WO2022166983A1 - Heteroarylopiperidine derivative, and pharmaceutical composition thereof and use thereof - Google Patents
Heteroarylopiperidine derivative, and pharmaceutical composition thereof and use thereof Download PDFInfo
- Publication number
- WO2022166983A1 WO2022166983A1 PCT/CN2022/075490 CN2022075490W WO2022166983A1 WO 2022166983 A1 WO2022166983 A1 WO 2022166983A1 CN 2022075490 W CN2022075490 W CN 2022075490W WO 2022166983 A1 WO2022166983 A1 WO 2022166983A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- tetrahydro
- fluoropropyl
- phenyl
- indol
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 419
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims description 74
- -1 -CONH 2 Chemical group 0.000 claims description 73
- 229910052736 halogen Inorganic materials 0.000 claims description 55
- 150000002367 halogens Chemical class 0.000 claims description 53
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 50
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 229910052731 fluorine Inorganic materials 0.000 claims description 46
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 30
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 102000015694 estrogen receptors Human genes 0.000 claims description 24
- 108010038795 estrogen receptors Proteins 0.000 claims description 24
- 229910052794 bromium Inorganic materials 0.000 claims description 23
- 229910052740 iodine Inorganic materials 0.000 claims description 23
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 claims description 12
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 8
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 8
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 8
- 125000003566 oxetanyl group Chemical group 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000006763 (C3-C9) cycloalkyl group Chemical group 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical compound C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 claims description 6
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 claims description 6
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 6
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 5
- 206010014733 Endometrial cancer Diseases 0.000 claims description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- SZSZDBFJCQKTRG-UHFFFAOYSA-N 1h-indole-6-carbonitrile Chemical compound N#CC1=CC=C2C=CNC2=C1 SZSZDBFJCQKTRG-UHFFFAOYSA-N 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- FDPKMJDUXJFKOI-UHFFFAOYSA-N azetidin-3-amine Chemical compound NC1CNC1 FDPKMJDUXJFKOI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000004440 column chromatography Methods 0.000 description 45
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 16
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- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Definitions
- the invention belongs to the field of medicine, and in particular relates to a heteroaryl piperidine derivative and a pharmaceutical composition and application thereof.
- Estrogen receptor is a transcriptional regulatory protein that mediates ligand-activated activation of multiple biological effects through its interaction with endogenous estrogens.
- ER contains two isoforms, ER ⁇ and ER ⁇ .
- ER ⁇ is mainly distributed in the uterus, ovary, testis, pituitary, kidney, epididymis and adrenal gland, while ER ⁇ is mainly distributed in the prostate, ovary, lung, bladder, brain and blood vessels. Because full agonists or full antagonists have serious side effects, the research of selective estrogen receptor modulator SERM came into being.
- SERM behaves as an agonist in certain tissues such as bone, liver, and ER ⁇ -concentrated areas of the cardiovascular system, and as an antagonist in other tissues such as breast. It can be either an agonist or an antagonist in the uterus (where ERa is more pronounced).
- SERMs include Tamoxifen, Raloxifene, Bazedoxifene, Toremifene, etc.
- SESDs Selective estrogen receptor downregulators
- AF1 and AF2 Drugs (complete antagonists).
- Fulvestrant is the only SERD drug currently approved for clinical use for the treatment of ER+ breast cancer, but it has poor druggable properties, is rapidly metabolized and must be administered by monthly intramuscular injections, in contrast to what has been seen in in vitro studies This limits the efficient degradation of ER compared to complete ER degradation ( ⁇ 50% ER degradation in clinical samples).
- Selective estrogen receptor down-regulators have shown some therapeutic advantages, but more orally available selective estrogen receptors still need to be developed, so that drug candidates have more excellent properties, such as better efficacy, lower side effects, oral It has better absorption, good pharmacokinetic properties and blood-brain barrier penetrating ability, etc., so that it can be better used for the prevention or treatment of estrogen receptor-related diseases.
- the present invention provides an oral selective estrogen receptor compound with good pharmacokinetic properties and blood-brain barrier penetrating ability, and a pharmaceutical composition and application thereof.
- the present invention provides a compound represented by formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt:
- W is selected from O, NH or S
- D is CR 9 or N
- E is CR 10 or N
- L 1 is selected from -O- or -NH-;
- L 2 is selected from -NH- or C 3 -C 8 heterocyclyl; the C 3 -C 8 heterocyclyl is optionally substituted with one or more R 7 ;
- R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl, -OR c , -N(R c ) 2 , -SR c , -COR d , -NO 2 , -S ( O) 2 R d , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein, the C 1 -C 3 alkyl , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 membered aryl, 5-10 membered heteroaryl optionally replaced by one or more H, halogen, -OH, -OC 1 -C 3 alkyl, -SO 2 C 1 -C 3 alkyl, -NH 2 , -NHSO 2 C 1 -C 3 alkyl, -NHC 1 -C 3
- R c is selected from H, C 1 -C 5 alkyl, -COC 1 -C 5 alkyl, -S(O) 2 C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered Heterocyclic group; wherein, the C 1 -C 5 alkyl group, C 3 -C 6 cycloalkyl group, 3-6 membered heterocyclic group are optionally replaced by one or more H, C 1 -C 3 alkyl group, -CONH 2 , -S(O) 2 C 1 -C 3 alkyl, -OC 1 -C 3 alkyl, -OH, -N(C 1 -C 3 alkyl) 2 , -P(O)(OH ) 2 replace;
- R d is selected from H, C 1 -C 5 alkyl, -NH 2 , -OH, -NHC 1 -C 5 alkyl, -N(C 1 -C 5 alkyl) 2 , -OC 1 -C 5 alkane base, -NHC 3 -C 6 cycloalkyl, 3-6 membered heterocyclyloxy; wherein, the C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl optionally substituted with H, -OH, C 1 -C 3 alkyl, -OC 1 -C 3 alkyl;
- R 2 is selected from C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -(C 1 -C 6 alkylene)-(C 3 -C 9 cycloalkyl), -(C 1 -C 6 alkylene)-(C 3 -C 9 heterocyclyl), -C(O)R b , -C(O)N(R a ) 2 , -SO 2 R a and -SO 2 N(R a ) 2 , wherein the C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -(C 1 -C 6 alkylene)-(C 3 -C 9 cycloalkyl), - (C 1 -
- Each R 5 is the same or different and each is independently selected from H, F, Cl, Br, I, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -CN, -NH 2 , - NO 2 , -COOH, -CHO, -OH, C 3 -C 6 cycloalkyl, 3-6-membered heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl; wherein, the C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently any C 1 -C 3 alkyl substituted by C 1 -C 3 alkyl, F, Cl, Br, I, -CN, -NH 2 , -NO 2 , -OH, hydroxyl, -OC 1 -C One of 3
- R7 is H, F, Cl, Br, I, OH or NH2 ;
- R8 is H, F or CN
- D is selected from CR 9 or N
- E is selected from CR 10
- R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
- R 10 is selected from halo of C 1 -C 6 alkoxy
- E is selected from CR 10 or N
- D is selected from CR 9
- R 9 is selected from halogenated C 1 -C 6 alkoxy
- R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated of C 1 -C 6 alkoxy;
- R a is selected from H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl, said C 1 -C 6 Alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl, and 3-6 membered heterocyclyl are optionally selected by one or more groups independently selected from the following: F, CI , Br, I, CN, OH, OCH 3 and SO 2 CH 3 substituted;
- R b is independently selected from H, OH, -O(C 1 -C 3 alkyl), C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkylene base)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl, wherein the C 1 -C 3 alkyl, C 1 -C 6 alkyl , C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl and 3-6 membered heteroalkyl
- the cyclyl group is optionally by one or more groups independently selected from: F, Cl , Br, I, CN, -CH2F , -CHF2 , -CF3 , -CH2CF3 ,
- n 0, 1, 2, 3 or 4;
- r 0, 1, 2 or 3;
- s is 1, 2 or 3.
- the above-mentioned compound is further a compound represented by formula (Ia):
- D is CR 9 or N
- E is CR 10 or N
- L 1 is selected from -O- or -NH-;
- L 2 is selected from -NH- or C 3 -C 8 heterocyclyl; the C 3 -C 8 heterocyclyl is optionally substituted by R 7 ;
- R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl
- R7 is H, F, Cl, Br, I, OH or NH2 ;
- R8 is H, F or CN
- R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
- R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
- E is selected from CR 10 or N
- D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
- R 11 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted with one or more halogens;
- R 12 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted by one or more of -OH, halogen, C 1 -C 3 alkoxy replaced;
- R 13 is H or halogen
- R 12 and R 13 together with the carbon atom to which they are attached form C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl;
- r 0, 1, 2 or 3;
- s is 1, 2 or 3.
- the above-mentioned compound is further a compound represented by formula (Ib):
- Ring A is selected from C 3 -C 8 heterocyclyl
- D is CR 9 or N
- E is CR 10 or N
- L 1 is selected from -O- or -NH-;
- R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl
- R7 is H, F, Cl, Br, I, OH or NH2 ;
- R8 is H, F or CN
- R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
- R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
- E is selected from CR 10 or N
- D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
- R 11 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted with one or more halogens;
- R 12 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted by one or more of -OH, halogen, C 1 -C 3 alkoxy replaced;
- R 13 is H or halogen
- R 12 and R 13 together with the carbon atom to which they are attached form C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl;
- r 0, 1, 2 or 3;
- s is 1, 2 or 3.
- the above-mentioned compound is further a compound represented by formula (Ic):
- D is CR 9 or N
- E is CR 10 or N
- L 1 is selected from -O- or -NH-;
- R 1 is selected from H, halogen, C 1 -C 3 alkyl
- R7 is H, F, Cl, Br, I, OH or NH2 ;
- R8 is H, F or CN
- R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
- R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
- E is selected from CR 10 or N
- D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
- R 11 is Me, F or CH 2 F
- R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH;
- R 13 is H or F
- R 12 and R 13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl;
- p 1, 2 or 3.
- the above-mentioned compound is further a compound represented by formula (Id):
- D is CR 9 or N
- E is CR 10 or N
- R 1 is selected from H, halogen, C 1 -C 3 alkyl
- R7 is H, F, Cl, Br, I, OH or NH2 ;
- R8 is H, F or CN
- R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
- R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
- E is selected from CR 10 or N
- D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
- R 11 is Me, F or CH 2 F
- R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH;
- R 13 is H or F
- R 12 and R 13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl;
- p 1, 2 or 3.
- the above-mentioned compound is further a compound represented by formula (Ie) or formula (If) or formula (Ig):
- the above-mentioned compound is further a compound represented by formula (Ih) or formula (Ii) or formula (Ij):
- R 1 , R 1 ' are the same or different, and are independently selected from H, -CH 3 .
- D is CR 9
- E is CR 10
- R 9 is selected from H, Cl, F, halogenated C 1 -C 6 alkoxy
- R 10 is selected from halogenated C 1 -C 6 alkoxy oxy
- R 9 is selected from H, Cl, F, -OCH 2 F, -OCHF 2 or -OCF 3
- R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
- D is N and E is CR 10 ;
- R 10 is selected from halogenated C 1 -C 6 alkoxy; further R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
- D is CR 9
- E is CR 10
- R 9 is selected from halogenated C 1 -C 6 alkoxy
- R 10 is selected from H, Cl, F, halogenated C 1 -C 6 alkane oxy
- R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3
- R 10 is selected from H, Cl, F, -OCH 2 F, -OCHF 2 or -OCF 3 .
- D is CR 9 and E is N; R 9 is selected from halogenated C 1 -C 6 alkoxy; further, R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
- D is CR9 and E is N; R9 is selected from -OCH2F , -OCHF2 or -OCF3 .
- D is N and E is CR 10 ; R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
- R 11 is Me, F or CH 2 F.
- R12 is Me, F, CH2F , CHF2 , CF3 , CH2OMe , or CH2OH .
- R 13 is H or F.
- R 12 and R 13 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or oxetanyl group.
- R 11 is F
- R 12 is F
- R 13 is F
- R 11 is F
- R 12 is CH 2 OH
- R 13 is F
- R 11 is F
- R 12 and R 13 together with the carbon atom to which they are attached form an oxetanyl group.
- R8 is H.
- R8 is F.
- R8 is CN
- r is 2; s is 2.
- r is 2; s is 1.
- Ring A is selected from C4 - C6 heterocyclyl; further, Ring A is azetidinyl, pyrrolidinyl, or piperidinyl.
- p is 1.
- p is 2.
- the compound represented by the formula (I) is selected from:
- the compound represented by the formula (I) is selected from:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by the formula (I) and at least one pharmaceutically acceptable excipient.
- the present invention also provides the use of the compound represented by formula (I) in the preparation of a medicament for treating estrogen receptor-related diseases.
- the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
- the present invention also provides a method for treating an estrogen receptor-related disease in a patient, which comprises administering to the patient a therapeutically effective amount of the compound represented by the above formula (I).
- the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
- halo and halogen as used herein refer to fluorine, chlorine, bromine or iodine.
- Preferred halogen groups include fluorine, chlorine and bromine.
- alkyl includes linear or branched monovalent saturated hydrocarbon groups. Alkyl groups as used herein may be optionally substituted with one to more substituents. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl) ) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like. Similarly, “C 1-8 " in "C 1-8 alkyl” refers to a linear or branched arrangement containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms group.
- Alkenyl and alkynyl groups include straight or branched chain alkenyl and alkynyl groups.
- C 2-8 alkenyl and “C 2-8 alkynyl” refer to alkenyl groups containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain or alkynyl.
- Alkoxy refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
- Haloalkoxy means the aforementioned "alkoxy” is substituted with one or more halogens; non-limiting examples of halogenated alkoxy groups include, but are not limited to, for example, -OCH2F, - OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 3 , -OCF 2 CH 3 , -OCHFCH 2 F and the like.
- compositions comprising "a” pharmaceutically acceptable excipient can be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
- aromatic ring refers to an unsubstituted or substituted monocyclic, polycyclic or fused-ring aromatic group including carbon atoms, or unsubstituted or substituted including heteroatoms, such as A monocyclic, paracyclic or condensed aromatic group of N, O or S, when it is a polycyclic or condensed ring, at least one ring is aromatic.
- the aromatic ring is a 5- to 10-membered monocyclic or bicyclic aromatic ring group. Examples of such aromatic rings include, but are not limited to, phenyl, pyridyl, pyrazolyl, pyrimidinyl, chromofuran, indolyl.
- cycloalkyl refers to monocyclic and polycyclic ring systems containing only carbon atoms in the ring, and which may be optionally substituted with one or more substituents.
- Cycloalkyl as used herein refers to and includes saturated or unsaturated non-aromatic ring systems.
- the term cycloalkyl further includes bridged, fused and spiro ring systems.
- Non-limiting examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[3.4]octyl, bicyclo[2.2.1]heptane, and the like.
- heterocyclyl in the present invention, unless otherwise specified, refers to unsubstituted or substituted monocyclic and polycyclic ring systems consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. , and includes saturated or unsaturated ring systems as well as polycyclic systems having unsaturated and/or aromatic moieties. Wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized.
- the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. It should be understood that polycyclic heterocycloalkyl groups additionally include fused, bridged, and spiro ring systems.
- Heterocycloalkyl groups used herein may be optionally substituted with one to more substituents.
- heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
- aryl refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms, at least one of which is aromatic in nature.
- Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
- heteroaryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo
- Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
- heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl , benzotriazolyl adenine, quinolinyl or isoquinolinyl.
- substituted refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively.
- the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
- substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.
- substituted alkoxy groups include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
- acids When the compounds provided herein are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases.
- the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
- Prodrugs of the compounds of the present invention are included within the scope of the present invention.
- the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo.
- any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
- Particularly preferred derivatives or prodrugs are those compounds that, when administered to a patient, increase the bioavailability of the compounds of the present application (eg, make orally administered compounds more readily absorbed into the blood), or promote the delivery of the parent compound to biological organs or Those compounds that are delivered to the site of action (eg, the brain or lymphatic system). Therefore, the term "administration" in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or, although not explicitly disclosed, can be transformed into the disclosure in vivo after administration to a subject compound of. Conventional methods for the selection and preparation of suitable prodrug derivatives are described in, for example, Design of Prodrugs (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
- the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers.
- the present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
- the above formula (I) does not exactly define the stereoscopic structure of the compound at a certain position.
- the present invention includes all stereoisomers of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. During synthetic procedures to prepare such compounds, or using racemization or epimerization procedures well known to those skilled in the art, the resulting product may be a mixture of stereoisomers.
- the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.
- the present invention includes any possible solvates and polymorphs.
- the type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
- composition refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention.
- some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention.
- some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
- the pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
- the pharmaceutical compositions of the present invention include oral, rectal, topical and Pharmaceutical compositions for parenteral (including subcutaneous, intramuscular, intravenous) administration.
- the pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.
- the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method.
- such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients.
- the pharmaceutical compositions are prepared by uniform intimate admixture of the active ingredient with liquid carriers or finely divided solid carriers, or a mixture of both.
- the product can be easily prepared to the desired appearance.
- the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or its stereoisomer, tautomer, polymorph, solvate, pharmaceutically acceptable Salts and their prodrugs.
- the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, combined with one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.
- the pharmaceutical carrier employed in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier.
- NaHCO 3 sodium bicarbonate
- TosCl p-toluenesulfonyl chloride
- H 2 hydrogen
- Pd(OH) 2 /C palladium hydroxide supported on carbon
- K 2 CO 3 potassium carbonate
- ACN/CH 3 CN acetonitrile
- i-PrMgCl isopropyl magnesium chloride (2mol/L tetrahydrofuran solution);
- TBDPSCl tert-butyldiphenylchlorosilane
- Tf 2 O trifluoromethanesulfonic anhydride
- Boc tert-butoxycarbonyl
- HOAc acetic acid
- DIEA/DIPEA N,N-diisopropylethylamine
- 1,4-dioxane 1,4-dioxane
- Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
- Xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
- TBAF tetrabutylammonium fluoride
- t-BuONa sodium tert-butoxide
- ER ⁇ estrogen receptor ⁇
- LC-MS or LCMS Liquid Chromatography-Mass Spectrometry.
- the starting materials and reagents used in the Example section can be obtained from commercial sources or prepared by conventional methods in the art.
- step 2 is the Pictet-Spengler cyclization reaction, which is used to provide the cyclized product mainly as the desired trans isomer (Chem. Rev. 1995, 95 (6). ), 1797-1842.), a small amount of cis diastereomer was removed by subsequent column chromatography purification.
- intermediate INT12-intermediate INT17, etc. are all obtained through Pictet-Spengler cyclization reaction to obtain cyclization products dominated by trans isomers.
- hydrochloride salts of compounds INT6, INT7, INT8, INT9, and INT10 can be synthesized according to the synthetic method of the similar compound INT5, using the corresponding raw materials and routes as above.
- Step 2 Synthesis of compound INT11 (Pictet-Spengler cyclization)
- step 3 of INT21 replace INT2 with INT15-1 to get INT22.
- step 2 of INT11 replace INT2 with INT23-1 to get INT23.
- compound INT24-6 (254mg, 1eq), methanol (10mL), potassium hydroxide (98mg, 3eq) were added, and the temperature was heated to 70°C and stirred for reaction for 3 hours. After the completion of the reaction, the reaction solution was concentrated, the residue was dissolved in ethyl acetate/water, and the layers were separated by stirring. The aqueous phase was extracted once with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate to obtain 198 mg of compound INT24.
- step 2 of INT11 replace INT21-2 with INT24 to get INT25.
- Example 1 Compound A1((S)-N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl) yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidine-3- amine) preparation
- Example 2 Compound A2 (N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2 ,3,4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine ) preparation
- Example 1 According to the similar experimental methods of Example 1, Example 2, Example 6, Example 12-13, Example 19-20, Example 32, etc., using the above-mentioned intermediates, and suitable commercially available raw materials and reagents, it can be prepared Examples shown in Table 1.
- Example 8 Compound A8 (1-(3-fluoropropyl)-N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)- 2,3,4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)azetidine-3- amine) preparation
- Example 9 Compound A9((S)-1-(3-fluoropropyl)-N-(4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl) yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidine-3- amine) preparation
- Example 15 Compound A15 (N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine) of preparation
- Example 8 Example 9, Example 15 and Example 27, using the above intermediates and suitable raw materials and reagents, the examples shown in Table 2 were prepared.
- compound A39-7 can be obtained by replacing compound INT2 with compound A39-6.
- Example 39 using the above intermediates and suitable raw materials and reagents, the examples shown in Table 3 can be prepared.
- reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by high pressure preparative liquid phase (mobile phase A: 0.1% aqueous formic acid solution, mobile phase B: acetonitrile; 25-55 %B in 20mins; flow rate: 40ml/min; detection wavelength: 254nm; peak: 43%B.), to obtain 27mg of compound A53.
- mobile phase A 0.1% aqueous formic acid solution
- mobile phase B acetonitrile
- Example 55-Example 61 According to the method similar to the above-mentioned embodiment, using the corresponding raw material, can synthesize Example 55-Example 61:
- Celltiter-glo luminescence viability assay kit (Promega, Cat#G7573) was used to detect compound cell proliferation inhibitory activity on breast cancer cell lines MCF7 and T47D. Cells in logarithmic growth phase were taken, trypsinized, seeded in 96-well cell culture plates at a cell density of 2000/well, and incubated overnight in a humidified incubator at 37°C, 5% CO2 . The next day, the serially diluted compound solution was added to the cell culture medium, so that the final compound concentration was 1 ⁇ M or 8-9 concentrations of 3-fold dilution from 20 nM. The same volume of DMSO was added to control wells as a solvent control.
- the degradation activity of the compounds on ER proteins in MCF7 and T47D cells was detected by In-Cell Western method.
- Cells in logarithmic growth phase were taken, trypsinized and collected, inoculated in 384-well plates and incubated overnight at 37°C, 5% CO 2 .
- the compound was serially diluted with DMSO, and 120nL/well compound solution was added to the well plate (the final concentration of DMSO was 0.5%), so that the final compound concentration was 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.001 nM and incubated overnight.
- Cells were fixed, washed with PBS, permeabilized and blocked.
- Mouse PK studies were performed using female BALB/c mice (20-30 g) purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Compound concentrations were 0.5 mg/mL and 1 mg/mL for oral (PO) doses of 5 mg/kg and 10 mg/kg, respectively, as-is formulated. Oral administration was by oral gavage at 5 mg/kg or 10 mL/kg. Blood was drawn through the orbital venous plexus of mice, and 100 ⁇ L of whole blood was loaded into K2 - EDTA tubes per time point. Blood collection time was 15min, 30min, 1h, 2h, 4h, 7h and 24h or 15min, 30min, 1h, 2h, 4h, 7h, 24h, 30h and 48h.
- the collected whole blood samples were centrifuged and plasma separated, and stored in a -80°C refrigerator for later use.
