6烷基)氨基、N-(C1-C6烷基)-N-(C1-C4烷 基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C6烷基取代的4-6元杂环基;R X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;R y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;Ar 2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基、C1-C8烷氧基;R m、R n各自独立地选自氢、羟基、C1-C8烷基、羟基C1-C8烷基,或R m、R n与其连接的碳原子一起形成C3-C8环烷基;R 6、R 7、R 8、R 9各自独立地选自氢、卤素、羟基、氨基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、4-8元杂环基、杂芳基、芳基、C2-C8烯基或C2-C8炔基;m为1或2;r为0、1、2或3。
- 如权利要求1所述的式I化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其中X 1为CH或N;X 2为CH或N;条件是X 1、X 2中至多有1个为N;Y 1为CH或N;Y 2为CH或N;Y 3为CH或N;Y 4为CH或N;且满足下列条件之一:Y 1、Y 2、Y 3和Y 4都为CH;仅Y 1或Y 2为N;或Y 1和Y 3都为N;A为氢;R 14选自氢、C1-C6烷基、C3-C8环烷基、4-8元杂环基、芳基、杂芳基、烯基或炔基,其中所述烷基、环烷基、杂环基、芳基、杂芳基、烯基或炔基任选被一个或多个选自下列的取代基所取代:卤素、氰基、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基;R 15选自氢、C1-C8烷基、羟基C1-C8烷基、C3-C8环烷基、含有1-2个选自N、O、S的杂原子的4-8元杂环基、芳基或杂芳基;D选自:D任选被一个选自卤素、氰基、羟基、氨基或C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:卤素、羟基、单或二(C1-C6烷基)氨基、N-(C1-C6烷基)-N-(C1-C4烷基羰基)氨基、任选被卤素、羟基、(C1-C4烷基)羰基或C1-C6烷基取代的4-6元杂环基;R X选自C1-C8烷氧基、任选被取代的芳基、任选被取代的含有1或2个选自N、O、S的杂原子的杂芳基、任选被取代的C1-C8烷基、 任选被取代的含有1或2个选自N、O、S的杂原子的4-8元杂环基、C3-C8环烷基或任选被C1-C8烷基取代的氨基;所述任选的取代基选自卤素、硝基、氰基、羟基、C1-C8烷氧基或C3-C8环烷基;R y选自任选被取代的氨基、C1-C8烷基、含有1或2个选自N、O、S的杂原子的4-8元杂环基、或C3-C8环烷基,所述取代基选自任选被芳基或杂芳基取代的C1-C8烷基;Ar 2选自任选被取代的芳基或杂芳基,所述取代基选自卤素、羟基、氨基或C1-C8烷氧基;R m、R n各自独立地选自氢、羟基、C1-C8烷基、羟基C1-C8烷基,或R m、R n与其连接的碳原子一起形成C3-C8环烷基;r为0、1、2或3。
- 如权利要求1所述的式I化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其中X 1为CH或N;X 2为CH或N;条件是X 1、X 2中至多有1个为N;Y 1为CH或N;Y 2为CH或N;Y 3为CH或N;Y 4为CH或N;且满足下列条件之一:Y 1、Y 2、Y 3和Y 4都为CH;仅Y 1或Y 2为N;或Y 1和Y 3都为N;A为氢;R 14选自氢、C1-C6烷基、C3-C8环烷基或4-8元杂环基,其中所述烷基、环烷基、杂环基任选被一个或多个选自下列的取代基所取代:卤素、羟基、C3-C8环烷基、任选被C1-C6烷基取代的4-8元杂环基;R 15选自氢、C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、或含有1-2个选自N、O、S的杂原子的4-8元杂环基;D选自:D任选被一个选自羟基、氨基或C1-C6烷基的取代基所取代,其中所述烷基任选被一个选自下列的取代基所取代:单或二(C1-C6烷基)氨基、N-(C1-C6烷基)-N-(C1-C4烷基)羰基氨基、任选被C1-C6烷基、乙酰基取代的4-6元杂环基;R