- the time points of brain collection were 4h and 24h or 4h and 48h.
- the collected brain tissue was weighed, diluted and homogenized by adding water at a ratio of 1:4, and stored in a -80°C refrigerator for later use.
- the brain/plasma drug concentration ratio of the compound of the present invention is higher than that of the control compound, indicating that the compound of the present invention has a good ability to cross the blood-brain barrier; at the same time, other compounds of the present invention
- brain tissue drug concentrations and brain/plasma drug concentration ratios are also higher than control compounds, eg, Example 20, Example 51, and the like.
Abstract
The present invention belongs to the field of medicine, and in particular relates to heteroarylopiperidine derivative, and a pharmaceutical composition thereof and the use thereof. The heteroarylopiperidine derivative as shown in formula (I) provided by the present invention can not only be prepared into an oral preparation, but also has good pharmacokinetic properties and blood brain barrier penetration capabilities.
Description
本发明属于医药领域，具体涉及一种杂芳基并哌啶类衍生物及其药物组合物和应用。The invention belongs to the field of medicine, and in particular relates to a heteroaryl piperidine derivative and a pharmaceutical composition and application thereof.
***受体(ER)是一种通过其与内源性***的相互作用介导多种生物效应诱导的配体活化的转录调节蛋白，ER包含ERα和ERβ两种亚型。ERα主要分布在子宫、卵巢、睾丸、垂体、肾、附睾和肾上腺中，而ERβ主要分布在***、卵巢、肺、膀胱、脑和血管中。由于全激动剂或全拮抗剂都有较严重的副作用，选择性***受体调节剂SERM的研究应运而生。其“选择性”是指SERM在某些组织如骨、肝、心血管***ERβ集中区中表现为激动剂，而在另外一些组织如乳腺中表现为拮抗剂。其在子宫(ERα较显著区)中可以是激动剂，也可以是拮抗剂。目前已上市的SERM包括他莫昔芬(Tamoxifen)、雷洛昔芬(Raloxifene)、苯卓昔芬(Bazedoxifene)、托瑞米芬(Toremifene)等，但研究发现目前已上市的SERM仍有严重的副作用，如他莫昔芬和托瑞米芬长期服用会引起子宫内膜增生、息肉和子宫内膜癌等，而雷洛昔芬常见的副作用包括潮热、腿痛、***触痛和静脉栓塞等。因此研究并开发新型的化合物仍是亟需解决的问题。Estrogen receptor (ER) is a transcriptional regulatory protein that mediates ligand-activated activation of multiple biological effects through its interaction with endogenous estrogens. ER contains two isoforms, ERα and ERβ. ERα is mainly distributed in the uterus, ovary, testis, pituitary, kidney, epididymis and adrenal gland, while ERβ is mainly distributed in the prostate, ovary, lung, bladder, brain and blood vessels. Because full agonists or full antagonists have serious side effects, the research of selective estrogen receptor modulator SERM came into being. Its "selectivity" means that SERM behaves as an agonist in certain tissues such as bone, liver, and ERβ-concentrated areas of the cardiovascular system, and as an antagonist in other tissues such as breast. It can be either an agonist or an antagonist in the uterus (where ERa is more pronounced). Currently listed SERMs include Tamoxifen, Raloxifene, Bazedoxifene, Toremifene, etc. However, studies have found that the currently listed SERMs are still serious Long-term use of tamoxifen and toremifene can cause endometrial hyperplasia, polyps, and endometrial cancer, while common side effects of raloxifene include hot flashes, leg pain, breast tenderness, and veins Embolism, etc. Therefore, research and development of new compounds is still an urgent problem to be solved.
选择性***受体下调剂(SERD)是一类能够通过抑制***受体两个转录激活域AF1和AF2的功能而阻断***的活性的药物，是一类经典的抗***类药物(完全拮抗剂)。氟维司群是目前被批准用于临床使用的唯一SERD类药物，用于治疗ER+乳腺癌，但其成药特性差，快速代谢并且必须通过每月肌肉注射来施用，与体外研究中见到的完全ER降解相比，其限制了ER的有效降解(在临床样品中～50％ER降解)。Selective estrogen receptor downregulators (SERDs) are a class of drugs that block the activity of estrogen by inhibiting the function of the two transcriptional activation domains of estrogen receptors, AF1 and AF2. Drugs (complete antagonists). Fulvestrant is the only SERD drug currently approved for clinical use for the treatment of ER+ breast cancer, but it has poor druggable properties, is rapidly metabolized and must be administered by monthly intramuscular injections, in contrast to what has been seen in in vitro studies This limits the efficient degradation of ER compared to complete ER degradation (~50% ER degradation in clinical samples).
临床上对能够抑制***受体活性、下调***受体表达水平或诱导***受体降解的药物需求强烈，以改善针对早期、转移性、或耐药性的乳腺癌或其它 与***受体过度活性相关疾病的治疗效果。There is a strong clinical need for drugs that can inhibit estrogen receptor activity, downregulate estrogen receptor expression levels, or induce estrogen receptor degradation to improve treatment for early-stage, metastatic, or drug-resistant breast cancer or other estrogen-related diseases. Therapeutic effects of diseases associated with receptor overactivity.
Roche/Genentech公司的WO2016097072A专利也公开了一系列SERD类化合物，包括临床阶段药物GDC-9545(实施例340)。Roche/Genentech's WO2016097072A patent also discloses a series of SERD compounds, including the clinical stage drug GDC-9545 (Example 340).
选择性***受体下调剂已显示一定治疗优势，但仍然需要开发更多的可口服的选择性***受体，使得候选药物具有更加优异的特性，如疗效更好、副作用更低、口服吸收更好、且具有很好的药代动力学特性和血脑屏障穿透能力等，从而更好的用于预防或治疗***受体相关疾病。Selective estrogen receptor down-regulators have shown some therapeutic advantages, but more orally available selective estrogen receptors still need to be developed, so that drug candidates have more excellent properties, such as better efficacy, lower side effects, oral It has better absorption, good pharmacokinetic properties and blood-brain barrier penetrating ability, etc., so that it can be better used for the prevention or treatment of estrogen receptor-related diseases.
发明内容SUMMARY OF THE INVENTION
为了解决上述问题，本发明提供一种具有很好的药代动力学性质和血脑屏障穿透能力的口服选择性***受体类化合物及其药物组合物和应用。In order to solve the above problems, the present invention provides an oral selective estrogen receptor compound with good pharmacokinetic properties and blood-brain barrier penetrating ability, and a pharmaceutical composition and application thereof.
本发明提供了一种如式(I)所示化合物、其立体异构体、互变异构体或药学上可接受的盐：The present invention provides a compound represented by formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt:
其中，in,
W选自O、NH或S；W is selected from O, NH or S;
D是CR
9或N；
D is CR 9 or N;
E是CR
10或N；
E is CR 10 or N;
L
1选自-O-或-NH-；
L 1 is selected from -O- or -NH-;
L
2选自-NH-或C
3-C
8杂环基；所述C
3-C
8杂环基任选地被一个或多个R
7取 代；
L 2 is selected from -NH- or C 3 -C 8 heterocyclyl; the C 3 -C 8 heterocyclyl is optionally substituted with one or more R 7 ;
R
1、R
1’分别独立地选自H、卤素、C
1-C
3烷基、-OR
c、-N(R
c)
2、-SR
c、-COR
d、-NO
2、-S(O)
2R
d、C
3-C
6环烷基、3-6元杂环基、C
6-C
10芳基、5-10元杂芳基；其中，所述C
1-C
3烷基、C
3-C
6环烷基、3-6元杂环基、C
6-C
10芳基、5-10元杂芳基任选地被一个或多个H、卤素、-OH、-OC
1-C
3烷基、-SO
2C
1-C
3烷基、-NH
2、-NHSO
2C
1-C
3烷基、-NHC
1-C
3烷基、-N(C
1-C
3烷基)
2、-CN、-CONH
2、C
3-C
6环烷基、3-6元杂环基取代；或者，R
1和R
1’一起形成＝O；
R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl, -OR c , -N(R c ) 2 , -SR c , -COR d , -NO 2 , -S ( O) 2 R d , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein, the C 1 -C 3 alkyl , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 membered aryl, 5-10 membered heteroaryl optionally replaced by one or more H, halogen, -OH, -OC 1 -C 3 alkyl, -SO 2 C 1 -C 3 alkyl, -NH 2 , -NHSO 2 C 1 -C 3 alkyl, -NHC 1 -C 3 alkyl, -N(C 1 -C 3 Alkyl) 2 , -CN, -CONH 2 , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl substituted; or, R 1 and R 1 ' together form =O;
R
c选自H、C
1-C
5烷基、-COC
1-C
5烷基、-S(O)
2C
1-C
5烷基、C
3-C
6环烷基、3-6元杂环基；其中，所述C
1-C
5烷基、C
3-C
6环烷基、3-6元杂环基任选地被一个或多个H、C
1-C
3烷基、-CONH
2、-S(O)
2C
1-C
3烷基、-OC
1-C
3烷基、-OH、-N(C
1-C
3烷基)
2、-P(O)(OH)
2取代；
R c is selected from H, C 1 -C 5 alkyl, -COC 1 -C 5 alkyl, -S(O) 2 C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered Heterocyclic group; wherein, the C 1 -C 5 alkyl group, C 3 -C 6 cycloalkyl group, 3-6 membered heterocyclic group are optionally replaced by one or more H, C 1 -C 3 alkyl group, -CONH 2 , -S(O) 2 C 1 -C 3 alkyl, -OC 1 -C 3 alkyl, -OH, -N(C 1 -C 3 alkyl) 2 , -P(O)(OH ) 2 replace;
R
d选自H、C
1-C
5烷基、-NH
2、-OH、-NHC
1-C
5烷基、-N(C
1-C
5烷基)
2、-OC
1-C
5烷基、-NHC
3-C
6环烷基、3-6元杂环基氧基；其中，所述C
1-C
5烷基、C
3-C
6环烷基、3-6元杂环基任选地被H、-OH、C
1-C
3烷基、-OC
1-C
3烷基取代；
R d is selected from H, C 1 -C 5 alkyl, -NH 2 , -OH, -NHC 1 -C 5 alkyl, -N(C 1 -C 5 alkyl) 2 , -OC 1 -C 5 alkane base, -NHC 3 -C 6 cycloalkyl, 3-6 membered heterocyclyloxy; wherein, the C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl optionally substituted with H, -OH, C 1 -C 3 alkyl, -OC 1 -C 3 alkyl;
R
2选自C
1-C
9烷基、C
3-C
9环烷基、C
3-C
9杂环基、C
6-C
10芳基、C
5-C
10杂芳基、-(C
1-C
6亚烷基)-(C
3-C
9环烷基)、-(C
1-C
6亚烷基)-(C
3-C
9杂环基)、-C(O)R
b、-C(O)N(R
a)
2、-SO
2R
a和-SO
2N(R
a)
2，其中，所述C
1-C
9烷基、C
3-C
9环烷基、C
3-C
9杂环基、C
6-C
10芳基、C
5-C
10杂芳基、-(C
1-C
6亚烷基)-(C
3-C
9环烷基)、-(C
1-C
6亚烷基)-(C
3-C
9杂环基)任选地被一个或多个F、Cl、Br、I、-CN、-OR
a、-N(R
a)
2、C
1-C
9烷基、C
3-C
9环烷基、C
3-C
9杂环基、C
6-C
10芳基、C
5-C
10杂芳基、-C(O)R
b、-C(O)NR
a、-SO
2R
a和-SO
2N(R
a)
2取代；
R 2 is selected from C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -(C 1 -C 6 alkylene)-(C 3 -C 9 cycloalkyl), -(C 1 -C 6 alkylene)-(C 3 -C 9 heterocyclyl), -C(O)R b , -C(O)N(R a ) 2 , -SO 2 R a and -SO 2 N(R a ) 2 , wherein the C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -(C 1 -C 6 alkylene)-(C 3 -C 9 cycloalkyl), - (C 1 -C 6 alkylene)-(C 3 -C 9 heterocyclyl) optionally surrounded by one or more of F, Cl, Br, I, -CN, -OR a , -N(R a ) 2 , C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -C(O) R b , -C(O)NR a , -SO 2 R a and -SO 2 N(R a ) 2 are substituted;
每一个R
5各自相同或不同，其各自独立地选自H、F、Cl、Br、I、C
1-C
6烷基、-OC
1-C
6烷基、-CN、-NH
2、-NO
2、-COOH、-CHO、-OH、C
3-C
6环烷基、3-6元杂环基、6-10元芳基和5-10元杂芳基；其中，所述C
1-C
6烷基、-OC
1-C
6烷基、C
3-C
6环烷基、3-6元杂环基、6-10元芳基和5-10元杂芳基各自独立地任选被选自C
1-C
3烷基、F、Cl、Br、I、-CN、-NH
2、-NO
2、-OH、羟基取代的C
1-C
3烷基、-OC
1-C
3烷氧基、卤代的C
1-C
3烷氧基、C
3-C
6环烷基、3-6元杂环基、6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；
Each R 5 is the same or different and each is independently selected from H, F, Cl, Br, I, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -CN, -NH 2 , - NO 2 , -COOH, -CHO, -OH, C 3 -C 6 cycloalkyl, 3-6-membered heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl; wherein, the C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently any C 1 -C 3 alkyl substituted by C 1 -C 3 alkyl, F, Cl, Br, I, -CN, -NH 2 , -NO 2 , -OH, hydroxyl, -OC 1 -C One of 3 -alkoxy, halogenated C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl or more substituents;
R
7是H、F、Cl、Br、I、OH或NH
2；
R7 is H, F, Cl, Br, I, OH or NH2 ;
R
8是H、F或CN；
R8 is H, F or CN;
当D选自CR
9或N时，E选自CR
10，R
9选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基，R
10选自卤代的C
1-C
6烷氧基；或
When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo of C 1 -C 6 alkoxy; or
当E选自CR
10或N时，D选自CR
9，R
9选自卤代的C
1-C
6烷氧基，R
10选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基；
When E is selected from CR 10 or N, D is selected from CR 9 , R 9 is selected from halogenated C 1 -C 6 alkoxy, R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated of C 1 -C 6 alkoxy;
R
a选自H、C
1-C
6烷基、C
2-C
8烯基、炔丙基、C
3-C
6环烷基和3-6元杂环基，所述C
1-C
6烷基、C
2-C
8烯基、炔丙基、C
3-C
6环烷基和3-6元杂环基任选地被一个或多个独立选自以下的基团：F、CI、Br、I、CN、OH、OCH
3和SO
2CH
3取代；
R a is selected from H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl, said C 1 -C 6 Alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl, and 3-6 membered heterocyclyl are optionally selected by one or more groups independently selected from the following: F, CI , Br, I, CN, OH, OCH 3 and SO 2 CH 3 substituted;
R
b独立选自H、OH、-O(C
1-C
3烷基)、C
1-C
6烷基、C
2-C
8烯基、炔丙基、-(C
1-C
6亚烷基)-(C
3-C
6环烷基)、C
3-C
6环烷基和3-6元杂环基，其中，所述C
1-C
3烷基、C
1-C
6烷基、C
2-C
8烯基、炔丙基、-(C
1-C
6亚烷基)-(C
3-C
6环烷基)、C
3-C
6环烷基和3-6元杂环基任选地被一个或多个独立选自以下的基团：F、Cl、Br、I、CN、-CH
2F、-CHF
2、-CF
3、-CH
2CF
3、-CH
2CHF
2、-CH
2CH
2F、-OH、-OCH
3和-SO
2CH
3取代；
R b is independently selected from H, OH, -O(C 1 -C 3 alkyl), C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkylene base)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl, wherein the C 1 -C 3 alkyl, C 1 -C 6 alkyl , C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl and 3-6 membered heteroalkyl The cyclyl group is optionally by one or more groups independently selected from: F, Cl , Br, I, CN, -CH2F , -CHF2 , -CF3 , -CH2CF3 , -CH2 CHF 2 , -CH 2 CH 2 F, -OH, -OCH 3 and -SO 2 CH 3 substituted;
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
r为0、1、2或3；r is 0, 1, 2 or 3;
s为1、2或3。s is 1, 2 or 3.
一些实施方式中，上述化合物进一步地为式(Ⅰa)所示化合物：In some embodiments, the above-mentioned compound is further a compound represented by formula (Ia):
其中，in,
D是CR
9或N；
D is CR 9 or N;
E是CR
10或N；
E is CR 10 or N;
L
1选自-O-或-NH-；
L 1 is selected from -O- or -NH-;
L
2选自-NH-或C
3-C
8杂环基；所述C
3-C
8杂环基任选地被R
7取代；
L 2 is selected from -NH- or C 3 -C 8 heterocyclyl; the C 3 -C 8 heterocyclyl is optionally substituted by R 7 ;
R
1、R
1’分别独立地选自H、卤素、C
1-C
3烷基；
R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl;
R
7是H、F、Cl、Br、I、OH或NH
2；
R7 is H, F, Cl, Br, I, OH or NH2 ;
R
8是H、F或CN；
R8 is H, F or CN;
当D选自CR
9或N时，E选自CR
10，R
9选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基，R
10选自卤代的C
1-C
6烷氧基(例如卤代的C
1-C
3烷氧基、卤代的C
1-C
4烷氧基、卤代的C
1-C
5烷氧基)；或
When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
当E选自CR
10或N时，D选自CR
9，R
9选自卤代的C
1-C
6烷氧基(例如卤代的C
1-C
3烷氧基、卤代的C
1-C
4烷氧基、卤代的C
1-C
5烷氧基)，R
10选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基；
When E is selected from CR 10 or N, D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
R
11选自H、卤素、C
1-C
3烷基；所述C
1-C
3烷基任选地被一个或多个卤素取代；
R 11 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted with one or more halogens;
R
12选自H、卤素、C
1-C
3烷基；所述C
1-C
3烷基任选地被-OH、卤素、C
1-C
3烷氧基中的一个或多个取代基所取代；
R 12 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted by one or more of -OH, halogen, C 1 -C 3 alkoxy replaced;
R
13是H或卤素；或者
R 13 is H or halogen; or
R
12和R
13连同它们附接至其上的碳原子一起形成C
3-C
8环烷基、C
3-C
8杂环基；
R 12 and R 13 together with the carbon atom to which they are attached form C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl;
r为0、1、2或3；r is 0, 1, 2 or 3;
s为1、2或3。s is 1, 2 or 3.
一些实施方式中，上述化合物进一步地为式(Ⅰb)所示化合物：In some embodiments, the above-mentioned compound is further a compound represented by formula (Ib):
其中，环A选自C
3-C
8杂环基；
wherein Ring A is selected from C 3 -C 8 heterocyclyl;
D是CR
9或N；
D is CR 9 or N;
E是CR
10或N；
E is CR 10 or N;
L
1选自-O-或-NH-；
L 1 is selected from -O- or -NH-;
R
1、R
1’分别独立地选自H、卤素、C
1-C
3烷基；
R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl;
R
7是H、F、Cl、Br、I、OH或NH
2；
R7 is H, F, Cl, Br, I, OH or NH2 ;
R
8是H、F或CN；
R8 is H, F or CN;
当D选自CR
9或N时，E选自CR
10，R
9选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基，R
10选自卤代的C
1-C
6烷氧基(例如卤代的C
1-C
3烷氧基、卤代的C
1-C
4烷氧基、卤代的C
1-C
5烷氧基)；或
When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
当E选自CR
10或N时，D选自CR
9，R
9选自卤代的C
1-C
6烷氧基(例如卤代的C
1-C
3烷氧基、卤代的C
1-C
4烷氧基、卤代的C
1-C
5烷氧基)，R
10选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基；
When E is selected from CR 10 or N, D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
R
11选自H、卤素、C
1-C
3烷基；所述C
1-C
3烷基任选地被一个或多个卤素取代；
R 11 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted with one or more halogens;
R
12选自H、卤素、C
1-C
3烷基；所述C
1-C
3烷基任选地被-OH、卤素、C
1-C
3烷氧基中的一个或多个取代基所取代；
R 12 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted by one or more of -OH, halogen, C 1 -C 3 alkoxy replaced;
R
13是H或卤素；或者
R 13 is H or halogen; or
R
12和R
13连同它们附接至其上的碳原子一起形成C
3-C
8环烷基、C
3-C
8杂环基；
R 12 and R 13 together with the carbon atom to which they are attached form C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl;
r为0、1、2或3；r is 0, 1, 2 or 3;
s为1、2或3。s is 1, 2 or 3.
一些实施方式中，上述化合物进一步地为式(Ⅰc)所示化合物：In some embodiments, the above-mentioned compound is further a compound represented by formula (Ic):
其中，in,
D是CR
9或N；
D is CR 9 or N;
E是CR
10或N；
E is CR 10 or N;
L
1选自-O-或-NH-；
L 1 is selected from -O- or -NH-;
R
1选自H、卤素、C
1-C
3烷基；
R 1 is selected from H, halogen, C 1 -C 3 alkyl;
R
7是H、F、Cl、Br、I、OH或NH
2；
R7 is H, F, Cl, Br, I, OH or NH2 ;
R
8是H、F或CN；
R8 is H, F or CN;
当D选自CR
9或N时，E选自CR
10，R
9选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基，R
10选自卤代的C
1-C
6烷氧基(例如卤代的C
1-C
3烷氧基、卤代的C
1-C
4烷氧基、卤代的C
1-C
5烷氧基)；或
When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
当E选自CR
10或N时，D选自CR
9，R
9选自卤代的C
1-C
6烷氧基(例如卤代的C
1-C
3烷氧基、卤代的C
1-C
4烷氧基、卤代的C
1-C
5烷氧基)，R
10选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基；
When E is selected from CR 10 or N, D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
R
11是Me、F或CH
2F；
R 11 is Me, F or CH 2 F;
R
12是Me、F、CH
2F、CHF
2、CF
3、CH
2OMe或CH
2OH；
R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH;
R
13是H或F；或者
R 13 is H or F; or
R
12和R
13连同它们附接至其上的碳原子一起形成环丙基、环丁基或氧杂环丁基；
R 12 and R 13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl;
p为1、2或3。p is 1, 2 or 3.
一些实施方式中，上述化合物进一步地为式(Ⅰd)所示化合物：In some embodiments, the above-mentioned compound is further a compound represented by formula (Id):
其中，in,
D是CR
9或N；
D is CR 9 or N;
E是CR
10或N；
E is CR 10 or N;
R
1选自H、卤素、C
1-C
3烷基；
R 1 is selected from H, halogen, C 1 -C 3 alkyl;
R
7是H、F、Cl、Br、I、OH或NH
2；
R7 is H, F, Cl, Br, I, OH or NH2 ;
R
8是H、F或CN；
R8 is H, F or CN;
当D选自CR
9或N时，E选自CR
10，R
9选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基，R
10选自卤代的C
1-C
6烷氧基(例如卤代的C
1-C
3烷氧基、卤代的C
1-C
4烷氧基、卤代的C
1-C
5烷氧基)；或
When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
当E选自CR
10或N时，D选自CR
9，R
9选自卤代的C
1-C
6烷氧基(例如卤代的C
1-C
3烷氧基、卤代的C
1-C
4烷氧基、卤代的C
1-C
5烷氧基)，R
10选自H、卤素、C
1-C
3烷基、卤代的C
1-C
6烷氧基；
When E is selected from CR 10 or N, D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
R
11是Me、F或CH
2F；
R 11 is Me, F or CH 2 F;
R
12是Me、F、CH
2F、CHF
2、CF
3、CH
2OMe或CH
2OH；
R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH;
R
13是H或F；或者
R 13 is H or F; or
R
12和R
13连同它们附接至其上的碳原子一起形成环丙基、环丁基或氧杂环丁基；
R 12 and R 13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl;
p为1、2或3。p is 1, 2 or 3.
一些实施方式中，上述化合物进一步地为式(Ⅰe)或式(Ⅰf)或式(Ⅰg)所示化合物：In some embodiments, the above-mentioned compound is further a compound represented by formula (Ie) or formula (If) or formula (Ig):
一些实施方式中，上述化合物进一步地为式(Ⅰh)或式(Ⅰi)或式(Ⅰj)所示化合物：In some embodiments, the above-mentioned compound is further a compound represented by formula (Ih) or formula (Ii) or formula (Ij):
一些实施方式中，R
1、R
1’相同或不同，独立地选自H、-CH
3。
In some embodiments, R 1 , R 1 ' are the same or different, and are independently selected from H, -CH 3 .
一些实施方式中，D是CR
9，E是CR
10；R
9选自H、Cl、F、卤代的C
1-C
6烷氧基，R
10选自卤代的C
1-C
6烷氧基；进一步地，R
9选自H、Cl、F、-OCH
2F、-OCHF
2或-OCF
3，R
10选自-OCH
2F、-OCHF
2或-OCF
3。
In some embodiments, D is CR 9 , E is CR 10 ; R 9 is selected from H, Cl, F, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halogenated C 1 -C 6 alkoxy oxy; further, R 9 is selected from H, Cl, F, -OCH 2 F, -OCHF 2 or -OCF 3 , and R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
一些实施方式中，D是N，E是CR
10；R
10选自卤代的C
1-C
6烷氧基；进一步地R
10选自-OCH
2F、-OCHF
2或-OCF
3。
In some embodiments, D is N and E is CR 10 ; R 10 is selected from halogenated C 1 -C 6 alkoxy; further R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
一些实施方式中，D是CR
9，E是CR
10；R
9选自卤代的C
1-C
6烷氧基，R
10选自H、Cl、F、卤代的C
1-C
6烷氧基；进一步地，R
9选自-OCH
2F、-OCHF
2或-OCF
3，R
10选自H、Cl、F、-OCH
2F、-OCHF
2或-OCF
3。
In some embodiments, D is CR 9 , E is CR 10 ; R 9 is selected from halogenated C 1 -C 6 alkoxy, and R 10 is selected from H, Cl, F, halogenated C 1 -C 6 alkane oxy; further, R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 , and R 10 is selected from H, Cl, F, -OCH 2 F, -OCHF 2 or -OCF 3 .
一些实施方式中，D是CR
9，E是N；R
9选自卤代的C
1-C
6烷氧基；进一步地，R
9选自-OCH
2F、-OCHF
2或-OCF
3。
In some embodiments, D is CR 9 and E is N; R 9 is selected from halogenated C 1 -C 6 alkoxy; further, R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
一些实施方式中，D是CR
9，E是N；R
9选自-OCH
2F、-OCHF
2或-OCF
3。
In some embodiments, D is CR9 and E is N; R9 is selected from -OCH2F , -OCHF2 or -OCF3 .
一些实施方式中，D是N，E是CR
10；R
10选自-OCH
2F、-OCHF
2或-OCF
3。
In some embodiments, D is N and E is CR 10 ; R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
一些实施方式中，R
11是Me、F或CH
2F。
In some embodiments, R 11 is Me, F or CH 2 F.
一些实施方式中，R
12是Me、F、CH
2F、CHF
2、CF
3、CH
2OMe或CH
2OH。
In some embodiments, R12 is Me, F, CH2F , CHF2 , CF3 , CH2OMe , or CH2OH .
一些实施方式中，R
13是H或F。
In some embodiments, R 13 is H or F.
一些实施方式中，R
12和R
13连同它们附接至其上的碳原子一起形成环丙基、 环丁基或氧杂环丁基。
In some embodiments, R 12 and R 13 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or oxetanyl group.
一些实施方式中，R
11为F，R
12为F，且R
13为F。
In some embodiments, R 11 is F, R 12 is F, and R 13 is F.
一些实施方式中，R
11为F，R
12为CH
2OH，且R
13为F。
In some embodiments, R 11 is F, R 12 is CH 2 OH, and R 13 is F.
一些实施方式中，R
11为F，R
12和R
13连同它们附接至其上的碳原子一起形成氧杂环丁基。
In some embodiments, R 11 is F, and R 12 and R 13 together with the carbon atom to which they are attached form an oxetanyl group.
一些实施方式中，R
8是H。
In some embodiments, R8 is H.
一些实施方式中，R
8是F。
In some embodiments, R8 is F.
一些实施方式中，R
8是CN。
In some embodiments, R8 is CN.
一些实施方式中，r为0；s为3。In some embodiments, r is 0; s is 3.
一些实施方式中，r为2；s为2。In some embodiments, r is 2; s is 2.
一些实施方式中，r为2；s为1。In some embodiments, r is 2; s is 1.
一些实施方式中，环A选自C
4-C
6杂环基；进一步地，环A为氮杂环丁烷基、吡咯烷基或哌啶基。
In some embodiments, Ring A is selected from C4 - C6 heterocyclyl; further, Ring A is azetidinyl, pyrrolidinyl, or piperidinyl.
一些实施方式中，p为1。In some embodiments, p is 1.
一些实施方式中，p为2。In some embodiments, p is 2.
一些实施方式中，所述式(I)所示化合物选自：In some embodiments, the compound represented by the formula (I) is selected from:
N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
4-((3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氨基)-1-(3-氟丙基)吡咯烷-3-醇；4-((3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyrido[3,4-b]indol-1-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;
4-((4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)氨基)-1-(3-氟丙基)吡咯烷-3-醇；4-((4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole- 1-yl)-3-(difluoromethoxy)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;
6-((2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-(二氟甲氧基)-N-(1-(3-氟丙基)氮杂环丁烷-3-基)吡啶-3-胺；6-((2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl )-5-(difluoromethoxy)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine;
N-(3-(二氟甲氧基)-4-(2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;
N-(3-(二氟甲氧基)-4-(2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((1-fluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
1-(3-氟丙基)-N-(4-((3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)氮杂环丁烷-3-胺；1-(3-Fluoropropyl)-N-(4-((3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)azetidin-3-amine;
1-(3-氟丙基)-N-(4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺；1-(3-Fluoropropyl)-N-(4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
3-(1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇；3-(1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-Tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
N-(3-(二氟甲氧基)-4-(2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
2,2-二氟-3-(1-(4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)-2-(三氟甲氧基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙-1-醇；2,2-Difluoro-3-(1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-(trifluoromethoxy)phenyl )-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propan-1-ol;
N-(3-(二氟甲氧基)-4-(2-((3-氟代氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
N-(3-(二氟甲氧基)-4-(2-((3-氟氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrakis Hydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
6-((2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-(二氟甲氧基)-N-(1-(3-氟丙基)吡咯烷-3-基)吡啶-3-胺；6-((2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl )-5-(difluoromethoxy)-N-(1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
5-(二氟甲氧基)-N-(1-(3-氟丙基)氮杂环丁烷-3-基)-6-((3-甲基-2- (2,2,2-三氟乙基)-2，3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)吡啶-3-胺；5-(Difluoromethoxy)-N-(1-(3-fluoropropyl)azetidine-3-yl)-6-((3-methyl-2-(2,2,2 - trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)pyridin-3-amine;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;
N1-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-N2-(3-氟丙基)乙烷-1,2-二胺；N1-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-propylazetidine-3-amine;
N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
1-(3-氟丙基)-N-(4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺；1-(3-Fluoropropyl)-N-(4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine;
N1-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-N2-(3-氟丙基)乙烷-1,2-二胺；N1-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;
N1-(3-氟丙基)-N2-(4-((3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)乙烷-1,2-二胺；N1-(3-Fluoropropyl)-N2-(4-((3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)ethane-1,2-diamine;
N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) yl[3,4-b]indol-1-yl)phenyl)-1-propylazetidine-3-amine;
N-(4-((3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(4-((3-Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridinyl[3,4-b]indole dol-1-yl)-3-(trifluoromethoxy)phenyl)-1-propylazetidine-3-amine;
N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;
1-(3-氟丙基)-N-(4-((3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)哌啶-4-胺；1-(3-Fluoropropyl)-N-(4-((3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)piperidin-4-amine;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;
4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-N-(2-(3-(氟甲基)氮杂环丁烷-1-基)乙基)-3-(三氟甲氧基)苯胺；4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl) -N-(2-(3-(fluoromethyl)azetidin-1-yl)ethyl)-3-(trifluoromethoxy)aniline;
N-(2-(3-(氟甲基)氮杂环丁烷-1-基)乙基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4，9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯胺；N-(2-(3-(Fluoromethyl)azetidine-1-yl)ethyl)-4-(3-methyl-2-(2,2,2-trifluoroethyl)- 2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)aniline;
1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2- (2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;
1-(3-(二氟甲氧基)-5-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)吡啶-2-基)-3-甲基-2-(2，2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；1-(3-(Difluoromethoxy)-5-((1-(3-fluoropropyl)azetidin-3-yl)oxy)pyridin-2-yl)-3-methyl -2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;
5-(二氟甲氧基)-N-(1-(3-氟丙基)吡咯烷-3-基)-6-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)吡啶-3-胺；5-(Difluoromethoxy)-N-(1-(3-fluoropropyl)pyrrolidin-3-yl)-6-(3-methyl-2-(2,2,2-trifluoroethyl) yl)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)pyridin-3-amine;
1-(3-(二氟甲氧基)-5-(((1-(3-氟丙基)吡咯烷-3-基)氧基)吡啶-2-基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；1-(3-(Difluoromethoxy)-5-(((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2 -(2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;
1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)吡咯烷-3-基)氧基)苯基)-3-甲基-2-(2，2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2, 2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;
N-(3-(二氟甲氧基)-4-(2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
N-(3-(二氟甲氧基)-4-(2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
N-(3-(二氟甲氧基)-4-(2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((1-fluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
3-(1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)吡咯烷-3-基)氨基)苯基)-3-甲基-1，3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇；3-(1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-1,3 ,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;
2,2-二氟-3-((1-(4-((1-(3-氟丙基)吡咯烷-3-基)氨基)-2-(三氟甲氧基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙-1-醇；2,2-Difluoro-3-((1-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2-(trifluoromethoxy)phenyl)- 3-Methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propan-1-ol;
N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-1- yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
3-(1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)吡咯烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇；3-(1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-1,3 ,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;
N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]Indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
1-(4-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)-2-(三氟甲氧基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚；1-(4-((1-(3-Fluoropropyl)azetidine-3-yl)oxy)-2-(trifluoromethoxy)phenyl)-3-methyl-2- (2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole;
1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-6-甲腈；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-( 2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-6-carbonitrile;
N-(3-(二氟甲氧基)-4-(3-甲基-2-((3-甲基氧杂环丁-3-基)甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-((3-methyloxetan-3-yl)methyl)-2,3,4,9- Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
N-(4-(2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-(2-(2-Fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole -1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
N-(3-(二氟甲氧基)-5-氟-4-(2-((3-氟代氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-5-fluoro-4-(2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-7-甲腈；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-( 2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-7-carbonitrile;
1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-8-甲腈；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-( 2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-8-carbonitrile;
N-(3-(二氟甲氧基)-4-(2-((3-氟氧代环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((3-fluorooxocyclobutan-3-yl)methyl)-3-methyl-2,3,4,9-tetra Hydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;
N-(3-(二氟甲氧基)-4-(2-((3-氟氮杂环丁烷-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；或N-(3-(Difluoromethoxy)-4-(2-((3-fluoroazetidin-3-yl)methyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine; or
4-(3-((3,5-二氟-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氨基)氮杂环丁烷-1-基)丁腈。4-(3-((3,5-Difluoro-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidin-1-yl)butyronitrile.
一些实施方式中，所述式(I)所示化合物选自：In some embodiments, the compound represented by the formula (I) is selected from:
(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
N-(3-(二氟甲氧基)-4-((1R,3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
(3R，4R)-4-((3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氨基)-1-(3-氟丙基)吡咯烷-3-醇；(3R,4R)-4-((3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2 ,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;
(3R，4R)-4-((4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)氨基)-1-(3-氟丙基)吡咯烷-3-醇；(3R,4R)-4-((4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(difluoromethoxy)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;
6-(((1S，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-(二氟甲氧基)-N-(1-(3-氟丙基)氮杂环丁烷-3-基)吡啶-3-胺；6-(((1S,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-1-yl)-5-(difluoromethoxy)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine;
N-(3-(二氟甲氧基)-4-((1R，3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
N-(3-(二氟甲氧基)-4-((1R，3R)-2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((1-fluorocyclobutyl)methyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
1-(3-氟丙基)-N-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)氮杂环丁烷-3-胺；1-(3-Fluoropropyl)-N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 - Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)azetidine-3-amine;
(S)-1-(3-氟丙基)-N-(4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺；(S)-1-(3-Fluoropropyl)-N-(4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine;
N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
(S)-N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[ 3,4-b]indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
(R)-N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(R)-N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[ 3,4-b]indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
3-((1R,3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇；3-((1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;
(S)-N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[ 3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
2,2-二氟-3-((1R,3R)-1-(4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)-2-(三氟甲氧基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙-1-醇；2,2-Difluoro-3-((1R,3R)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-(trifluoro Methoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propan-1-ol;
N-(3-(二氟甲氧基)-4-((1R,3R)-2-((3-氟代氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2, 3,4,9-Tetrahydro-1H-pyridinyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-2-((3-氟氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl -2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
6-(((1S，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-(二氟甲氧基)-N-((S)-1-(3-氟丙基)吡咯烷-3-基)吡啶-3-胺；6-(((1S,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-1-yl)-5-(difluoromethoxy)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine;
(R)-N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(R)-N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[ 3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
5-(二氟甲氧基)-N-(1-(3-氟丙基)氮杂环丁烷-3-基)-6-(((1S，3R)-3-甲基-2-(2,2,2-三氟乙基)-2，3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)吡啶-3-胺；5-(Difluoromethoxy)-N-(1-(3-fluoropropyl)azetidine-3-yl)-6-(((1S,3R)-3-methyl-2- (2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)pyridin-3-amine;
N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;
N1-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶 基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-N2-(3-氟丙基)乙烷-1,2-二胺；N1-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4- b] Indol-1-yl)-3-(trifluoromethoxy)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;
N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-propylazetidine-3-amine;
(R)-N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(R)-N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
(R)-1-(3-氟丙基)-N-(4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺；(R)-1-(3-Fluoropropyl)-N-(4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine;
N1-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-N2-(3-氟丙基)乙烷-1,2-二胺；N1-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;
N1-(3-氟丙基)-N2-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)乙烷-1,2-二胺；N1-(3-Fluoropropyl)-N2-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 - Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)ethane-1,2-diamine;
N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-propylazetidine-3-amine;
N-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridinyl[3 ,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-propylazetidine-3-amine;
N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;
1-(3-氟丙基)-N-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)哌啶-4-胺；1-(3-Fluoropropyl)-N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 - Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)piperidin-4-amine;
N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;
4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-N-(2-(3-(氟甲基)氮杂环丁烷-1-基)乙基)-3-(三氟甲氧基)苯胺；4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole dol-1-yl)-N-(2-(3-(fluoromethyl)azetidin-1-yl)ethyl)-3-(trifluoromethoxy)aniline;
N-(2-(3-(氟甲基)氮杂环丁烷-1-基)乙基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4，9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯胺；N-(2-(3-(Fluoromethyl)azetidin-1-yl)ethyl)-4-((1R,3R)-3-methyl-2-(2,2,2- trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)aniline;
(1R，3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；(1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3 -methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;
(1S，3R)-1-(3-(二氟甲氧基)-5-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)吡啶-2-基)-3-甲基-2-(2，2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；(1S,3R)-1-(3-(difluoromethoxy)-5-((1-(3-fluoropropyl)azetidin-3-yl)oxy)pyridin-2-yl )-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;
5-(二氟甲氧基)-N-((S)-1-(3-氟丙基)吡咯烷-3-基)-6-((1S，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)吡啶-3-胺；5-(Difluoromethoxy)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((1S,3R)-3-methyl-2- (2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)pyridin-3-amine;
(1S，3R)-1-(3-(二氟甲氧基)-5-((((S)-1-(3-氟丙基)吡咯烷-3-基)氧基)吡啶-2-基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；(1S,3R)-1-(3-(difluoromethoxy)-5-((((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridine-2 -yl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;
(1R，3R)-1-(2-(二氟甲氧基)-4-(((S)-1-(3-氟丙基)吡咯烷-3-基)氧基)苯基)-3-甲基-2-(2，2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；(1R,3R)-1-(2-(difluoromethoxy)-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;
N-(3-(二氟甲氧基)-4-((1R，3R)-2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3, 4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-2-((1-fluorocyclobutyl)methyl)-3-methyl-2,3, 4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
3-((1R，3R)-1-(2-(二氟甲氧基)-4-(((S)-1-(3-氟丙基)吡咯烷-3-基)氨基)苯基)-3-甲基-1，3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇；3-((1R,3R)-1-(2-(difluoromethoxy)-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl )-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;
2,2-二氟-3-(((1R，3R)-1-(4-(((S)-1-(3-氟丙基)吡咯烷-3-基)氨基)-2-(三氟甲氧基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙-1-醇；2,2-Difluoro-3-(((1R,3R)-1-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2-( trifluoromethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propan-1-ol;
N-(4-((1R,3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine[3,4-b ]indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
3-((1R,3R)-1-(2-(二氟甲氧基)-4-(((S)-1-(3-氟丙基)吡咯烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇；3-((1R,3R)-1-(2-(difluoromethoxy)-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl )-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;
(S)-N-(3-(二氟甲氧基)-4-((1S,3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;
(1R,3R)-1-(4-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)-2-(三氟甲氧基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚；(1R,3R)-1-(4-((1-(3-Fluoropropyl)azetidin-3-yl)oxy)-2-(trifluoromethoxy)phenyl)-3 -methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole;
(1R,3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-6-甲腈；(1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3- Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-6-carbonitrile;
N-(3-(二氟甲氧基)-4-((1R,3R)-3-甲基-2-((3-甲基氧杂环丁-3-基)甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-((3-methyloxetan-3-yl)methyl)-2, 3,4,9-Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;
N-(4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]Indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
N-(3-(二氟甲氧基)-5-氟-4-((1R,3R)-2-((3-氟代氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-5-fluoro-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl yl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine- 3-amine;
(1R,3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-7-甲腈；(1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3- Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-7-carbonitrile;
(1R,3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-8-甲腈；(1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3- Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-8-carbonitrile;
N-(3-(二氟甲氧基)-4-((1R,3R)-2-((3-氟氧代环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((3-fluorooxocyclobutan-3-yl)methyl)-3-methyl-2,3 ,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;
N-(3-(二氟甲氧基)-4-((1R,3R)-2-((3-氟氮杂环丁烷-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；或N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((3-fluoroazetidin-3-yl)methyl)-3-methyl-2, 3,4,9-Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine; or
4-(3-((3,5-二氟-4-((1R,3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢 -1H-吡啶并[3,4-b]吲哚-1-基)苯基)氨基)氮杂环丁烷-1-基)丁腈。4-(3-((3,5-Difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 -Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidin-1-yl)butyronitrile.
本发明还提供了一种药物组合物，所述药物组合物包含治疗有效量的至少一种所述式(I)所示化合物和至少一种药学上可接受的辅料。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by the formula (I) and at least one pharmaceutically acceptable excipient.
本发明还提供了式(I)所示化合物在制备用于治疗***受体相关疾病的药物中的用途。The present invention also provides the use of the compound represented by formula (I) in the preparation of a medicament for treating estrogen receptor-related diseases.
一些实施方式中，所述***受体相关疾病为选自以下的癌症：乳腺癌、肺癌、卵巢癌、子宫内膜癌、***癌和子宫癌。In some embodiments, the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
本发明还提供了一种在患者中治疗***受体相关疾病的方法，其包括向所述患者给予治疗有效量的上述式(I)所示化合物。The present invention also provides a method for treating an estrogen receptor-related disease in a patient, which comprises administering to the patient a therapeutically effective amount of the compound represented by the above formula (I).
一些实施方式中，所述***受体相关疾病为选自以下的癌症：乳腺癌、肺癌、卵巢癌、子宫内膜癌、***癌和子宫癌。In some embodiments, the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
定义definition
上述结构通式中使用的一般化学术语具有通常的含义。The general chemical terms used in the general formulae above have their usual meanings.
例如，除非另有说明，本发明所用的术语“卤代”和“卤素”是指氟、氯、溴或碘。优选的卤素基团包括氟、氯和溴。For example, unless otherwise specified, the terms "halo" and "halogen" as used herein refer to fluorine, chlorine, bromine or iodine. Preferred halogen groups include fluorine, chlorine and bromine.
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。本文中使用的烷基基团可以任选地被一至多个取代基取代。烷基基团的非限制性实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“C
1-8烷基”中的“C
1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链或支链形式排列的基团。
In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. Alkyl groups as used herein may be optionally substituted with one to more substituents. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl) ) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like. Similarly, "C 1-8 " in "C 1-8 alkyl" refers to a linear or branched arrangement containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms group.
烯基和炔基包括直链或支链的烯基和炔基。同样地，“C
2-8烯基”和“C
2-8炔基”是指含有2、3、4、5、6、7或者8个碳原子以直链或支链形式排列的烯基或炔基。
Alkenyl and alkynyl groups include straight or branched chain alkenyl and alkynyl groups. Likewise, "C 2-8 alkenyl" and "C 2-8 alkynyl" refer to alkenyl groups containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain or alkynyl.
“烷氧基”是指前述的直链或支链烷基的氧醚形式，即-O-烷基。"Alkoxy" refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
“卤代的烷氧基”是指前述的“烷氧基”被1个或多个卤素取代；卤代的烷氧基基团的非限制性实例包括但不限于例如-OCH
2F、-OCHF
2、-OCF
3、-OCH
2CH
2F、-OCH
2CHF
2、-OCH
2CF
3、-OCHFCH
3、-OCF
2CH
3、-OCHFCH
2F等。
" Haloalkoxy " means the aforementioned "alkoxy" is substituted with one or more halogens; non-limiting examples of halogenated alkoxy groups include, but are not limited to, for example, -OCH2F, - OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 3 , -OCF 2 CH 3 , -OCHFCH 2 F and the like.