X选自C1-C6烷氧基、任选被取代的6元芳基、任选被取代的含有1或2个选自N、O的杂原子的5-6元杂芳基、任选被取代的C1-C6烷基、任选被取代的含有1或2个选自N、O、S的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C6烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C6烷氧基或C3-C6环烷基;R y选自任选被取代的氨基、C1-C6烷基、含有1或2个选自N、O、S的杂原子的4-6元杂环基、或C3-C6环烷基,所述取代基选自任选被芳基取代的C1-C6烷基;Ar 2选自任选被单或二取代的5-6元芳基或杂芳基,所述取代基选自卤素或C1-C6烷氧基;R m、R n各自独立地选自氢、羟基、C1-C6烷基或羟基C1-C6烷基,或R m、R n与其连接的碳原子一起形成C3-C6环烷基;r为0、1、2或3。
- 如权利要求1所述的式I化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其中X 1为CH或N;X 2为CH或N;条件是X 1、X 2中至多有1个为N;Y 1为N,Y 2、Y 3和Y 4都为CH;或Y 1和Y 3为N,Y 2和Y 4为CH;A为氢;R 14选自C1-C4烷基、C3-C6环烷基或4-6元杂环基,其中所述烷基、环烷基或杂环基任选被一个或多个选自下列的取代基所取代:卤素、羟基、任选被C1-C4烷基取代的4-6元杂环基;R 15选自氢、C1-C4烷基、羟基C1-C4烷基、C3-C6环烷基或含有1-2个各自独立地选自N、O或S的杂原子的4-6元杂环基;D选自:D任选被一个选自羟基、氨基或C1-C4烷基的取代基所取代,所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;R X选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;R y选自任选被C1-C4烷基或苄基取代的氨基、C1-C4烷基、含有1或2个选自N、O的杂原子的4-6元杂环基或C3-C6环烷基;Ar 2选自任选被单或二取代的苯基、任选被单或二取代的吡啶基,所述取代基选自卤素或C1-C4烷氧基;R m、R n各自独立地选自氢、羟基、羟基C1-C4烷基,或R m、R n与其连接的碳原子一起形成环丙基;r为0、1或2。
- 如权利要求1所述的式I化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其中X 1为CH或N;X 2为CH或N;条件是X 1、X 2中至多有1个为N;Y 1为N,Y 2、Y 3和Y 4都为CH;或Y 1和Y 3为N,Y 2和Y 4为CH;A为氢;R 14选自任选被1-甲基哌啶-4-基取代的C1-C4烷基;R 15为C1-C4烷基;D选自D任选被一个选自羟基、氨基或C1-C4烷基的取代基取代,所述烷基任选被一个选自羟基、二(C1-C4烷基)氨基、N-乙酰基-N-甲基氨基、吗啉-4-基、1-乙基哌嗪-4-基或1-乙酰基哌嗪-4-基的取代基所取代;R X选自C1-C4烷氧基、任选被单或二取代的苯基、任选被单或二取代的吡啶基、含有1或2个选自N、O的杂原子的5元杂芳基、任选被取代的C1-C4烷基、任选被取代的含有1或2个选自N、O的杂原子的4-6元杂环基、C3-C6环烷基或任选被C1-C4烷基取代的氨基;所述任选的取代基选自卤素、羟基、C1-C4烷氧基或C3-C6环烷基;R y选自任选被C1-C4烷基或苄基取代的氨基、C1-C4烷基、含有1或2个选自N、O的杂原子的4-6元杂环基或C3-C6环烷基;Ar 2选自任选被单或二取代的苯基、任选被单或二取代的吡啶基,所述取代基选自卤素、C1-C4烷氧基;R m、R n各自独立地选自氢、羟基、羟基C1-C4烷基,或R m、R n与其连接的碳原子一起形成环丙基;r为0、1或2。
- 根据权利要求1-9任一项的式I化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐在制备用作RET激酶抑制剂的药物中的用途。
- 根据权利要求1-9任一项的式I化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐在制备用于治疗或预防由RET激酶介导的相关疾病的药物中的用途,所述相关疾病例如肿瘤,所述肿瘤选自恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤。
- 药物组合物,其含有根据权利要求1-9任一项的式I化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,任选地一种或多种其它RET激酶抑制剂,以及一种或多种药学上可接受的载体、稀释剂和赋形剂。
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