在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换 使用。因此，例如，包含“一种”药学上可接受的赋形剂的组合物可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋形剂。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
术语“芳香环”，在本发明中，除非另有说明，是指未取代或取代的包括碳原子的单环、并环或稠环芳香基团，或者未取代或取代的包括杂原子，例如N、O或S的单环、并环或稠环芳香基团，当为并环或稠环时，至少有一个环具有芳香性。优选芳香环为5到10元的单环或双环的芳香环基团。这些芳香环的实例包括但不限于苯基、吡啶基、吡唑基、嘧啶基、苯并二氢呋喃、吲哚基。The term "aromatic ring", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic, polycyclic or fused-ring aromatic group including carbon atoms, or unsubstituted or substituted including heteroatoms, such as A monocyclic, paracyclic or condensed aromatic group of N, O or S, when it is a polycyclic or condensed ring, at least one ring is aromatic. Preferably, the aromatic ring is a 5- to 10-membered monocyclic or bicyclic aromatic ring group. Examples of such aromatic rings include, but are not limited to, phenyl, pyridyl, pyrazolyl, pyrimidinyl, chromofuran, indolyl.
术语“环烷基”，是指在环中仅含碳原子的单环和多环***，并且可以任选地被一至多个取代基取代。本文中使用的环烷基是指并且包括饱和的或不饱和的非芳香的环状***。术语环烷基另外包括桥环、稠环和螺环的环状***。环烷基的非限制性实例包括例如环丙基、环丁基、环戊基、环己基、环己烯基、螺[3.4]辛基、双环[2.2.1]庚烷等。The term "cycloalkyl" refers to monocyclic and polycyclic ring systems containing only carbon atoms in the ring, and which may be optionally substituted with one or more substituents. Cycloalkyl as used herein refers to and includes saturated or unsaturated non-aromatic ring systems. The term cycloalkyl further includes bridged, fused and spiro ring systems. Non-limiting examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[3.4]octyl, bicyclo[2.2.1]heptane, and the like.
术语“杂环基”，在本发明中，除非另有说明，是指由碳原子和1-3个选自N、O或S的杂原子组成的未取代或取代的单环和多环***，并且包括饱和的或不饱和的环状***以及具有不饱和部分和/或芳香部分的多环***。其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。应该理解，多环杂环烷基基团另外包括稠环、桥环和螺环的环状***。本文中使用的杂环烷基基团可以任选地被一至多个取代基取代。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。The term "heterocyclyl", in the present invention, unless otherwise specified, refers to unsubstituted or substituted monocyclic and polycyclic ring systems consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. , and includes saturated or unsaturated ring systems as well as polycyclic systems having unsaturated and/or aromatic moieties. Wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. It should be understood that polycyclic heterocycloalkyl groups additionally include fused, bridged, and spiro ring systems. Heterocycloalkyl groups used herein may be optionally substituted with one to more substituents. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
除非另有说明，本文所用的术语“芳基”是指含有碳环原子的未取代或取代的单环或多环环系，至少一个环具有芳香性。优选的芳基是单环或双环6-10元芳环***。苯基和萘基是优选的芳基。最优选的芳基是苯基。As used herein, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms, at least one of which is aromatic in nature. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
术语“杂芳基”，在本发明中，除非另有说明，是指未取代或取代的稳定的5元或6元单环芳族环***或未取代或取代的9元或10元苯并稠合杂芳族环***或双环杂芳族环***，其由碳原子和1-4个选自N、O或S的杂原子组成，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季 铵化。杂芳基可以连接在任何杂原子或碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、***基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻二唑基、苯并***基腺嘌呤、喹啉基或异喹啉基。The term "heteroaryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo A fused heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may be optionally replaced by oxidation, the nitrogen heteroatom can be selectively quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl , benzotriazolyl adenine, quinolinyl or isoquinolinyl.
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于卤素(F、Cl、Br或I)、C
1-8烷基、C
3-12环烷基、-OR
1、-SR
1、＝O、＝S、-C(O)R
1、-C(S)R
1、＝NR
1、-C(O)OR
1、-C(S)OR
1、-NR
1R
2、-C(O)NR
1R
2、氰基、硝基、-S(O)
2R
1、-O-S(O
2)OR
1、-O-S(O)
2R
1、-OP(O)(OR
1)(OR
2)；其中R
1和R
2独立地选自-H、C
1-6烷基、C
1-6卤代烷基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH
3、-SC
2H
5、甲醛基、-C(OCH
3)、氰基、硝基、-CF
3、-OCF
3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。
The term "substituted" refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C 1-8 alkyl, C 3-12 cycloalkyl, -OR 1 , -SR 1 , =O, =S, -C (O)R 1 , -C(S)R 1 , =NR 1 , -C(O)OR 1 , -C(S)OR 1 , -NR 1 R 2 , -C(O)NR 1 R 2 , cyano, nitro, -S(O) 2 R 1 , -OS(O 2 )OR 1 , -OS(O) 2 R 1 , -OP(O)(OR 1 )(OR 2 ); wherein R 1 and R 2 are independently selected from -H, C 1-6 alkyl, C 1-6 haloalkyl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
取代烷基的实例包括但不限于2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基和哌嗪基甲基。Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.
取代烷氧基的实例包括但不限于氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羟基丙氧基。Examples of substituted alkoxy groups include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，方便地制得其相应的盐。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds provided herein are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases.
由于式(I)所示化合物将作为药物应用，较优地，使用一定纯度，例如，至少为60％纯度，比较合适的纯度为至少75％，特别合适地纯度为至少98％(％是重量比)。Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。特别优选的衍生物或前药是在施用于患者时可以提高本申请化合物生物利用度的那些化合物(例 如，可以使口服的化合物更易于被吸收到血液中)，或者促进母体化合物向生物器官或作用位点(例如脑部或淋巴***)递送的那些化合物。因此，本发明提供的治疗方法中的术语“给药”是指施用能治疗不同疾病的本发明公开的化合物，或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的化合物。有关选择和制备合适药物前体衍生物的常规方法，已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。Prodrugs of the compounds of the present invention are included within the scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues. Particularly preferred derivatives or prodrugs are those compounds that, when administered to a patient, increase the bioavailability of the compounds of the present application (eg, make orally administered compounds more readily absorbed into the blood), or promote the delivery of the parent compound to biological organs or Those compounds that are delivered to the site of action (eg, the brain or lymphatic system). Therefore, the term "administration" in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or, although not explicitly disclosed, can be transformed into the disclosure in vivo after administration to a subject compound of. Conventional methods for the selection and preparation of suitable prodrug derivatives are described in, for example, Design of Prodrugs (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
显然的，一个分子中任何取代基或特定位置的变量的定义是独立于分子中其他位置的。很容易理解，本领域技术人员可以通过现有技术手段及本发明中所述的方法来选择本发明中的化合物的取代基或取代形式，以获得化学上稳定且易于合成的化合物。Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of other positions in the molecule. It is easy to understand that those skilled in the art can select the substituents or substituted forms of the compounds of the present invention by means of the prior art and the methods described in the present invention, so as to obtain chemically stable and easy-to-synthesize compounds.
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
上述式(I)没有确切定义该化合物某一位置的立体结构。本发明包括式(I)所示化合物的所有立体异构体及其药学上可接受的盐。进一步地，立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中，或使用本领域技术人员公知的外消旋化或差向异构化的过程中，制得的产品可以是立体异构体的混合物。The above formula (I) does not exactly define the stereoscopic structure of the compound at a certain position. The present invention includes all stereoisomers of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. During synthetic procedures to prepare such compounds, or using racemization or epimerization procedures well known to those skilled in the art, the resulting product may be a mixture of stereoisomers.
当式(I)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药学上可接受的盐，及它们的混合物。When the compound represented by formula (I) exists as a tautomer, unless otherwise stated, the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.
当式(I)所示化合物及其药学上可接受的盐存在溶剂化物或多晶型时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药学上可以接受的。术语“组合物”，在本发明中，是指包括包含指定量的各指定成分的产品，以及直接或间接地由指定量的各指定成分的组合生产的任何产品。因此，含有本发明的化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外，化合物的一些结晶形式可以多晶型存在，并且此多晶型包括在本发明中。另外，一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物，并且此类溶剂化物也落入本发明的范围内。When the compounds of formula (I) and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. The term "composition", in the present invention, refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下，最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度，但是本发明的药物组合物包括适于口腔、直肠、局部和不经肠道(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。The pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories. Although the most suitable mode of administration of the active ingredient in any given situation will depend on the particular subject being administered, the nature of the subject and the severity of the condition, the pharmaceutical compositions of the present invention include oral, rectal, topical and Pharmaceutical compositions for parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.
本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下，这种方法包括使活性组分和组成一个或多个必要成分的载体缔合的步骤。一般情况下，所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过统一的密切的混合制得。另外，该产品可以方便地制备成所需要的外观。The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients. In general, the pharmaceutical compositions are prepared by uniform intimate admixture of the active ingredient with liquid carriers or finely divided solid carriers, or a mixture of both. In addition, the product can be easily prepared to the desired appearance.
因此，本发明的药物组合物包括药学上可接受的载体和式(I)所示化合物或其立体异构体、互变异构体，多晶型物、溶剂化物、其药学上可接受的盐、其药物前体。式(I)所示化合物或其药学上可接受的盐，与其他一种或多种具有治疗活性的化合物的联合用药也包括在本发明的药物组合物中。Therefore, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or its stereoisomer, tautomer, polymorph, solvate, pharmaceutically acceptable Salts and their prodrugs. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, combined with one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.
本发明采用的药物载体可以是，例如，固体载体、液体载体或气体载体。The pharmaceutical carrier employed in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier.
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content clearer and clearer, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention, so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiments of the present invention, the technical means or methods that are not specifically described are conventional technical means or methods in the field.
除非另有说明，本发明所有的一部分和百分比均按重量计算，所有温度均指摄氏度。All parts and percentages herein are by weight and all temperatures are in degrees Celsius unless otherwise indicated.
实施例中使用了下列缩略语：The following abbreviations are used in the examples:
CbzCl：氯甲酸苄酯；CbzCl: benzyl chloroformate;
NaHCO
3：碳酸氢钠；
NaHCO 3 : sodium bicarbonate;
THF：四氢呋喃；THF: tetrahydrofuran;
Et
3N/TEA：三乙胺；
Et 3 N/TEA: triethylamine;
TosCl：对甲苯磺酰氯；TosCl: p-toluenesulfonyl chloride;
H
2：氢气；
H 2 : hydrogen;
Pd(OH)
2/C：碳负载氢氧化钯；
Pd(OH) 2 /C: palladium hydroxide supported on carbon;
EtOH：乙醇；EtOH: ethanol;
KI：碘化钾；KI: potassium iodide;
Cs
2CO
3：碳酸铯；
Cs 2 CO 3 : cesium carbonate;
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
I
2：碘；
I 2 : iodine;
Na
2CO
3：碳酸钠；
Na 2 CO 3 : sodium carbonate;
H
2O：水；
H 2 O: water;
K
2CO
3：碳酸钾；
K 2 CO 3 : potassium carbonate;
ACN/CH
3CN：乙腈；
ACN/CH 3 CN: acetonitrile;
i-PrMgCl(2M in THF)：异丙基氯化镁(2mol/L的四氢呋喃溶液)；i-PrMgCl (2M in THF): isopropyl magnesium chloride (2mol/L tetrahydrofuran solution);
NaH：氢化钠；NaH: sodium hydride;
TBDPSCl：叔丁基二苯基氯硅烷；TBDPSCl: tert-butyldiphenylchlorosilane;
Tf
2O：三氟甲磺酸酐；
Tf 2 O: trifluoromethanesulfonic anhydride;
2,6-Lutidine：2,6-二甲基吡啶；2,6-Lutidine: 2,6-lutidine;
DCM：二氯甲烷；DCM: dichloromethane;
HCl(4M in二氧六环)：4mol/L盐酸的1,4-二氧六环溶液；HCl (4M in dioxane): 1,4-dioxane solution of 4mol/L hydrochloric acid;
EA/EtOAc：乙酸乙酯；EA/EtOAc: ethyl acetate;
Boc：叔丁氧羰基；Boc: tert-butoxycarbonyl;
HOAc：醋酸；HOAc: acetic acid;
甲苯/Tol：甲苯；Toluene/Tol: Toluene;
DIEA/DIPEA：N,N-二异丙基乙胺；DIEA/DIPEA: N,N-diisopropylethylamine;
1,4-二氧六环：1,4-二氧六环；1,4-dioxane: 1,4-dioxane;
Pd
2(dba)
3：三(二亚苄基丙酮)二钯；
Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium;
Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene;
TBAF：四丁基氟化铵；TBAF: tetrabutylammonium fluoride;
BrettPhos Pd G3：甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基 -1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)；BrettPhos Pd G3: Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2' -amino-1,1'-biphenyl-2-yl)palladium(II);
t-BuONa：叔丁醇钠；t-BuONa: sodium tert-butoxide;
ERα：***受体α；ERα: estrogen receptor α;
LC-MS或LCMS：液相色谱-质谱。LC-MS or LCMS: Liquid Chromatography-Mass Spectrometry.
实施例部分所用的原料、试剂可以从商业来源获得或通过本领域的常规方法制备得到。The starting materials and reagents used in the Example section can be obtained from commercial sources or prepared by conventional methods in the art.
另外，如制备中间体INT11合成路线中，步骤2为Pictet-Spengler环化反应，通过该反应以提供作为所需反式异构体为主的环化产物(Chem.Rev.1995,95(6),1797-1842.)，少量顺式的非对映异构体通过后续柱层析纯化去除。类似地，中间体INT12-中间体INT17等均通过Pictet-Spengler环化反应得到反式异构体为主的环化产物。In addition, as in the synthetic route for the preparation of the intermediate INT11, step 2 is the Pictet-Spengler cyclization reaction, which is used to provide the cyclized product mainly as the desired trans isomer (Chem. Rev. 1995, 95 (6). ), 1797-1842.), a small amount of cis diastereomer was removed by subsequent column chromatography purification. Similarly, intermediate INT12-intermediate INT17, etc. are all obtained through Pictet-Spengler cyclization reaction to obtain cyclization products dominated by trans isomers.
中间体的合成Synthesis of Intermediates
化合物INT1的合成：Synthesis of compound INT1:
步骤1：化合物INT1-2的合成Step 1: Synthesis of Compound INT1-2
向1L单口瓶中，加入化合物INT1-1(30.00g，1eq)，THF(300mL)，NaHCO
3(39.74g，3eq)。降温至0℃，向其中滴加CbzCl(32.28g，1.2eq)，室温下搅拌反应过夜。反应完毕后，浓缩反应液，残余物加DCM稀释，水洗，饱和食盐水洗，有机相干燥，浓缩，柱层析纯化(PE:EA＝100:0-50:50)，得40.80g化合物INT1-2。
Into a 1L single-neck flask, add compound INT1-1 (30.00 g, 1 eq), THF (300 mL), NaHCO 3 (39.74 g, 3 eq). The temperature was lowered to 0° C., CbzCl (32.28 g, 1.2 eq) was added dropwise thereto, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated, the residue was diluted with DCM, washed with water, washed with saturated brine, the organic phase was dried, concentrated, and purified by column chromatography (PE:EA=100:0-50:50) to obtain 40.80 g of compound INT1- 2.
LC-MS[M+H]
+：325。
LC-MS [M+H] + : 325.
1H NMR(500MHz,DMSO-d6)δ10.77(d,J＝2.4Hz,1H),7.58(d,J＝7.8Hz,1H),7.40-7.25(m,6H),7.12-7.02(m,3H),6.96(t,J＝7.4Hz,1H),4.98(s,2H),4.69(t,J＝5.6Hz,1H),3.80-3.67(m,1H),3.44-3.34(m,2H),2.95-2.90(m,1H),2.77-2.71(m,1H).
1 H NMR (500MHz, DMSO-d6) δ 10.77 (d, J=2.4Hz, 1H), 7.58 (d, J=7.8Hz, 1H), 7.40-7.25 (m, 6H), 7.12-7.02 (m ,3H),6.96(t,J＝7.4Hz,1H),4.98(s,2H),4.69(t,J＝5.6Hz,1H),3.80-3.67(m,1H),3.44-3.34(m, 2H), 2.95-2.90(m, 1H), 2.77-2.71(m, 1H).
步骤2：化合物INT1-3的合成Step 2: Synthesis of compounds INT1-3
向1L三口瓶中，加入化合物INT1-2(39.80g，1eq)，THF(400mL)，Et
3N (37.25g，3eq)。降温至0℃，向其中滴加TosCl(42.11g，1.8eq)溶于THF(200mL)的溶液，室温下搅拌反应过夜。反应完毕后，浓缩反应液，残余物加DCM稀释，水洗，饱和食盐水洗，有机相干燥，浓缩，柱层析纯化(PE:EA＝100:0-50:50)，得39.50g化合物INT1-3。
Into a 1L three-necked flask, add compound INT1-2 (39.80 g, 1 eq), THF (400 mL), Et 3 N (37.25 g, 3 eq). The temperature was lowered to 0° C., a solution of TosCl (42.11 g, 1.8 eq) dissolved in THF (200 mL) was added dropwise thereto, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated, the residue was diluted with DCM, washed with water, washed with saturated brine, the organic phase was dried, concentrated, and purified by column chromatography (PE:EA=100:0-50:50) to obtain 39.50 g of compound INT1- 3.
LC-MS[M+H]
+：479。
LC-MS [M+H] + : 479.
步骤3：化合物INT1的合成Step 3: Synthesis of Compound INT1
向1L单口瓶中，加入化合物INT1-3(39.50g，1eq)，EtOH(600mL)，Pd(OH)
2/C(19.71g)，氢气置换，室温下搅拌反应过夜。反应完毕后，过滤反应液，浓缩，柱层析纯化(DCM:MeOH＝100:0-90:10)，得14.00g化合物INT1。
Into a 1L single-neck flask, add compound INT1-3 (39.50g, 1eq), EtOH (600mL), Pd(OH) 2 /C (19.71g), replace with hydrogen, and stir the reaction at room temperature overnight. After completion of the reaction, the reaction solution was filtered, concentrated, and purified by column chromatography (DCM:MeOH=100:0-90:10) to obtain 14.00 g of compound INT1.
LC-MS[M+H]
+：175。
LC-MS [M+H] + : 175.
1H NMR(500MHz,Chloroform-d)δ8.74-8.49(m,1H),7.54(d,J＝7.8Hz,2H),7.06-6.91(m,3H),3.26(q,J＝6.6Hz,1H),2.90-2.70(m,2H),1.06(d,J＝6.4Hz,3H)。
1 H NMR (500MHz, Chloroform-d) δ 8.74-8.49 (m, 1H), 7.54 (d, J=7.8Hz, 2H), 7.06-6.91 (m, 3H), 3.26 (q, J=6.6Hz) , 1H), 2.90-2.70 (m, 2H), 1.06 (d, J=6.4Hz, 3H).
化合物INT2的合成：Synthesis of compound INT2:
步骤1：化合物INT2的合成Step 1: Synthesis of Compound INT2
向50ml单口瓶中，加入化合物INT2-1(2.00g，1eq)，DMF(25mL)，Cs
2CO
3(4.86g，1.5eq)，KI(0.20g，0.12eq)，化合物INT2-2(2.94g，1.5eq)，升温至75℃搅拌反应过夜。反应完毕后，乙酸乙酯稀释，水洗，饱和食盐水洗，有机相干燥，浓缩，柱层析纯化(PE:EA＝100:0-80:20)，得0.50g化合物INT2。
Into a 50ml single-neck bottle, add compound INT2-1 (2.00g, 1eq), DMF (25mL), Cs2CO3 ( 4.86g , 1.5eq), KI (0.20g, 0.12eq), compound INT2-2 (2.94 g, 1.5eq), warmed to 75°C and stirred the reaction overnight. After the reaction was completed, it was diluted with ethyl acetate, washed with water, washed with saturated brine, the organic phase was dried, concentrated, and purified by column chromatography (PE:EA=100:0-80:20) to obtain 0.50 g of compound INT2.
1H NMR(500MHz,DMSO-d6)δ10.22(s,1H),7.78(d,J＝8.2Hz,1H),7.71-7.64(m,2H),7.45(t,J＝72.9Hz,1H).
1 H NMR(500MHz, DMSO-d6)δ10.22(s,1H),7.78(d,J=8.2Hz,1H),7.71-7.64(m,2H),7.45(t,J=72.9Hz,1H) ).
化合物INT3的合成：Synthesis of compound INT3:
步骤1：化合物INT3-2的合成Step 1: Synthesis of compound INT3-2
向500ml单口瓶中，加入化合物INT3-1(16.00g，1eq)，H
2O(160mL)，Na
2CO
3(29.24g，3eq)，I
2(12.84g，1.1eq)。室温下搅拌反应过夜。反应完毕后，用2mol/L的HCl溶液调节反应液PH＝1-2，滴加过程中析出固体，搅拌0.5小时，过滤，滤饼用水洗2-3次，收集滤饼，干燥，得15.70g化合物INT3-2。
Into a 500ml single-neck flask, add compound INT3-1 (16.00g, 1eq), H2O (160mL), Na2CO3 (29.24g, 3eq), I2 ( 12.84g, 1.1eq). The reaction was stirred at room temperature overnight. After the completion of the reaction, adjust the pH of the reaction solution to 1-2 with 2 mol/L HCl solution, precipitate solids during the dropwise addition, stir for 0.5 hours, filter, wash the filter cake with water 2-3 times, collect the filter cake, and dry to obtain 15.70 g Compound INT3-2.
LC-MS[M+H]
+：300/302。
LC-MS [M+H] + : 300/302.
步骤2：化合物INT3-4的合成Step 2: Synthesis of Compound INT3-4
向250ml单口瓶中，加入化合物INT3-2(10.00g，1eq)，ACN(50mL)，K
2CO
3(13.83g，3eq)，化合物INT3-3(7.63g，1.5eq)。85℃搅拌反应6小时，反应完毕后，过滤，滤液浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得7.50g化合物INT3-4。
Into a 250ml single-neck flask, add compound INT3-2 (10.00g, 1eq), ACN (50mL), K 2 CO 3 (13.83g, 3eq), compound INT3-3 (7.63g, 1.5eq). The reaction was stirred at 85° C. for 6 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 7.50 g of compound INT3-4.
LC-MS[M+H]
+：350/352。
LC-MS [M+H] + : 350/352.
1H NMR(500MHz,DMSO-d6)δ8.46(d,J＝2.1Hz,1H),7.95(d,J＝2.1Hz,1H),7.41(t,J＝72.4Hz,1H).
1 H NMR (500MHz, DMSO-d6)δ8.46(d,J=2.1Hz,1H),7.95(d,J=2.1Hz,1H),7.41(t,J=72.4Hz,1H).
步骤3：化合物INT3的合成Step 3: Synthesis of Compound INT3
向50ml三口瓶中，加入化合物INT3-4(1.37g，1eq)，THF(14mL)，氮气保护，降温至0℃。向其中滴加i-PrMgCl(2.0M in THF)(3.9mL，2eq)，滴加完毕后，0℃下搅拌反应1小时。向其中加入DMF(0.86g，3eq)，加完后，0℃搅拌反应1小时。反应完毕后，用饱和氯化铵水溶液淬灭反应，EA萃取，有机相浓缩，柱层析纯化(PE:EA＝100:0-60:40)，得0.25g化合物INT3。Into a 50 ml three-necked flask, add compound INT3-4 (1.37 g, 1 eq), THF (14 mL), under nitrogen protection, and cool to 0°C. i-PrMgCl (2.0 M in THF) (3.9 mL, 2 eq) was added dropwise thereto, and the reaction was stirred at 0° C. for 1 hour after the dropwise addition was completed. DMF (0.86g, 3eq) was added thereto, and after the addition, the reaction was stirred at 0°C for 1 hour. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with EA, the organic phase was concentrated, and purified by column chromatography (PE:EA=100:0-60:40) to obtain 0.25 g of compound INT3.
LC-MS[M+H]
+：252/254。
LC-MS [M+H] + : 252/254.
化合物INT4的合成：Synthesis of compound INT4:
步骤1：化合物INT4-2的合成Step 1: Synthesis of compound INT4-2
向250ml三口瓶中，加入化合物INT4-1(4.00g，1eq)，THF(50mL)，氮气保护，降温至0℃，缓慢向其中加入NaH(60％含量，1.5g，1.05eq)，冰浴搅拌30分钟，加入TBDPSCl(9.7mL，1.05eq)。室温下搅拌反应4小时，冰浴下 用水淬灭反应，乙酸乙酯萃取，有机相干燥，浓缩，柱层析纯化(PE:EA＝5:1)，得8.60g化合物INT4-2。To a 250ml three-necked flask, add compound INT4-1 (4.00g, 1eq), THF (50mL), nitrogen protection, cool down to 0°C, slowly add NaH (60% content, 1.5g, 1.05eq) to it, ice bath After stirring for 30 minutes, TBDPSCl (9.7 mL, 1.05 eq) was added. The reaction was stirred at room temperature for 4 hours, quenched with water in an ice bath, extracted with ethyl acetate, the organic phase was dried, concentrated, and purified by column chromatography (PE:EA=5:1) to obtain 8.60 g of compound INT4-2.
步骤2：化合物INT4的合成Step 2: Synthesis of Compound INT4
向250ml三口瓶中，加入化合物INT4-2(8.60g，1eq)，DCM(100mL)，2,6-Lutidine(7.89g，3eq)，氮气保护，降温至0℃，缓慢向其中加入Tf
2O(6.19mL，1.5eq)，室温下搅拌反应过夜。冰浴下用水淬灭反应，乙酸乙酯萃取，有机相干燥，浓缩，柱层析纯化(PE:EA＝5:1)，得3.00g化合物INT4。
To a 250ml three-necked flask, add compound INT4-2 (8.60g, 1eq), DCM (100mL), 2,6-Lutidine (7.89g, 3eq), under nitrogen protection, cool down to 0°C, slowly add Tf 2 O to it (6.19 mL, 1.5 eq), and the reaction was stirred at room temperature overnight. The reaction was quenched with water under an ice bath, extracted with ethyl acetate, the organic phase was dried, concentrated, and purified by column chromatography (PE:EA=5:1) to obtain 3.00 g of compound INT4.
1H NMR(500MHz,DMSO-d6)δ7.75-7.60(m,4H),7.56-7.39(m,6H),5.21(t,J＝13.6Hz,2H),4.01(t,J＝12.9Hz,2H),1.02(s,9H).
1 H NMR(500MHz,DMSO-d6)δ7.75-7.60(m,4H),7.56-7.39(m,6H),5.21(t,J=13.6Hz,2H),4.01(t,J=12.9Hz) ,2H),1.02(s,9H).
化合物INT5的合成：Synthesis of compound INT5:
步骤1：化合物INT5-3的合成Step 1: Synthesis of compound INT5-3
向250ml单口瓶中，加入化合物INT5-1(2.00g，1eq)，CH
3CN(50mL)，K
2CO
3(4.82g，3eq)，化合物INT5-2(2.40g，1.1eq)。70℃搅拌反应过夜，反应完毕后，浓缩反应液，残余物加DCM/H
2O分层，有机相水洗、浓缩，得2.30g化合物INT5-3。
Into a 250ml single-neck flask, compound INT5-1 (2.00g, 1eq), CH3CN (50mL), K2CO3 ( 4.82g , 3eq), compound INT5-2 (2.40g, 1.1eq) were added. The reaction was stirred at 70°C overnight. After the reaction was completed, the reaction solution was concentrated, the residue was added with DCM/H 2 O to separate layers, the organic phase was washed with water and concentrated to obtain 2.30 g of compound INT5-3.
LC-MS[M+H]
+：233。
LC-MS [M+H] + : 233.
步骤6：化合物INT5的合成Step 6: Synthesis of Compound INT5
向250ml单口瓶中，加入化合物INT5-3(2.30g，1eq)，EA(50mL)，HCl(4M in二氧六环)(50mL)。室温搅拌反应过夜，反应完毕后，过滤，干燥滤饼，得1.60g化合物INT5(盐酸盐)。To a 250ml single-neck bottle, add compound INT5-3 (2.30g, 1 eq), EA (50mL), HCl (4M in dioxane) (50mL). The reaction was stirred at room temperature overnight. After the reaction was completed, it was filtered and the filter cake was dried to obtain 1.60 g of compound INT5 (hydrochloride).
LC-MS[M+H]
+：133。
LC-MS [M+H] + : 133.
化合物INT6/INT7/INT8/INT9/INT10的合成：Synthesis of compounds INT6/INT7/INT8/INT9/INT10:
按照类似化合物INT5的合成方法，采用如上相应的原料和路线，即可合成化合物INT6、INT7、INT8、INT9、INT10的盐酸盐。The hydrochloride salts of compounds INT6, INT7, INT8, INT9, and INT10 can be synthesized according to the synthetic method of the similar compound INT5, using the corresponding raw materials and routes as above.
化合物INT11的合成：Synthesis of compound INT11:
步骤1：化合物INT11-2的合成Step 1: Synthesis of compound INT11-2
向500ml三口瓶中，加入化合物INT1(5.00g，1eq)，ACN(100mL)，K
2CO
3(11.90g，3eq)，化合物INT11-1(9.99g，1.5eq)，升温至55℃搅拌反应2小时。反应完毕后，过滤反应液，浓缩，柱层析纯化(PE:EA＝100:0-85:15)，得2.17g化合物INT11-2。
Into a 500ml three-necked flask, add compound INT1 (5.00g, 1eq), ACN (100mL), K 2 CO 3 (11.90g, 3eq), compound INT11-1 (9.99g, 1.5eq), heat up to 55°C and stir the reaction 2 hours. After completion of the reaction, the reaction solution was filtered, concentrated, and purified by column chromatography (PE:EA=100:0-85:15) to obtain 2.17 g of compound INT11-2.
LC-MS[M+H]
+：257。
LC-MS [M+H] + : 257.
1H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.60(d,J＝7.8,1H),7.40-7.30(m,1H),7.23-7.17(m,1H),7.15-7.09(m,1H),7.05(d,J＝2.3Hz,1H),3.18-3.13(m,3H),2.84(d,J＝6.6Hz,2H),1.14(d,J＝6.2Hz,3H).
1 H NMR (500MHz, Chloroform-d) δ8.01(s, 1H), 7.60(d, J=7.8, 1H), 7.40-7.30(m, 1H), 7.23-7.17(m, 1H), 7.15- 7.09(m, 1H), 7.05(d, J=2.3Hz, 1H), 3.18-3.13(m, 3H), 2.84(d, J=6.6Hz, 2H), 1.14(d, J=6.2Hz, 3H) ).
步骤2：化合物INT11的合成(Pictet-Spengler环化反应)Step 2: Synthesis of compound INT11 (Pictet-Spengler cyclization)
向100ml单口瓶中，加入化合物INT11-2(2.11g，1eq)，甲苯(30mL)，化合物INT2(2.69g，1.3eq)，HOAc(1.48g,3eq)。升温至90℃搅拌反应过夜。反应完毕后，用饱和碳酸氢钠溶液调节PH＝8，乙酸乙酯萃取，有机相浓缩，柱层析纯化(PE:EA＝100:0-90:10)，得2.78g化合物INT11。Into a 100ml single-neck flask, add compound INT11-2 (2.11g, 1eq), toluene (30mL), compound INT2 (2.69g, 1.3eq), HOAc (1.48g, 3eq). The temperature was raised to 90°C and the reaction was stirred overnight. After completion of the reaction, adjust pH=8 with saturated sodium bicarbonate solution, extract with ethyl acetate, concentrate the organic phase, and purify by column chromatography (PE:EA=100:0-90:10) to obtain 2.78g of compound INT11.
LC-MS[M+H]
+：489/491。
LC-MS [M+H] + : 489/491.
1H NMR(500MHz,DMSO-d6)δ10.66(s,1H),7.49(d,J＝1.8Hz,1H),7.46(d,J＝7.8Hz,1H),7.44-7.38(m,1H),7.34-7.28(m,1H),7.25(d,J＝7.5Hz,1H),7.06(t,J＝7.5Hz,1H),6.99(t,J＝7.4Hz,1H),6.63(d,J＝8.3Hz,1H),5.30(s,1H),3.53-3.49(m,1H),3.29-3.17(m,1H),3.02-2.92(m,1H),2.78-2.74(m,1H),2.62-2.58(m,1H),1.08(d,J＝6.6Hz,3H).
1 H NMR(500MHz,DMSO-d6)δ10.66(s,1H),7.49(d,J=1.8Hz,1H),7.46(d,J=7.8Hz,1H),7.44-7.38(m,1H) ),7.34-7.28(m,1H),7.25(d,J=7.5Hz,1H),7.06(t,J=7.5Hz,1H),6.99(t,J=7.4Hz,1H),6.63(d , J=8.3Hz, 1H), 5.30(s, 1H), 3.53-3.49(m, 1H), 3.29-3.17(m, 1H), 3.02-2.92(m, 1H), 2.78-2.74(m, 1H) ), 2.62-2.58(m, 1H), 1.08(d, J=6.6Hz, 3H).
化合物INT12的合成：Synthesis of compound INT12:
步骤1：化合物INT12-2的合成Step 1: Synthesis of compound INT12-2
向100mL单口瓶中加入化合物INT1(1.50g，1eq)，THF(30mL)，TEA(2.61g，3eq)，化合物INT12-1(2.40g，1.3eq)，升温至50℃搅拌反应2小时。反应完毕后，反应液加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-60:40)，得0.88g化合物INT12-2。Compound INT1 (1.50 g, 1 eq), THF (30 mL), TEA (2.61 g, 3 eq), and compound INT12-1 (2.40 g, 1.3 eq) were added to a 100 mL single-neck flask, and the temperature was raised to 50° C. and stirred for 2 hours. After the completion of the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-60:40) to obtain 0.88g of compound INT12-2 .
LC-MS[M+H]
+：239。
LC-MS [M+H] + : 239.
1H NMR(500MHz,Chloroform-d)δ8.03(s,1H),7.62-7.58(m,1H),7.39-7.35(m,1H),7.23-7.17(m,1H),7.15-7.10(m,1H),7.05(d,J＝2.3Hz,1H),5.95-5.65(m,1H),3.14-3.04(m,1H),3.03-2.89(m,2H),2.88-2.74(m,2H),1.13(d,J＝6.2Hz,3H).
1 H NMR (500MHz, Chloroform-d) δ8.03(s,1H), 7.62-7.58(m,1H), 7.39-7.35(m,1H), 7.23-7.17(m,1H), 7.15-7.10( m, 1H), 7.05(d, J=2.3Hz, 1H), 5.95-5.65(m, 1H), 3.14-3.04(m, 1H), 3.03-2.89(m, 2H), 2.88-2.74(m, 2H), 1.13(d, J=6.2Hz, 3H).
步骤2：化合物INT12的合成Step 2: Synthesis of compound INT12
向50mL单口瓶中加入化合物INT12-2(280mg，1eq)，甲苯(5mL)，化合物INT2(442mg，1.5eq)，HOAc(212mg，3eq)，升温至100℃搅拌反应4小时。反应完毕后，加饱和碳酸氢钠溶液调节PH＝8，乙酸乙酯萃取，有机相用无水硫酸钠干燥，浓缩，反相柱层析纯化(H
2O:MeOH＝95:5-0:100)，得502mg化合物INT12。
Compound INT12-2 (280 mg, 1 eq), toluene (5 mL), compound INT2 (442 mg, 1.5 eq), and HOAc (212 mg, 3 eq) were added to a 50 mL single-neck flask, and the temperature was raised to 100° C. and stirred for 4 hours. After the completion of the reaction, add saturated sodium bicarbonate solution to adjust pH=8, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by reverse phase column chromatography (H 2 O:MeOH=95:5-0: 100) to obtain 502 mg of compound INT12.
LC-MS[M+H]
+：471/473。
LC-MS [M+H] + : 471/473.
化合物INT13的合成：Synthesis of compound INT13:
步骤1：化合物INT13-2的合成Step 1: Synthesis of compound INT13-2
向250mL单口瓶中加入化合物INT13-1(3.00g，1eq)，DCM(120mL)，2,6-Lutidine(4.19g，1.2eq)，冰浴下向其中滴加Tf
2O(11.03g，1.2eq)，滴加完毕后室温搅拌反应2小时。反应完毕后，加冰水淬灭反应，依次用1mol/L盐酸、饱和碳酸氢钠溶液洗涤，有机相浓缩得6.30g化合物INT13-2，直接用于下一步。
Compound INT13-1 (3.00g, 1eq), DCM (120mL), 2,6-Lutidine (4.19g, 1.2eq) were added to a 250mL single-neck flask, and Tf 2 O (11.03g, 1.2 eq) was added dropwise to it under ice bath. eq), after the dropwise addition was completed, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, ice water was added to quench the reaction, washed with 1 mol/L hydrochloric acid and saturated sodium bicarbonate solution successively, and the organic phase was concentrated to obtain 6.30 g of compound INT13-2, which was directly used in the next step.
步骤2：化合物INT13-3的合成Step 2: Synthesis of compound INT13-3
向50mL单口瓶中加入化合物INT1(800mg，1eq)，1,4-二氧六环(10mL)，DIEA(1.19g，2eq)，INT13-2(1.03g，1eq)，升温至100℃搅拌反应5小时。反应完毕后，加乙酸乙酯稀释反应液，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-50:50)，得300mg化合物INT13-3。Add compound INT1 (800mg, 1eq), 1,4-dioxane (10mL), DIEA (1.19g, 2eq), INT13-2 (1.03g, 1eq) to a 50mL single-neck flask, and the temperature was raised to 100°C and stirred for reaction 5 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-50:50) to obtain 300 mg of compound INT13-3.
LC-MS[M+H]
+：249。
LC-MS [M+H] + : 249.
步骤3：化合物INT13的合成Step 3: Synthesis of compound INT13
向50mL单口瓶中加入化合物INT13-3(280mg，1eq)，甲苯(10mL)，化合物INT2(340mg，1.2eq)，HOAc(1mL)。升温至90℃搅拌反应4小时，反应完毕后，用饱和碳酸氢钠溶液调节PH＝8，乙酸乙酯萃取，有机相水洗、饱和食盐水洗、无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-90:10)，得300mg化合物INT13。Compound INT13-3 (280 mg, 1 eq), toluene (10 mL), compound INT2 (340 mg, 1.2 eq), and HOAc (1 mL) were added to a 50 mL single-neck flask. The temperature was raised to 90°C and the reaction was stirred for 4 hours. After the reaction was completed, PH=8 was adjusted with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography ( PE:EA=100:0-90:10) to obtain 300 mg of compound INT13.
LC-MS[M+H]
+：481/483。
LC-MS [M+H] + : 481/483.
化合物INT14的合成：Synthesis of compound INT14:
步骤1：化合物INT14的合成Step 1: Synthesis of compound INT14
向50mL单口瓶中加入化合物INT11-2(136mg，0.67eq)，甲苯(5mL)，化合物INT3(200mg，1eq)，HOAc(95mg，2eq)，升温至100℃搅拌反应2小时。反应完毕后，用饱和碳酸氢钠溶液调节PH＝8，乙酸乙酯萃取，有机相用无水硫酸钠干燥、浓缩，柱层析纯化(PE:EA＝100:0-90:10)，得140mg化合物INT14。Compound INT11-2 (136 mg, 0.67 eq), toluene (5 mL), compound INT3 (200 mg, 1 eq), HOAc (95 mg, 2 eq) were added to a 50 mL single-neck flask, and the temperature was raised to 100° C. and stirred for 2 hours. After completion of the reaction, adjust pH=8 with saturated sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography (PE:EA=100:0-90:10) to obtain 140 mg of compound INT14.
LC-MS[M+H]
+：490/492。
LC-MS [M+H] + : 490/492.
1H NMR(500MHz,DMSO-d6)δ10.55(s,1H),8.41(d,J＝1.8Hz,1H), 7.65-7.29(m,2H),7.21(d,J＝7.9Hz,1H),7.08-6.90(m,2H),5.42(s,1H),3.67-3.43(m,2H),3.08-3.00(m,1H),2.72-2.52(m,2H),1.09(d,J＝6.8Hz,3H).
1 H NMR (500MHz, DMSO-d6) δ 10.55(s, 1H), 8.41(d, J=1.8Hz, 1H), 7.65-7.29(m, 2H), 7.21(d, J=7.9Hz, 1H) ), 7.08-6.90(m, 2H), 5.42(s, 1H), 3.67-3.43(m, 2H), 3.08-3.00(m, 1H), 2.72-2.52(m, 2H), 1.09(d, J =6.8Hz,3H).
化合物INT15/INT16/INT17的合成：Synthesis of compounds INT15/INT16/INT17:
按照INT14的合成方法，选用合适的原料，可以合成INT15、INT16、INT17。According to the synthesis method of INT14, select appropriate raw materials, INT15, INT16, INT17 can be synthesized.
化合物INT18/INT19/INT20的合成：Synthesis of compounds INT18/INT19/INT20:
按照INT13的合成方法，选用合适的原料，可以合成INT18、INT19、INT20。According to the synthesis method of INT13, select appropriate raw materials, can synthesize INT18, INT19, INT20.
INT18的合成路线：Synthetic route of INT18:
INT19的合成路线：Synthetic route of INT19:
INT20的合成路线：Synthetic route of INT20:
化合物INT21的合成：Synthesis of compound INT21:
步骤1：化合物INT21-1的合成Step 1: Synthesis of compound INT21-1
向50ml单口瓶中，加入化合物INT1(1.50g，1eq)，ACN(30mL)，化合物INT4(6.23g，1.5eq)，K
2CO
3(3.57g，3eq)，升温至90℃搅拌反应2小时。反应完毕后，过滤反应液，浓缩，柱层析纯化(PE:EA＝100:0-80:20)，得1.63g化合物INT21-1。
Into a 50ml single-necked flask, add compound INT1 (1.50g, 1eq), ACN (30mL), compound INT4 (6.23g, 1.5eq), K 2 CO 3 (3.57g, 3eq), heat up to 90°C and stir for 2 hours . After the reaction was completed, the reaction solution was filtered, concentrated, and purified by column chromatography (PE:EA=100:0-80:20) to obtain 1.63 g of compound INT21-1.
LC-MS[M+H]
+：507。
LC-MS [M+H] + : 507.
1H NMR(500MHz,Chloroform-d)δ7.94(s,1H),7.71-7.67(m,4H),7.66-7.61(m,1H),7.52-7.35(m,7H),7.24-7.20(m,1H),7.16-7.12(m,1H),7.03(d,J＝2.3Hz,1H),4.18-4.14(m,1H),3.93-3.72(m,2H),3.25-3.21(m,1H),3.18-3.06(m,2H),2.99-2.75(m,2H),1.15(d,J＝6.2Hz,3H),1.08(s,9H)。
1 H NMR (500MHz, Chloroform-d) δ7.94(s,1H), 7.71-7.67(m,4H), 7.66-7.61(m,1H), 7.52-7.35(m,7H), 7.24-7.20( m, 1H), 7.16-7.12(m, 1H), 7.03(d, J=2.3Hz, 1H), 4.18-4.14(m, 1H), 3.93-3.72(m, 2H), 3.25-3.21(m, 1H), 3.18-3.06 (m, 2H), 2.99-2.75 (m, 2H), 1.15 (d, J=6.2Hz, 3H), 1.08 (s, 9H).
步骤2：化合物INT21-2的合成Step 2: Synthesis of compound INT21-2
向50ml单口瓶中，加入化合物INT21-1(1.63g，1eq)，THF(20mL)，TBAF(6.45mL，1mol/L in THF，2eq)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，柱层析纯化(PE:EA＝100:0-0:100)，得0.80g化合物INT21-2。Into a 50ml single-neck flask, compound INT21-1 (1.63g, 1eq), THF (20mL), TBAF (6.45mL, 1mol/L in THF, 2eq) were added, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (PE:EA=100:0-0:100) to obtain 0.80 g of compound INT21-2.
LC-MS[M+H]
+：269。
LC-MS [M+H] + : 269.
步骤3：化合物INT21-3的合成Step 3: Synthesis of Compound INT21-3
向10ml单口瓶中，加入化合物INT21-2(160mg，1eq)，甲苯(3.5mL)，化合物INT2(179mg，1.2eq)，HOAc(107mg，3eq)，升温至90℃搅拌反应2小时。反应完毕后，浓缩反应液，柱层析纯化(PE:EA＝100:0-80:20)，得193mg化合物INT21-3。Into a 10ml single-necked flask, compound INT21-2 (160mg, 1eq), toluene (3.5mL), compound INT2 (179mg, 1.2eq), HOAc (107mg, 3eq) were added, the temperature was raised to 90°C and the reaction was stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (PE:EA=100:0-80:20) to obtain 193 mg of compound INT21-3.
LC-MS[M+H]
+：501/503。
LC-MS [M+H] + : 501/503.
化合物INT22的合成：Synthesis of compound INT22:
按照INT21步骤3的实验方法，将INT2替换成INT15-1，即可得到INT22。According to the experimental method of step 3 of INT21, replace INT2 with INT15-1 to get INT22.
化合物INT23的合成：Synthesis of compound INT23:
按照INT11步骤2的实验方法，将INT2替换成INT23-1，即可得到INT23。According to the experimental method of step 2 of INT11, replace INT2 with INT23-1 to get INT23.
化合物INT24的合成：Synthesis of compound INT24:
步骤1：化合物INT24-2的合成Step 1: Synthesis of compound INT24-2
向50ml单口瓶中，加入化合物INT24-1(900mg，1eq)，对甲苯磺酰氯(707mg，1.1eq)，TEA(1.02g，3eq)，DMAP(41mg，0.1eq)，DCM(18mL)，室温搅拌反应3小时。反应完毕后，用水淬灭，分层，有机相用无硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-75:25)，得996mg化合物INT24-2。Into a 50ml single-neck flask, add compound INT24-1 (900mg, 1eq), p-toluenesulfonyl chloride (707mg, 1.1eq), TEA (1.02g, 3eq), DMAP (41mg, 0.1eq), DCM (18mL), room temperature The reaction was stirred for 3 hours. After the reaction was completed, quenched with water, separated into layers, the organic phase was dried over sodium sulfate free, concentrated, and purified by column chromatography (PE:EA=100:0-75:25) to obtain 996 mg of compound INT24-2.
LC-MS[M+H]
+：375。
LC-MS [M+H] + : 375.
步骤2：化合物INT24-4的合成Step 2: Synthesis of compound INT24-4
于50ml三口瓶中，加入化合物INT24-2(1.63g，1eq)，THF(12mL)，氮气保护下，降温至-60℃，滴加2.5M正丁基锂(1.7ml，2eq)，搅拌30分钟，滴加化合物INT24-3(755mg，1.5eq)的THF(6ml)溶液，加完自然升温搅拌，控温再-20℃左右，搅拌1.5h，加2ml饱和氯化铵溶液和5ml1M的HCl水溶液淬灭，室温下搅拌反应1小时。反应完毕后，乙酸乙酯稀释，水洗一次，饱和食盐水洗一次，干燥，浓缩反应液，柱层析纯化(PE:EA＝100:0-75:25)，得324mg化合物INT24-4。In a 50ml three-necked flask, add compound INT24-2 (1.63g, 1eq), THF (12mL), under nitrogen protection, cool down to -60°C, dropwise add 2.5M n-butyllithium (1.7ml, 2eq), stir for 30 minutes minutes, add the THF (6ml) solution of compound INT24-3 (755mg, 1.5eq) dropwise, after the addition, the temperature rises and stirs naturally, the temperature is controlled to about -20°C, and the stirring is for 1.5h, and 2ml of saturated ammonium chloride solution and 5ml of 1M HCl are added. The aqueous solution was quenched and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was diluted with ethyl acetate, washed once with water, once with saturated brine, dried, concentrated and purified by column chromatography (PE:EA=100:0-75:25) to obtain 324 mg of compound INT24-4.
LC-MS[M+H]
+：454。
LC-MS [M+H] + : 454.
步骤3：化合物INT24-5的合成Step 3: Synthesis of compound INT24-5
于25ml单口瓶中，加入化合物INT24-4(324mg，1eq)，DCM(6mL)，4N HCl的二氧六环溶液(3ml)，室温搅拌反应2小时。反应完毕后，浓缩反应液，得278mg化合物INT24-5。In a 25ml single-necked flask, compound INT24-4 (324mg, 1eq), DCM (6mL), 4N HCl solution in dioxane (3ml) were added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain 278 mg of compound INT24-5.
LC-MS[M+H]
+：354。
LC-MS [M+H] + : 354.
步骤4：化合物INT24-6的合成Step 4: Synthesis of compound INT24-6
于50ml单口瓶中，加入化合物INT24-5(268mg，1eq)，乙腈(10mL)，碳酸钾(285mg，3eq)化合物INT11-1(239mg，1.5eq)，加热升温至60℃搅拌反应8小时。反应完毕后，浓缩反应液，乙酸乙酯稀释，水洗一次，饱和食盐水洗一次，干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得254mg化合物INT24-6。In a 50ml single-neck flask, compound INT24-5 (268mg, 1eq), acetonitrile (10mL), potassium carbonate (285mg, 3eq) and compound INT11-1 (239mg, 1.5eq) were added, and the mixture was heated to 60°C and stirred for 8 hours. After completion of the reaction, the reaction solution was concentrated, diluted with ethyl acetate, washed once with water, once with saturated brine, dried, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 254 mg of compound INT24-6.
LC-MS[M+H]
+：436。
LC-MS [M+H] + : 436.
步骤5：化合物INT24的合成Step 5: Synthesis of compound INT24
于50ml单口瓶中，加入化合物INT24-6(254mg，1eq)，甲醇(10mL)， 氢氧化钾(98mg，3eq)，加热升温至70℃搅拌反应3小时。反应完毕后，浓缩反应液，残余物溶于乙酸乙酯/水中，搅拌分层，水相用乙酸乙酯萃取一次，合并有机相，无水硫酸钠干燥，得198mg化合物INT24。In a 50ml single-necked bottle, compound INT24-6 (254mg, 1eq), methanol (10mL), potassium hydroxide (98mg, 3eq) were added, and the temperature was heated to 70°C and stirred for reaction for 3 hours. After the completion of the reaction, the reaction solution was concentrated, the residue was dissolved in ethyl acetate/water, and the layers were separated by stirring. The aqueous phase was extracted once with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate to obtain 198 mg of compound INT24.
LC-MS[M+H]
+：282。
LC-MS [M+H] + : 282.
化合物INT25的合成：Synthesis of compound INT25:
按照INT11步骤2的实验方法，将INT21-2替换成INT24，即可得到INT25。According to the experimental method of step 2 of INT11, replace INT21-2 with INT24 to get INT25.
实施例1：化合物A1((S)-N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺)的制备Example 1: Compound A1((S)-N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl) yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidine-3- amine) preparation
步骤1：化合物A1-2的合成Step 1: Synthesis of Compound A1-2
向10ml单口瓶中，加入化合物INT11(175mg，1eq)，化合物A1-1(100mg，1.5eq)，Pd
2dba
3(65mg,0.2eq)，xantphos(83mg,0.4eq),Cs
2CO
3(350mg,3.0eq),1,4-二氧六环(2mL)，氮气保护，升温至110℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得121mg化合物A1-2。
Into a 10ml single-neck bottle, add compound INT11 (175mg, 1eq), compound A1-1 (100mg, 1.5eq), Pd 2 dba 3 (65mg, 0.2eq), xantphos (83mg, 0.4eq), Cs 2 CO 3 ( 350mg, 3.0eq), 1,4-dioxane (2mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 121 mg of compound A1-2 .
LC-MS[M+H]
+：595。
LC-MS [M+H] + : 595.
步骤2：化合物A1-3的合成Step 2: Synthesis of Compound A1-3
向50ml单口瓶中，加入化合物A1-2(121mg，1eq)，DCM(5mL),HCl/dioxane(4M,5mL)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，得122mg化合物A1-3(盐酸盐)。Into a 50 ml single-neck flask, compound A1-2 (121 mg, 1 eq), DCM (5 mL), HCl/dioxane (4 M, 5 mL) were added, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain 122 mg of compound A1-3 (hydrochloride).
LC-MS[M+H]
+：495。
LC-MS [M+H] + : 495.
步骤3：化合物A1的合成Step 3: Synthesis of Compound A1
向10ml单口瓶中，加入化合物A1-3(118mg，1eq)，DMF(5mL),DIPEA(0.19mL,6eq)，化合物A1-4(73mg，2eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，反相柱层析纯化(H
2O:CH
3CN＝55:45-20:80)，得15mg化合物A1。
Into a 10ml single-neck flask, compound A1-3 (118mg, 1eq), DMF (5mL), DIPEA (0.19mL, 6eq), compound A1-4 (73mg, 2eq) were added, and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column chromatography (H 2 O:CH 3 CN=55:45-20:80), 15 mg of compound A1 were obtained.
LC-MS[M+H]
+：555。
LC-MS [M+H] + : 555.
实施例2：化合物A2(N-(3-(二氟甲氧基)-4-((1R,3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺)的制备Example 2: Compound A2 (N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2 ,3,4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine ) preparation
步骤1：化合物A2-2的合成Step 1: Synthesis of Compound A2-2
向10ml单口瓶中，加入化合物INT11(175mg，1eq)，化合物A2-1(92mg，1.5eq)，Pd
2dba
3(65mg,0.2eq)，xantphos(83mg,0.4eq),Cs
2CO
3(350mg,3.0eq),1,4-二氧六环(2mL)，氮气保护，升温至110℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得159mg化合物A2-2。
Into a 10ml single-neck bottle, add compound INT11 (175mg, 1eq), compound A2-1 (92mg, 1.5eq), Pd 2 dba 3 (65mg, 0.2eq), xantphos (83mg, 0.4eq), Cs 2 CO 3 ( 350mg, 3.0eq), 1,4-dioxane (2mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 159 mg of compound A2-2 .
LC-MS[M+H]
+：581。
LC-MS [M+H] + : 581.
步骤2：化合物A2-3的合成Step 2: Synthesis of Compound A2-3
向50ml单口瓶中，加入化合物A2-2(159mg，1eq)，DCM(5mL),HCl/dioxane(4M,5mL)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，得162mg化合物A2-3(盐酸盐)。Into a 50 ml single-necked flask, compound A2-2 (159 mg, 1 eq), DCM (5 mL), HCl/dioxane (4 M, 5 mL) were added, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain 162 mg of compound A2-3 (hydrochloride).
LC-MS[M+H]
+：481。
LC-MS [M+H] + : 481.
步骤3：化合物A2的合成Step 3: Synthesis of Compound A2
向10ml单口瓶中，加入化合物A2-3(157mg，1eq)，DMF(5mL),DIPEA(206mg,6eq)，化合物A1-4(100mg，2eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，反相柱层析纯化(H
2O:CH
3CN＝55:45-30:70)，得48mg化合物A2。
Compound A2-3 (157 mg, 1 eq), DMF (5 mL), DIPEA (206 mg, 6 eq), and Compound A1-4 (100 mg, 2 eq) were added to a 10 ml single-neck flask, and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column chromatography (H 2 O:CH 3 CN=55:45-30:70), 48 mg of compound A2 were obtained.
LC-MS[M+H]
+：541。
LC-MS [M+H] + : 541.
实施例6化合物A6的制备The preparation of embodiment 6 compound A6
步骤1：化合物A6-1的合成Step 1: Synthesis of Compound A6-1
向50ml单口瓶中，加入化合物INT13(300mg，1eq)，化合物A2-1(161mg，1.5eq)，Pd
2dba
3(114mg,0.2eq)，xantphos(144mg,0.4eq),Cs
2CO
3(609mg,3.0eq),1,4-二氧六环(10mL)，氮气保护，升温至110℃搅拌反应2小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得179mg化合物A6-1。
Into a 50ml single-neck bottle, add compound INT13 (300mg, 1eq), compound A2-1 (161mg, 1.5eq), Pd 2 dba 3 (114mg, 0.2eq), xantphos (144mg, 0.4eq), Cs 2 CO 3 ( 609mg, 3.0eq), 1,4-dioxane (10mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 179 mg of compound A6-1 .
LC-MS[M+H]
+：573。
LC-MS [M+H] + : 573.
步骤2：化合物A6-2的合成Step 2: Synthesis of Compound A6-2
向50ml单口瓶中，加入化合物A6-1(179mg，1eq)，DCM(5mL),HCl/dioxane(4M,3mL)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，得181mg化合物A6-2(盐酸盐)。Into a 50 ml single-neck flask, compound A6-1 (179 mg, 1 eq), DCM (5 mL), HCl/dioxane (4 M, 3 mL) were added, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain 181 mg of compound A6-2 (hydrochloride).
LC-MS[M+H]
+：473。
LC-MS [M+H] + : 473.
步骤3：化合物A6的合成Step 3: Synthesis of Compound A6
向10ml单口瓶中，加入化合物A6-2(181mg，1eq)，DMF(5mL),DIPEA(241mg,6eq)，化合物A1-4(117mg，2eq)，室温下搅拌反应4小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，薄层层析纯化(DCM:MeOH＝15:1)，得148mg化合物A6。Into a 10ml single-neck flask, compound A6-2 (181mg, 1eq), DMF (5mL), DIPEA (241mg, 6eq), and compound A1-4 (117mg, 2eq) were added, and the reaction was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography (DCM:MeOH=15:1) to obtain 148 mg of compound A6.
LC-MS[M+H]
+：533。
LC-MS [M+H] + : 533.
实施例12化合物A12的制备Example 12 Preparation of compound A12
步骤1：化合物A12-1的合成Step 1: Synthesis of Compound A12-1
向50ml单口瓶中，加入化合物INT12(310mg，1eq)，化合物A2-1(170mg，1.5eq)，Pd
2dba
3(121mg,0.2eq)，xantphos(152mg,0.4eq),Cs
2CO
3(643mg,3.0eq),1,4-二氧六环(10mL)，氮气保护，升温至110℃搅拌反应2小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得135mg化合物A12-1。
To a 50ml single-neck bottle, add compound INT12 (310mg, 1eq), compound A2-1 (170mg, 1.5eq), Pd 2 dba 3 (121mg, 0.2eq), xantphos (152mg, 0.4eq), Cs 2 CO 3 ( 643mg, 3.0eq), 1,4-dioxane (10mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 135 mg of compound A12-1 .
LC-MS[M+H]
+：563。
LC-MS [M+H] + : 563.
步骤2：化合物A12-2的合成Step 2: Synthesis of Compound A12-2
向50ml单口瓶中，加入化合物A12-1(135mg，1eq)，DCM(5mL),HCl/dioxane(4M,3mL)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，得100mg化合物A12-2(盐酸盐)。Into a 50 ml single-neck flask, compound A12-1 (135 mg, 1 eq), DCM (5 mL), HCl/dioxane (4 M, 3 mL) were added, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain 100 mg of compound A12-2 (hydrochloride).
LC-MS[M+H]
+：463。
LC-MS [M+H] + : 463.
步骤3：化合物A12的合成Step 3: Synthesis of Compound A12
向10ml单口瓶中，加入化合物A12-2(100mg，1eq)，DMF(5mL),DIPEA(168mg,6eq)，化合物A1-4(81mg，2eq)，室温下搅拌反应4小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，薄层层析纯化(DCM:MeOH＝15:1)，得19mg化合物A12。Compound A12-2 (100 mg, 1 eq), DMF (5 mL), DIPEA (168 mg, 6 eq), and Compound A1-4 (81 mg, 2 eq) were added to a 10 ml single-neck flask, and the reaction was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography (DCM:MeOH=15:1) to obtain 19 mg of compound A12.
LC-MS[M+H]
+：523。
LC-MS [M+H] + : 523.
实施例13化合物A13的制备Example 13 Preparation of Compound A13
步骤1：化合物A13-1的合成Step 1: Synthesis of Compound A13-1
向10ml单口瓶中，加入化合物INT12(150mg，1eq)，化合物A1-1(77mg，1.3eq)，Pd
2dba
3(58mg,0.2eq)，xantphos(74mg,0.4eq),Cs
2CO
3(207mg,3.0eq),1,4-二氧六环(5mL)，氮气保护，升温至110℃搅拌反应2小时。反应完毕后，用 乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-50:50)，得120mg化合物A13-1。
Into a 10ml single-neck bottle, add compound INT12 (150mg, 1eq), compound A1-1 (77mg, 1.3eq), Pd 2 dba 3 (58mg, 0.2eq), xantphos (74mg, 0.4eq), Cs 2 CO 3 ( 207mg, 3.0eq), 1,4-dioxane (5mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-50:50) to obtain 120 mg of compound A13-1 .
LC-MS[M+H]
+：577。
LC-MS [M+H] + : 577.
步骤2：化合物A13-2的合成Step 2: Synthesis of Compound A13-2
向50ml单口瓶中，加入化合物A13-1(120mg，1eq)，DCM(5mL),HCl/dioxane(4M,5mL)，室温下搅拌反应1小时。反应完毕后，静置，吸出上清液，将残余的固体干燥，得55mg化合物A13-2(盐酸盐)。Into a 50 ml single-neck flask, compound A13-1 (120 mg, 1 eq), DCM (5 mL), and HCl/dioxane (4 M, 5 mL) were added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was left to stand, the supernatant was sucked out, and the residual solid was dried to obtain 55 mg of compound A13-2 (hydrochloride).
LC-MS[M+H]
+：477。
LC-MS [M+H] + : 477.
步骤3：化合物A13的合成Step 3: Synthesis of Compound A13
向10ml单口瓶中，加入化合物A13-2(55mg，1eq)，DMF(5mL),DIPEA(73mg,6eq)，化合物A1-4(35mg，2eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，薄层层析纯化(DCM:MeOH＝10:1)，得21mg化合物A13。Compound A13-2 (55 mg, 1 eq), DMF (5 mL), DIPEA (73 mg, 6 eq), and Compound A1-4 (35 mg, 2 eq) were added to a 10 ml single-neck flask, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography (DCM:MeOH=10:1) to obtain 21 mg of compound A13.
LC-MS[M+H]
+：537。
LC-MS [M+H] + : 537.
实施例19化合物A19的制备Example 19 Preparation of compound A19
步骤1：化合物A19-1的合成Step 1: Synthesis of Compound A19-1
向10ml单口瓶中，加入化合物INT22(200mg，1eq)，化合物A2-1(99mg，1.5eq)，Pd
2dba
3(71mg,0.2eq)，xantphos(89mg,0.4eq),Cs
2CO
3(376mg,3.0eq), 1,4-二氧六环(2mL)，氮气保护，升温至110℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(DCM:MeOH＝100:0-90:10)，得190mg化合物A19-1。
Into a 10ml single-neck bottle, add compound INT22 (200mg, 1eq), compound A2-1 (99mg, 1.5eq), Pd 2 dba 3 (71mg, 0.2eq), xantphos (89mg, 0.4eq), Cs 2 CO 3 ( 376mg, 3.0eq), 1,4-dioxane (2mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:0-90:10) to obtain 190 mg of compound A19-1 .
LC-MS[M+H]
+：611。
LC-MS [M+H] + : 611.
步骤2：化合物A19-2的合成Step 2: Synthesis of Compound A19-2
向50ml单口瓶中，加入化合物A19-1(190mg，1eq)，DCM(5mL),HCl/dioxane(4M,5mL)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，得180mg化合物A19-2(盐酸盐)。Into a 50 ml single-necked flask, compound A19-1 (190 mg, 1 eq), DCM (5 mL), HCl/dioxane (4 M, 5 mL) were added, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain 180 mg of compound A19-2 (hydrochloride).
LC-MS[M+H]
+：511。
LC-MS [M+H] + : 511.
步骤3：化合物A19的合成Step 3: Synthesis of Compound A19
向10ml单口瓶中，加入化合物A19-2(180mg，1eq)，DMF(5mL),DIPEA(255mg,6eq)，化合物A1-4(124mg，2eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，反相柱层析纯化(H
2O:CH
3CN＝100:0-20:80)，得56mg化合物A19。
Into a 10ml single-neck flask, compound A19-2 (180mg, 1eq), DMF (5mL), DIPEA (255mg, 6eq), compound A1-4 (124mg, 2eq) were added, and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column chromatography (H 2 O:CH 3 CN=100:0-20:80), 56 mg of compound A19 were obtained.
LC-MS[M+H]
+：571。
LC-MS [M+H] + : 571.
实施例20化合物A20的制备Example 20 Preparation of compound A20
步骤1：化合物A20-1的合成Step 1: Synthesis of Compound A20-1
向10ml单口瓶中，加入化合物INT19(100mg，1eq)，化合物A2-1(52mg，1.5eq)，Pd
2dba
3(37mg,0.2eq)，xantphos(47mg,0.4eq),Cs
2CO
3(197mg,3.0eq),1,4-二氧六环(2mL)，氮气保护，升温至110℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得99mg化合物A20-1。
To a 10ml single-neck bottle, add compound INT19 (100mg, 1eq), compound A2-1 (52mg, 1.5eq), Pd 2 dba 3 (37mg, 0.2eq), xantphos (47mg, 0.4eq), Cs 2 CO 3 ( 197mg, 3.0eq), 1,4-dioxane (2mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 99 mg of compound A20-1 .
LC-MS[M+H]
+：587。
LC-MS [M+H] + : 587.
步骤2：化合物A20-2的合成Step 2: Synthesis of Compound A20-2
向50ml单口瓶中，加入化合物A2-2(99mg，1eq)，DCM(2mL),HCl/dioxane(4M,2mL)，室温下搅拌反应2小时。反应完毕后，过滤，收集滤饼得80mg化合物A20-2(盐酸盐)。Into a 50ml single-neck flask, compound A2-2 (99mg, 1eq), DCM (2mL), HCl/dioxane (4M, 2mL) were added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, filter and collect the filter cake to obtain 80 mg of compound A20-2 (hydrochloride).
LC-MS[M+H]
+：487。
LC-MS [M+H] + : 487.
步骤3：化合物A20的合成Step 3: Synthesis of Compound A20
向10ml单口瓶中，加入化合物A20-2(80mg，1eq)，DMF(2mL),DIPEA(127mg,6eq)，化合物A1-4(62mg，2eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，反相柱层析纯化(H
2O:CH
3CN＝100:0-60:40)，得28mg化合物A20。
Into a 10ml single-neck flask, compound A20-2 (80mg, 1eq), DMF (2mL), DIPEA (127mg, 6eq), compound A1-4 (62mg, 2eq) were added, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column chromatography (H 2 O:CH 3 CN=100:0-60:40), 28 mg of compound A20 were obtained.
LC-MS[M+H]
+：547。
LC-MS [M+H] + : 547.
实施例32化合物A32的制备Example 32 Preparation of compound A32
步骤1：化合物A32的合成Step 1: Synthesis of Compound A32
向10ml单口瓶中，加入化合物A2-3(125mg，1eq)，DMF(2mL),DIPEA(164mg,6eq)，化合物A32-1(72mg，2eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，薄层层析纯化(DCM:MeOH＝10:1)，得25mg化合物A32。Compound A2-3 (125 mg, 1 eq), DMF (2 mL), DIPEA (164 mg, 6 eq), and Compound A32-1 (72 mg, 2 eq) were added to a 10 ml single-neck flask, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography (DCM:MeOH=10:1) to obtain 25 mg of compound A32.
LC-MS[M+H]
+：523。
LC-MS [M+H] + : 523.
按照实施例1、实施例2、实施例6、实施例12-13、实施例19-20、实施例 32等类似的实验方法，采用上述中间体、及合适的市售原料和试剂，可制备表1所示的实施例。According to the similar experimental methods of Example 1, Example 2, Example 6, Example 12-13, Example 19-20, Example 32, etc., using the above-mentioned intermediates, and suitable commercially available raw materials and reagents, it can be prepared Examples shown in Table 1.
表1Table 1
实施例8：化合物A8(1-(3-氟丙基)-N-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)氮杂环丁烷-3-胺)的制备Example 8: Compound A8 (1-(3-fluoropropyl)-N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)- 2,3,4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)azetidine-3- amine) preparation
步骤1：化合物A8的合成Step 1: Synthesis of Compound A8
向10ml单口瓶中，加入化合物INT15(110mg，1eq)，化合物INT5(111mg，盐酸盐，2.5eq)，BrettPhos Pd G3(39mg,0.2eq)，t-BuONa(104mg,5eq),1,4-二氧六环(5mL)，氮气保护，升温至80℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，浓缩，柱层析纯化(DCM:MeOH＝100:0-90:10)，得33mg化合物A8。To a 10ml single-neck bottle, add compound INT15 (110mg, 1eq), compound INT5 (111mg, hydrochloride, 2.5eq), BrettPhos Pd G3 (39mg, 0.2eq), t-BuONa (104mg, 5eq), 1,4 -Dioxane (5 mL), under nitrogen protection, heated to 80°C and stirred for 3 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:0-90:10) to obtain 33 mg of compound A8.
LC-MS[M+H]
+：559。
LC-MS [M+H] + : 559.
1H NMR(500MHz,DMSO-d6)δ10.70(d,J＝18.0Hz,1H),7.50-7.37(m,1H),7.25-7.21(m,1H),7.01-6.97(m,2H),6.63-6.42(m,2H),6.36-6.24(m,1H),5.15(s,1H),4.52-4.33(m,2H),3.92-3.88(m,1H),3.63-3.59(m,2H),3.52-3.41(m,1H),3.39(s,1H),3.26-3.11(m,1H),2.94-2.90(m,1H),2.78-2.63(m,3H),2.45(t,J＝6.9Hz,2H),2.06-1.92(m,1H),1.85-1.56(m,2H),1.16-0.97(m,3H).
1 H NMR (500MHz, DMSO-d6) δ10.70(d, J=18.0Hz, 1H), 7.50-7.37(m, 1H), 7.25-7.21(m, 1H), 7.01-6.97(m, 2H) ,6.63-6.42(m,2H),6.36-6.24(m,1H),5.15(s,1H),4.52-4.33(m,2H),3.92-3.88(m,1H),3.63-3.59(m, 2H), 3.52-3.41(m, 1H), 3.39(s, 1H), 3.26-3.11(m, 1H), 2.94-2.90(m, 1H), 2.78-2.63(m, 3H), 2.45(t, J=6.9Hz, 2H), 2.06-1.92(m, 1H), 1.85-1.56(m, 2H), 1.16-0.97(m, 3H).
实施例9：化合物A9((S)-1-(3-氟丙基)-N-(4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺)的制备Example 9: Compound A9((S)-1-(3-fluoropropyl)-N-(4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl) yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidine-3- amine) preparation
步骤1：化合物A9的合成Step 1: Synthesis of Compound A9
向10ml单口瓶中，加入化合物INT15(100mg，1eq)，化合物INT6(108mg，盐酸盐，2.5eq)，BrettPhos Pd G3(36mg,0.2eq)，t-BuONa(95mg,5eq),1,4-二氧六环(3mL)，氮气保护，升温至80℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，浓缩，柱层析纯 化(DCM:MeOH＝100:0-90:10)，得49mg化合物A9。To a 10ml single-neck bottle, add compound INT15 (100mg, 1eq), compound INT6 (108mg, hydrochloride, 2.5eq), BrettPhos Pd G3 (36mg, 0.2eq), t-BuONa (95mg, 5eq), 1,4 -Dioxane (3 mL), under nitrogen protection, heated to 80°C and stirred for 3 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:0-90:10) to obtain 49 mg of compound A9.
LC-MS[M+H]
+：573。
LC-MS [M+H] + : 573.
1H NMR(500MHz,DMSO-d6)δ10.69(s,1H),7.44(d,J＝7.8Hz,1H),7.25(d,J＝8.0Hz,1H),7.06(t,J＝7.3Hz,1H),6.98(t,J＝7.3Hz,1H),6.58(s,1H),6.32(s,2H),6.26(d,J＝6.6Hz,1H),5.15(s,1H),4.52(t,J＝5.9Hz,1H),4.42(t,J＝5.9Hz,1H),3.79(s,1H),3.53–3.34(m,1H),3.25-3.21(m,1H),2.92(dd,J＝16.4,9.0Hz,1H),2.82–2.54(m,2H),2.50-2.44(m,4H),2.31(s,1H),2.18–2.11(m,1H),1.84–1.73(m,2H),1.25–1.22(m,2H),1.07(d,J＝6.8Hz,3H).
1 H NMR(500MHz,DMSO-d6)δ10.69(s,1H),7.44(d,J=7.8Hz,1H),7.25(d,J=8.0Hz,1H),7.06(t,J=7.3 Hz, 1H), 6.98(t, J＝7.3Hz, 1H), 6.58(s, 1H), 6.32(s, 2H), 6.26(d, J＝6.6Hz, 1H), 5.15(s, 1H), 4.52(t,J=5.9Hz,1H),4.42(t,J=5.9Hz,1H),3.79(s,1H),3.53-3.34(m,1H),3.25-3.21(m,1H),2.92 (dd, J=16.4, 9.0Hz, 1H), 2.82–2.54 (m, 2H), 2.50–2.44 (m, 4H), 2.31 (s, 1H), 2.18–2.11 (m, 1H), 1.84–1.73 (m, 2H), 1.25–1.22 (m, 2H), 1.07 (d, J=6.8Hz, 3H).
实施例15：化合物A15(N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺)的制备Example 15: Compound A15 (N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine) of preparation
步骤1：化合物A15的合成Step 1: Synthesis of Compound A15
向10ml单口瓶中，加入化合物INT16(200mg，1eq)，化合物INT5(210mg，盐酸盐，2.5eq)，BrettPhos Pd G3(74mg,0.2eq)，t-BuONa(236mg,6eq),1,4-二氧六环(3mL)，氮气保护，升温至80℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，浓缩，薄层层析纯化(DCM:MeOH＝20:1)，得64mg化合物A15。To a 10ml single-neck bottle, add compound INT16 (200mg, 1eq), compound INT5 (210mg, hydrochloride, 2.5eq), BrettPhos Pd G3 (74mg, 0.2eq), t-BuONa (236mg, 6eq), 1,4 -Dioxane (3 mL), under nitrogen protection, heated to 80°C and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography (DCM:MeOH=20:1) to obtain 64 mg of compound A15.
LC-MS[M+H]
+：541。
LC-MS [M+H] + : 541.
1H NMR(500MHz,DMSO-d6)δ10.60(s,1H),7.43(d,J＝7.8Hz,1H),7.24(d,J＝8.0Hz,1H),7.06-7.02(m,1H),6.99-6.95(m,1H),6.55-6.50(m,2H),6.38(d,J＝8.5Hz,1H),6.31-6.27(m,1H),6.00-5.96(m,1H),5.11(s,1H),4.48(t,J＝6.1Hz,1H),4.39(t,J＝6.1Hz,1H),3.91-3.87(m,1H),3.59(t,J＝6.9Hz,2H),3.21-3.17(m,1H),3.08-3.04(m,1H),2.75-2.68(m,2H),2.67-2.60(m,1H),2.45(t,J＝7.0Hz,2H),1.69-1.58(m,2H),1.27-1.23(m,2H),1.05(d,J＝6.7Hz,3H).
1 H NMR(500MHz,DMSO-d6)δ10.60(s,1H),7.43(d,J=7.8Hz,1H),7.24(d,J=8.0Hz,1H),7.06-7.02(m,1H) ),6.99-6.95(m,1H),6.55-6.50(m,2H),6.38(d,J=8.5Hz,1H),6.31-6.27(m,1H),6.00-5.96(m,1H), 5.11(s, 1H), 4.48(t, J＝6.1Hz, 1H), 4.39(t, J＝6.1Hz, 1H), 3.91-3.87(m, 1H), 3.59(t, J＝6.9Hz, 2H) ), 3.21-3.17(m, 1H), 3.08-3.04(m, 1H), 2.75-2.68(m, 2H), 2.67-2.60(m, 1H), 2.45(t, J=7.0Hz, 2H), 1.69-1.58(m, 2H), 1.27-1.23(m, 2H), 1.05(d, J=6.7Hz, 3H).
实施例27化合物A27的制备Example 27 Preparation of compound A27
步骤1：化合物A27的合成Step 1: Synthesis of Compound A27
向10ml单口瓶中，加入化合物INT16(70mg，1eq)，化合物INT10(67mg，2.5eq)，Brettphos Pd G3(26mg,0.2eq)，叔丁醇钠(83mg,6eq),1,4-二氧六环(2mL)，氮气保护，升温至70℃搅拌反应2小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，残余物拌硅胶过flash硅胶柱纯化(DCM/MeOH＝100/0-90/10,15分钟)，得28mg化合物A27。To a 10ml single-necked bottle, add compound INT16 (70mg, 1eq), compound INT10 (67mg, 2.5eq), Brettphos Pd G3 (26mg, 0.2eq), sodium tert-butoxide (83mg, 6eq), 1,4-dioxane Hexacyclic (2 mL), under nitrogen protection, was heated to 70°C and stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was mixed with silica gel and purified by flash silica gel column (DCM/MeOH=100/0-90/10, 15 minutes). ) to obtain 28 mg of compound A27.
LC-MS[M+H]
+：523。
LC-MS [M+H] + : 523.
按照实施例8、实施例9、实施例15和实施例27等类似的实验方法，采用上述中间体及合适的原料和试剂，制备得到表2所示的实施例。According to the similar experimental methods of Example 8, Example 9, Example 15 and Example 27, using the above intermediates and suitable raw materials and reagents, the examples shown in Table 2 were prepared.
表2Table 2
实施例16化合物A16的制备Example 16 Preparation of compound A16
步骤1：化合物A16-1的合成Step 1: Synthesis of Compound A16-1
向10ml单口瓶中，加入化合物INT21(134mg，1eq)，化合物A2-1(69mg，1.5eq)，Pd
2dba
3(49mg,0.2eq)，xantphos(62mg,0.4eq),Cs
2CO
3(261mg,3.0eq),1,4-二氧六环(10mL)，氮气保护，升温至110℃搅拌反应2小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-50:50)，得150mg化合物A16-1。
To a 10ml single-neck bottle, add compound INT21 (134mg, 1eq), compound A2-1 (69mg, 1.5eq), Pd 2 dba 3 (49mg, 0.2eq), xantphos (62mg, 0.4eq), Cs 2 CO 3 ( 261mg, 3.0eq), 1,4-dioxane (10mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-50:50) to obtain 150 mg of compound A16-1 .
LC-MS[M+H]
+：593。
LC-MS [M+H] + : 593.
步骤2：化合物A16-2的合成Step 2: Synthesis of Compound A16-2
向50ml单口瓶中，加入化合物A2-2(150mg，1eq)，DCM(5mL),HCl/dioxane(4M,5mL)，室温下搅拌反应2小时。反应完毕后，浓缩反应液，得150mg化合物A16-2(盐酸盐)。Into a 50ml single-neck flask, compound A2-2 (150mg, 1eq), DCM (5mL), HCl/dioxane (4M, 5mL) were added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain 150 mg of compound A16-2 (hydrochloride).
LC-MS[M+H]
+：493。
LC-MS [M+H] + : 493.
步骤3：化合物A16的合成Step 3: Synthesis of Compound A16
向10ml单口瓶中，加入化合物A2-3(150mg，1eq)，DMF(5mL),DIPEA(97mg,3eq)，化合物A1-4(52mg，1.1eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(DCM:MeOH＝100:0-90:10)，得20mg化合物A16。Into a 10ml single-neck flask, compound A2-3 (150mg, 1eq), DMF (5mL), DIPEA (97mg, 3eq), compound A1-4 (52mg, 1.1eq) were added, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=100:0-90:10) to obtain 20 mg of compound A16.
LC-MS[M+H]
+：553。
LC-MS [M+H] + : 553.
实施例37：化合物A37的制备Example 37: Preparation of Compound A37
步骤1：化合物A37-3的合成Step 1: Synthesis of Compound A37-3
向50mL单口瓶中加入化合物A37-1(1.00g，1eq)，化合物A37-2(560mg，盐酸盐，1eq)，CH
3CN(20mL)，K
2CO
3(1.85g，3eq)，升温至80℃搅拌反应过夜。反应完毕后，浓缩反应液，加乙酸乙酯稀释，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，浓缩，得1.01g化合物A37-3粗品，直接用于下一步。
Add compound A37-1 (1.00 g, 1 eq), compound A37-2 (560 mg, hydrochloride, 1 eq), CH 3 CN (20 mL), K 2 CO 3 (1.85 g, 3 eq) to a 50 mL single-neck flask, and the temperature rises. The reaction was stirred at 80°C overnight. After the reaction was completed, the reaction solution was concentrated, diluted with ethyl acetate, washed with water, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 1.01 g of crude compound A37-3, which was directly used in the next step.
LC-MS[M+H]
+：233。
LC-MS [M+H] + : 233.
步骤2：化合物A37-4的合成Step 2: Synthesis of Compound A37-4
向50mL单口瓶中加入化合物A37-3(1.01g，1eq)，DCM(10mL)，HCl/dioxane(4.0M，10mL)，室温下搅拌反应3小时。反应完毕后，过滤反应液，滤饼用少量DCM洗涤，真空干燥，得636mg化合物A37-4(盐酸盐)。Compound A37-3 (1.01 g, 1 eq), DCM (10 mL), HCl/dioxane (4.0 M, 10 mL) were added to a 50 mL one-neck flask, and the reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was filtered, and the filter cake was washed with a small amount of DCM and dried in vacuo to obtain 636 mg of compound A37-4 (hydrochloride).
LC-MS[M+H]
+：133。
LC-MS [M+H] + : 133.
步骤3：化合物A37的合成Step 3: Synthesis of Compound A37
向10ml单口瓶中，加入化合物INT16(100mg，1eq)，化合物37-4(84mg，盐酸盐，2eq)，BrettPhos Pd G3(37mg,0.2eq)，t-BuONa(118mg,6eq),1,4-二氧六环(3mL)，氮气保护，升温至80℃搅拌反应3小时。反应完毕后，用乙酸乙酯 稀释反应液，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，浓缩，薄层层析纯化(DCM:MeOH＝15:1)，得52mg化合物A37。To a 10ml single-neck bottle, add compound INT16 (100mg, 1eq), compound 37-4 (84mg, hydrochloride, 2eq), BrettPhos Pd G3 (37mg, 0.2eq), t-BuONa (118mg, 6eq), 1, 4-Dioxane (3 mL), under nitrogen protection, was heated to 80°C and stirred for 3 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography (DCM:MeOH=15:1) to obtain 52 mg of compound A37.
LC-MS[M+H]
+：541。
LC-MS [M+H] + : 541.
实施例38：化合物A38的制备Example 38: Preparation of Compound A38
步骤1：化合物A38的合成Step 1: Synthesis of Compound A38
向10ml单口瓶中，加入化合物INT15(100mg，1eq)，化合物37-4(91mg，盐酸盐，2eq)，BrettPhos Pd G3(36mg,0.2eq)，t-BuONa(95mg,6eq),1,4-二氧六环(3mL)，氮气保护，升温至80℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，浓缩，薄层层析纯化(DCM:MeOH＝15:1)，得68mg化合物A38。To a 10ml single-neck bottle, add compound INT15 (100mg, 1eq), compound 37-4 (91mg, hydrochloride, 2eq), BrettPhos Pd G3 (36mg, 0.2eq), t-BuONa (95mg, 6eq), 1, 4-Dioxane (3 mL), under nitrogen protection, was heated to 80°C and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by thin layer chromatography (DCM:MeOH=15:1) to obtain 68 mg of compound A38.
LC-MS[M+H]
+：559。
LC-MS [M+H] + : 559.
1H NMR(500MHz,DMSO-d6)δ10.67(s,1H),7.44(d,J＝7.7Hz,1H),7.25(d,J＝8.0Hz,1H),7.07–6.96(dt,J＝33.0,8.0Hz,2H),6.59(s,1H),6.33-6.32(m,2H),5.98(t,J＝5.6Hz,1H),5.15(s,1H),4.53(d,J＝6.2Hz,1H),4.44(d,J＝6.2Hz,1H),3.50-3.41(m,1H),3.27-3.21(m,3H),2.95-2.88(m,5H),2.74–2.63(m,2H),2.60–2.54(m,2H),1.30–1.21(m,1H),1.06(d,J＝6.7Hz,3H).
1 H NMR(500MHz,DMSO-d6)δ10.67(s,1H),7.44(d,J=7.7Hz,1H),7.25(d,J=8.0Hz,1H),7.07-6.96(dt,J =33.0,8.0Hz,2H),6.59(s,1H),6.33-6.32(m,2H),5.98(t,J=5.6Hz,1H),5.15(s,1H),4.53(d,J= 6.2Hz, 1H), 4.44(d, J=6.2Hz, 1H), 3.50-3.41(m, 1H), 3.27-3.21(m, 3H), 2.95-2.88(m, 5H), 2.74-2.63(m , 2H), 2.60–2.54 (m, 2H), 1.30–1.21 (m, 1H), 1.06 (d, J=6.7Hz, 3H).
实施例39化合物A39的制备Example 39 Preparation of compound A39
步骤1：化合物A39-3的合成Step 1: Synthesis of Compound A39-3
向500ml单口瓶中，加入化合物A39-1(10.00g,1eq)，A39-2(12.38g,1eq)，TBAI(2.67g,0.1eq)，无水碳酸钾(12.01g,1.2eq)，丙酮(200mL)，升温至60℃搅拌反应8小时。反应完毕后，将反应液浓缩，残余物溶于乙酸乙酯/水(200ml/200ml)中，搅拌分层，收集有机相，水相用乙酸乙酯萃取一次，合并有机相，饱和食盐水洗一次，干燥，过滤，浓缩；残余物拌硅胶，柱层析纯化(PE:EA＝100:0-80:20)，得5.00g化合物A39-3。Into a 500ml single-neck bottle, add compound A39-1 (10.00g, 1eq), A39-2 (12.38g, 1eq), TBAI (2.67g, 0.1eq), anhydrous potassium carbonate (12.01g, 1.2eq), acetone (200 mL), the temperature was raised to 60°C and the reaction was stirred for 8 hours. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in ethyl acetate/water (200ml/200ml), the layers were stirred and separated, the organic phase was collected, the aqueous phase was extracted once with ethyl acetate, the organic phases were combined, and washed once with saturated brine. , dried, filtered and concentrated; the residue was mixed with silica gel and purified by column chromatography (PE:EA=100:0-80:20) to obtain 5.00 g of compound A39-3.
LC-MS[M+H]+：229。LC-MS [M+H]+: 229.
步骤2：化合物A39-5的合成Step 2: Synthesis of Compound A39-5
向250ml单口瓶中，加入化合物A39-3(5.00g，1eq)，A39-4(5.01g，1.5eq)，无水碳酸钾(9.08g，3eq)，ACN(100mL)，加热至90℃下搅拌反应16小时。反应完毕后，浓缩反应液，加入乙酸乙酯/水(100ml/100ml)，搅拌分层，水洗用乙酸乙酯萃取一次，合并有机相，水洗一次，饱和食盐水洗一次，干燥，过滤，滤液浓缩，柱层析纯化(PE:EA＝100:0-0:100)，得2.93g化合物A39-5To a 250ml single-neck flask, add compound A39-3 (5.00g, 1eq), A39-4 (5.01g, 1.5eq), anhydrous potassium carbonate (9.08g, 3eq), ACN (100mL), heat to 90°C The reaction was stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated, ethyl acetate/water (100ml/100ml) was added, the layers were stirred and separated, washed with water and extracted with ethyl acetate once, combined the organic phases, washed with water once, washed with saturated brine once, dried, filtered, and the filtrate was concentrated. , purified by column chromatography (PE:EA=100:0-0:100) to obtain 2.93g of compound A39-5
LC-MS[M+H]+：279。LC-MS [M+H]+: 279.
步骤3：化合物A39-6的合成Step 3: Synthesis of Compound A39-6
向10ml单口瓶中，加入化合物A39-5(2.30g，1eq)，DMA(30mL)，氮气保护，然后加入NaH(0.50g，1.5eq)，醋酸钯(0.19g，0.1eq)，室温搅拌反 应2小时。反应完毕后，将反应液倒入冰水中，乙酸乙酯萃取两次，合并有机相，水洗三次，饱和食盐水洗一次，干燥，过滤，浓缩；残余物拌硅胶柱层析纯化(PE:EA＝100:0-50:50)，得1.25g化合物A39-6。Into a 10ml single-neck flask, add compound A39-5 (2.30g, 1eq), DMA (30mL), nitrogen protection, then add NaH (0.50g, 1.5eq), palladium acetate (0.19g, 0.1eq), stir the reaction at room temperature 2 hours. After the reaction was completed, the reaction solution was poured into ice water, extracted twice with ethyl acetate, the organic phases were combined, washed three times with water, once with saturated brine, dried, filtered, and concentrated; the residue was purified by silica gel column chromatography (PE:EA= 100:0-50:50) to obtain 1.25 g of compound A39-6.
LC-MS[M+H]+：189。LC-MS [M+H]+: 189.
步骤4：化合物A39-7的合成Step 4: Synthesis of Compound A39-7
参照化合物INT11的合成方法，将化合物INT2替换为化合物A39-6，即可得到化合物A39-7。Referring to the synthesis method of compound INT11, compound A39-7 can be obtained by replacing compound INT2 with compound A39-6.
LC-MS[M+H]
+：427。
LC-MS [M+H] + : 427.
步骤5：化合物A39-8的合成Step 5: Synthesis of Compound A39-8
向50ml单口瓶中，加入化合物A39-7(500mg，1eq)，化合物A52-1(498mg，1.5eq)，Cs
2CO
3(1.15g,3.0eq),N,N-二甲基甲酰胺(10mL)，升温至100℃搅拌反应2小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得500mg化合物A39-8。
Into a 50ml single-neck bottle, add compound A39-7 (500mg, 1eq), compound A52-1 (498mg, 1.5eq), Cs 2 CO 3 (1.15g, 3.0eq), N,N-dimethylformamide ( 10 mL), the temperature was raised to 100 °C and the reaction was stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 500 mg of compound A39-8 .
LC-MS[M+H]
+：582。
LC-MS [M+H] + : 582.
步骤6：化合物A39-9的合成Step 6: Synthesis of Compound A39-9
向25ml单口瓶中，加入化合物A39-8(300mg，1eq)，DCM(5mL),TFA(1mL)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，得311mg化合物A39-9(三氟乙酸盐)。Into a 25ml single-neck flask, compound A39-8 (300mg, 1eq), DCM (5mL), TFA (1mL) were added, and the reaction was stirred at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated to obtain 311 mg of compound A39-9 (trifluoroacetate).
LC-MS[M+H]
+：482。
LC-MS [M+H] + : 482.
步骤7：化合物A39的合成Step 7: Synthesis of Compound A39
向10ml单口瓶中，加入化合物A39-9(311mg，1eq)，DMF(5mL),DIPEA(405mg,6eq)，化合物A1-4(147mg，1.5eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，反相柱层析纯化(H
2O:CH
3CN＝55:45-30:70)，得45mg化合物A39。
Into a 10ml single-neck flask, compound A39-9 (311mg, 1eq), DMF (5mL), DIPEA (405mg, 6eq), compound A1-4 (147mg, 1.5eq) were added, and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column chromatography (H 2 O:CH 3 CN=55:45-30:70), 45 mg of compound A39 were obtained.
LC-MS[M+H]
+：542。
LC-MS [M+H] + : 542.
参照上述实施例39等的实验方法，采用上述中间体及合适的原料和试剂，可制备表3所示的实施例。Referring to the experimental methods of Example 39, etc. above, using the above intermediates and suitable raw materials and reagents, the examples shown in Table 3 can be prepared.
表3table 3
实施例49化合物A49的制备Example 49 Preparation of compound A49
步骤1：化合物A49-1的合成Step 1: Synthesis of Compound A49-1
向50ml单口瓶中，加入化合物INT12(310mg，1eq)，化合物A2-1(170mg，1.5eq)，Pd
2dba
3(121mg,0.2eq)，xantphos(152mg,0.4eq),Cs
2CO
3(643mg,3.0eq),1,4-二氧六环(10mL)，氮气保护，升温至110℃搅拌反应3小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得135mg化合物A49-1。
Into a 50ml single-neck bottle, add compound INT12 (310mg, 1eq), compound A2-1 (170mg, 1.5eq), Pd 2 dba 3 (121mg, 0.2eq), xantphos (152mg, 0.4eq), Cs 2 CO 3 ( 643mg, 3.0eq), 1,4-dioxane (10mL), under nitrogen protection, the temperature was raised to 110°C and the reaction was stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 135 mg of compound A49-1 .
LC-MS[M+H]
+：563。
LC-MS [M+H] + : 563.
步骤2：化合物A49-2的合成Step 2: Synthesis of Compound A49-2
向50ml单口瓶中，加入化合物A2-2(159mg，1eq)，DCM(5mL),HCl/ dioxane(4M,5mL)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，得120mg化合物A49-2(盐酸盐)。Into a 50ml single-neck flask, compound A2-2 (159mg, 1eq), DCM (5mL), HCl/dioxane (4M, 5mL) were added, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain 120 mg of compound A49-2 (hydrochloride).
LC-MS[M+H]
+：463。
LC-MS [M+H] + : 463.
步骤3：化合物A49的合成Step 3: Synthesis of Compound A49
向10ml单口瓶中，加入化合物A49-2(120mg，1eq)，DMF(5mL),DIPEA(201mg,6eq)，化合物A1-4(98mg，2eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，反相柱层析纯化(H
2O:CH
3CN＝55:45-30:70)，得29mg化合物A49。
To a 10ml single-neck flask, compound A49-2 (120mg, 1eq), DMF (5mL), DIPEA (201mg, 6eq), and compound A1-4 (98mg, 2eq) were added, and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column chromatography (H 2 O:CH 3 CN=55:45-30:70), 29 mg of compound A49 were obtained.
LC-MS[M+H]
+：523。
LC-MS [M+H] + : 523.
实施例52化合物A52的制备Example 52 Preparation of compound A52
步骤1：化合物A52-2的合成Step 1: Synthesis of Compound A52-2
向50ml单口瓶中，加入化合物INT23(800mg，1eq)，化合物A52-1(797mg，1.5eq)，Cs
2CO
3(1.83g,3.0eq),N,N-二甲基甲酰胺(10mL)，升温至100℃搅拌反应2小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得800mg化合物A52-2。
Into a 50ml single-neck bottle, add compound INT23 (800mg, 1eq), compound A52-1 (797mg, 1.5eq), Cs2CO3 ( 1.83g , 3.0eq), N,N-dimethylformamide (10mL) , the temperature was raised to 100 °C and the reaction was stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 800 mg of compound A52-2 .
LC-MS[M+H]
+：600。
LC-MS [M+H] + : 600.
步骤2：化合物A52-3的合成Step 2: Synthesis of Compound A52-3
向25ml单口瓶中，加入化合物A52-2(300mg，1eq)，DCM(5mL),TFA(1mL)，室温下搅拌反应1小时。反应完毕后，浓缩反应液，得349mg化合物A52-3 (三氟乙酸盐)。Into a 25 ml single-neck flask, compound A52-2 (300 mg, 1 eq), DCM (5 mL), TFA (1 mL) were added, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain 349 mg of compound A52-3 (trifluoroacetate).
LC-MS[M+H]
+：500。
LC-MS [M+H] + : 500.
步骤3：化合物A52的合成Step 3: Synthesis of Compound A52
向10ml单口瓶中，加入化合物A52-3(349mg，1eq)，DMF(5mL),DIPEA(333mg,6eq)，化合物A1-4(145mg，1.5eq)，室温下搅拌反应16小时。反应完毕后，反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，反相柱层析纯化(H
2O:CH
3CN＝55:45-30:70)，得52mg化合物A52。
To a 10ml single-neck flask, compound A52-3 (349 mg, 1 eq), DMF (5 mL), DIPEA (333 mg, 6 eq), and compound A1-4 (145 mg, 1.5 eq) were added, and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column chromatography (H 2 O:CH 3 CN=55:45-30:70), 52 mg of compound A52 were obtained.
LC-MS[M+H]
+：560。
LC-MS [M+H] + : 560.
1H NMR(500MHz,DMSO-d6)δ10.74(s,1H),7.46(d,J＝7.8Hz,1H),7.26(d,J＝8.0Hz,1H),7.03(dt,J＝33.5,7.3Hz,2H),6.85(m,1H),6.70(dd,J＝8.7,2.5Hz,1H),6.52(d,J＝8.6Hz,1H),5.24(s,1H),4.84–4.78(m,1H),4.49(t,J＝6.0Hz,1H),4.39(t,J＝6.0Hz,1H),3.74(s,2H),3.56–3.46(m,1H),3.18-3.13(m,1H),3.00-2.93(m,2H),2.73–2.62(m,2H),2.62–2.52(m,2H),1.67(dq,J＝25.3,6.5Hz,2H),1..28-1.24(m,1H),1.06(d,J＝6.7Hz,3H).
1 H NMR(500MHz, DMSO-d6)δ10.74(s,1H),7.46(d,J=7.8Hz,1H),7.26(d,J=8.0Hz,1H),7.03(dt,J=33.5 ,7.3Hz,2H),6.85(m,1H),6.70(dd,J=8.7,2.5Hz,1H),6.52(d,J=8.6Hz,1H),5.24(s,1H),4.84–4.78 (m,1H),4.49(t,J=6.0Hz,1H),4.39(t,J=6.0Hz,1H),3.74(s,2H),3.56-3.46(m,1H),3.18-3.13( m,1H),3.00-2.93(m,2H),2.73-2.62(m,2H),2.62-2.52(m,2H),1.67(dq,J=25.3,6.5Hz,2H),1..28 -1.24(m,1H),1.06(d,J=6.7Hz,3H).
实施例53化合物A53的制备Example 53 Preparation of compound A53
步骤1：化合物A53的合成Step 1: Synthesis of Compound A53
向50ml单口瓶中，加入化合物INT25(120mg，1eq)，化合物A2-1(123mg，4eq)，Brettphos Pd G3(42mg,0.2eq)，叔丁醇钠(135mg,6eq),1,4-二氧六环(10mL)，氮气保护，升温至70℃搅拌反应2小时。反应完毕后，用乙酸乙酯稀释反应液，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，高压制备液相纯化(流动相A:0.1％甲酸水溶液，流动相B:乙腈；25-55％B in 20mins；流速:40ml/min；检测波长:254nm；出峰:43％B。)，得27mg化合物A53。To a 50ml single-neck bottle, add compound INT25 (120mg, 1eq), compound A2-1 (123mg, 4eq), Brettphos Pd G3 (42mg, 0.2eq), sodium tert-butoxide (135mg, 6eq), 1,4-di Oxane (10 mL), under nitrogen protection, was heated to 70 °C and stirred for 2 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by high pressure preparative liquid phase (mobile phase A: 0.1% aqueous formic acid solution, mobile phase B: acetonitrile; 25-55 %B in 20mins; flow rate: 40ml/min; detection wavelength: 254nm; peak: 43%B.), to obtain 27mg of compound A53.
LC-MS[M+H]
+：566。
LC-MS [M+H] + : 566.
按照上述实施例类似的方法，使用相应的原料，可以合成实施例55-实施例61：According to the method similar to the above-mentioned embodiment, using the corresponding raw material, can synthesize Example 55-Example 61:
药理实验Pharmacological experiments
对照例1Comparative Example 1
上述化合物按照WO2016097072A实施例340制备得到。The above compound was prepared according to Example 340 of WO2016097072A.
实施例A：细胞增殖实验Example A: Cell Proliferation Experiment
在乳腺癌细胞系MCF7和T47D上使用celltiter-glo发光法活力检测试剂盒(Promega,Cat#G7573)检测化合物细胞增殖抑制活性。取对数生长期细胞，胰蛋白酶消化后，以2000/孔的细胞密度接种在96孔细胞培养板中，在37℃、5％CO
2的潮湿培养箱中孵育过夜。次日，在细胞培养液中加入梯度稀释后的化合物溶液，使化合物终浓度为1μM或20nM起3倍稀释的8-9个浓度。将相同体积的DMSO作为溶剂对照加入对照孔中。细胞与化合物共孵育5天，在室温下将50μl的celltiter-glo工作液加入各孔中，避光振荡10分钟。使用PerkinElmer EnVision读取化学发光信号。使用Graph Pad Prism 8.0软件的非线性回归方程Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))拟合细胞生长抑制的半数抑制浓度IC
50，部分实施例具体结果详见表4。其中，A代表IC
50值≤1nM。
Celltiter-glo luminescence viability assay kit (Promega, Cat#G7573) was used to detect compound cell proliferation inhibitory activity on breast cancer cell lines MCF7 and T47D. Cells in logarithmic growth phase were taken, trypsinized, seeded in 96-well cell culture plates at a cell density of 2000/well, and incubated overnight in a humidified incubator at 37°C, 5% CO2 . The next day, the serially diluted compound solution was added to the cell culture medium, so that the final compound concentration was 1 μM or 8-9 concentrations of 3-fold dilution from 20 nM. The same volume of DMSO was added to control wells as a solvent control. Cells were incubated with compounds for 5 days, and 50 μl of celltiter-glo working solution was added to each well at room temperature and shaken in the dark for 10 minutes. Chemiluminescent signals were read using PerkinElmer EnVision. Using the nonlinear regression equation Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) of Graph Pad Prism 8.0 software to fit the IC50 of cell growth inhibition, some examples The specific results are shown in Table 4. Among them, A represents IC50 value ≤ 1 nM.
表4Table 4
结论：由表4可知，本发明化合物具有较好的肿瘤细胞增殖抑制活性。Conclusion: It can be seen from Table 4 that the compounds of the present invention have good tumor cell proliferation inhibitory activity.
实施例B：靶点降解实验Example B: Target Degradation Experiment
用In-Cell Western方法检测化合物对MCF7和T47D细胞内ER蛋白的降解活性。取对数生长期细胞，胰蛋白酶消化并收集细胞，将其接种于384孔板，37℃、5％CO
2条件下孵育过夜。用DMSO连续稀释化合物，并向孔板中加入120nL/孔化合物溶液(DMSO终浓度为0.5％)，使化合物最终浓度依次为100、33、11、3.7、1.2、0.41、0.14、0.046、0.015、0.001nM，并孵育过夜。固定细胞，PBS洗涤后进行透化、封闭。使用ER兔一抗和GAPDH鼠一抗在室温孵育，PBST洗涤3次后，用羊抗兔(800CW)和羊抗鼠(680RD)的荧光二抗于室温避光孵育，并用PBST洗涤3次，1000rpm，1min离心弃上清后，用Odyssey Clx读数，使用非线性回归方程Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))进行拟合求得IC
50，部分实施例具体结果详见表5。其中，A代表IC
50值≤1nM。
The degradation activity of the compounds on ER proteins in MCF7 and T47D cells was detected by In-Cell Western method. Cells in logarithmic growth phase were taken, trypsinized and collected, inoculated in 384-well plates and incubated overnight at 37°C, 5% CO 2 . The compound was serially diluted with DMSO, and 120nL/well compound solution was added to the well plate (the final concentration of DMSO was 0.5%), so that the final compound concentration was 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.001 nM and incubated overnight. Cells were fixed, washed with PBS, permeabilized and blocked. Use ER rabbit primary antibody and GAPDH mouse primary antibody to incubate at room temperature, wash 3 times with PBST, incubate with goat anti-rabbit (800CW) and goat anti-mouse (680RD) fluorescent secondary antibodies at room temperature in the dark, and wash 3 times with PBST, 1000rpm, 1min centrifugation to discard the supernatant, read with Odyssey Clx, use the nonlinear regression equation Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) to fit the IC50 , the specific results of some examples are shown in Table 5. Among them, A represents IC50 value ≤ 1 nM.
表5table 5
注：“/”代表未检测。Note: "/" means not detected.
结论：由表5可知，本发明化合物具有较好的ER蛋白降解活性。Conclusion: It can be seen from Table 5 that the compounds of the present invention have good ER protein degradation activity.
实施例C：小鼠药代动力学试验Example C: Pharmacokinetic test in mice
使用从北京维通利华实验动物技术有限公司购买得到的雌性BALB/c小鼠(20-30g)进行小鼠PK研究。对于5mg/kg和10mg/kg的口服(PO)剂量，化合物浓度分别为0.5mg/mL和1mg/mL，现用现配。口服给药以5mg/kg或10mL/kg通过口服灌胃进行。通过小鼠眼眶静脉丛采血，每个时间点将100μL的全血装至K
2-EDTA管中。采血时间为15min、30min、1h、2h、4h、7h和24h或者15min、 30min、1h、2h、4h、7h、24h、30h和48h。将采集的全血样品，离心并分离血浆，放入-80℃冰箱保存备用。取脑时间点为4h和24h或4h和48h。将采集的脑组织进行称重，按1：4加入水进行稀释匀浆，放入-80℃冰箱保存备用。
Mouse PK studies were performed using female BALB/c mice (20-30 g) purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Compound concentrations were 0.5 mg/mL and 1 mg/mL for oral (PO) doses of 5 mg/kg and 10 mg/kg, respectively, as-is formulated. Oral administration was by oral gavage at 5 mg/kg or 10 mL/kg. Blood was drawn through the orbital venous plexus of mice, and 100 μL of whole blood was loaded into K2 - EDTA tubes per time point. Blood collection time was 15min, 30min, 1h, 2h, 4h, 7h and 24h or 15min, 30min, 1h, 2h, 4h, 7h, 24h, 30h and 48h. The collected whole blood samples were centrifuged and plasma separated, and stored in a -80°C refrigerator for later use. The time points of brain collection were 4h and 24h or 4h and 48h. The collected brain tissue was weighed, diluted and homogenized by adding water at a ratio of 1:4, and stored in a -80°C refrigerator for later use.
将上述血浆及组织样品，通过乙腈沉淀蛋白后，取上清液，并与水1:1混合，取10μL至LC-MS/MS检测。化合物在BALB/c小鼠的血浆中标准曲线的定量限为1.00-1000ng/mL，脑组织中标准曲线的定量限为5.00-5000ng/mL。试验数据结果分别如表6和表7所示：After the above plasma and tissue samples were precipitated by acetonitrile, the supernatant was taken, mixed with water 1:1, and 10 μL was taken for LC-MS/MS detection. The limit of quantification of the standard curve of the compound in the plasma of BALB/c mice was 1.00-1000 ng/mL, and the limit of quantification of the standard curve in the brain tissue was 5.00-5000 ng/mL. The test data results are shown in Table 6 and Table 7 respectively:
表6 小鼠体内药代动力学参数Table 6 Pharmacokinetic parameters in mice
由表6可知，本发明化合物相比对照化合物的小鼠口服暴露量具有显著提高。As can be seen from Table 6, the oral exposure of the compounds of the present invention to mice was significantly increased compared to the control compounds.
表7 小鼠体内药代动力学参数Table 7 Pharmacokinetic parameters in mice
注：“*”代表表中数据为3只小鼠数据的均值；Note: "*" represents the data in the table is the mean of the data of 3 mice;
“**”代表表中B/P比值为3只小鼠各自的比值再求均值得到。"**" represents that the B/P ratio in the table is the ratio of each of the three mice and then averaged.
由表7可知，本发明化合物与对照化合物相比，本发明化合物脑/血浆药物浓度比高于对照化合物，说明本发明化合物具有很好的穿过血脑屏障的能力；同时，本发明其他化合物也具有高于对照化合物的脑组织药物浓度和脑/血浆药物浓度比，例如实施例20和实施例51等。It can be seen from Table 7 that, compared with the control compound, the brain/plasma drug concentration ratio of the compound of the present invention is higher than that of the control compound, indicating that the compound of the present invention has a good ability to cross the blood-brain barrier; at the same time, other compounds of the present invention There are also higher brain tissue drug concentrations and brain/plasma drug concentration ratios than control compounds, eg, Example 20, Example 51, and the like.
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。Although the present invention has been fully described in terms of its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims of the present invention.
Claims (37)
- 一种如式(I)所示化合物、其立体异构体、互变异构体或药学上可接受的盐：A compound represented by formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt:
其中，in,W选自O、NH或S；W is selected from O, NH or S;D是CR 9或N； D is CR 9 or N;E是CR 10或N； E is CR 10 or N;L 1选自-O-或-NH-； L 1 is selected from -O- or -NH-;L 2选自-NH-或C 3-C 8杂环基；所述C 3-C 8杂环基任选地被一个或多个R 7取代； L 2 is selected from -NH- or C 3 -C 8 heterocyclyl; the C 3 -C 8 heterocyclyl is optionally substituted with one or more R 7 ;R 1、R 1 ’分别独立地选自H、卤素、C 1-C 3烷基、-OR c、-N(R c) 2、-SR c、-COR d、-NO 2、-S(O) 2R d、C 3-C 6环烷基、3-6元杂环基、C 6-C 10芳基、5-10元杂芳基；其中，所述C 1-C 3烷基、C 3-C 6环烷基、3-6元杂环基、C 6-C 10芳基、5-10元杂芳基任选地被一个或多个H、卤素、-OH、-OC 1-C 3烷基、-SO 2C 1-C 3烷基、-NH 2、-NHSO 2C 1-C 3烷基、-NHC 1-C 3烷基、-N(C 1-C 3烷基) 2、-CN、-CONH 2、C 3-C 6环烷基、3-6元杂环基取代；或者，R 1和R 1 ’一起形成＝O； R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl, -OR c , -N(R c ) 2 , -SR c , -COR d , -NO 2 , -S ( O) 2 R d , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein, the C 1 -C 3 alkyl , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 membered aryl, 5-10 membered heteroaryl optionally replaced by one or more H, halogen, -OH, -OC 1 -C 3 alkyl, -SO 2 C 1 -C 3 alkyl, -NH 2 , -NHSO 2 C 1 -C 3 alkyl, -NHC 1 -C 3 alkyl, -N(C 1 -C 3 Alkyl) 2 , -CN, -CONH 2 , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl substituted; or, R 1 and R 1 ' together form =O;R c选自H、C 1-C 5烷基、-COC 1-C 5烷基、-S(O) 2C 1-C 5烷基、C 3-C 6环烷基、3-6元杂环基；其中，所述C 1-C 5烷基、C 3-C 6环烷基、3-6元杂环基任选地被一个或多个H、C 1-C 3烷基、-CONH 2、-S(O) 2C 1-C 3烷基、-OC 1-C 3烷基、-OH、-N(C 1-C 3烷基) 2、-P(O)(OH) 2取代； R c is selected from H, C 1 -C 5 alkyl, -COC 1 -C 5 alkyl, -S(O) 2 C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered Heterocyclic group; wherein, the C 1 -C 5 alkyl group, C 3 -C 6 cycloalkyl group, 3-6 membered heterocyclic group are optionally replaced by one or more H, C 1 -C 3 alkyl group, -CONH 2 , -S(O) 2 C 1 -C 3 alkyl, -OC 1 -C 3 alkyl, -OH, -N(C 1 -C 3 alkyl) 2 , -P(O)(OH ) 2 replace;R d选自H、C 1-C 5烷基、-NH 2、-OH、-NHC 1-C 5烷基、-N(C 1-C 5烷基) 2、-OC 1-C 5烷基、-NHC 3-C 6环烷基、3-6元杂环基氧基；其中，所述C 1-C 5烷基、C 3-C 6环烷 基、3-6元杂环基任选地被H、-OH、C 1-C 3烷基、-OC 1-C 3烷基取代； R d is selected from H, C 1 -C 5 alkyl, -NH 2 , -OH, -NHC 1 -C 5 alkyl, -N(C 1 -C 5 alkyl) 2 , -OC 1 -C 5 alkane base, -NHC 3 -C 6 cycloalkyl, 3-6 membered heterocyclyloxy; wherein, the C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl optionally substituted with H, -OH, C 1 -C 3 alkyl, -OC 1 -C 3 alkyl;R 2选自C 1-C 9烷基、C 3-C 9环烷基、C 3-C 9杂环基、C 6-C 10芳基、C 5-C 10杂芳基、-(C 1-C 6亚烷基)-(C 3-C 9环烷基)、-(C 1-C 6亚烷基)-(C 3-C 9杂环基)、-C(O)R b、-C(O)N(R a) 2、-SO 2R a和-SO 2N(R a) 2，其中，所述C 1-C 9烷基、C 3-C 9环烷基、C 3-C 9杂环基、C 6-C 10芳基、C 5-C 10杂芳基、-(C 1-C 6亚烷基)-(C 3-C 9环烷基)、-(C 1-C 6亚烷基)-(C 3-C 9杂环基)任选地被一个或多个F、Cl、Br、I、-CN、-OR a、-N(R a) 2、C 1-C 9烷基、C 3-C 9环烷基、C 3-C 9杂环基、C 6-C 10芳基、C 5-C 10杂芳基、-C(O)R b、-C(O)NR a、-SO 2R a和-SO 2N(R a) 2取代； R 2 is selected from C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -(C 1 -C 6 alkylene)-(C 3 -C 9 cycloalkyl), -(C 1 -C 6 alkylene)-(C 3 -C 9 heterocyclyl), -C(O)R b , -C(O)N(R a ) 2 , -SO 2 R a and -SO 2 N(R a ) 2 , wherein the C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -(C 1 -C 6 alkylene)-(C 3 -C 9 cycloalkyl), - (C 1 -C 6 alkylene)-(C 3 -C 9 heterocyclyl) optionally surrounded by one or more of F, Cl, Br, I, -CN, -OR a , -N(R a ) 2 , C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -C(O) R b , -C(O)NR a , -SO 2 R a and -SO 2 N(R a ) 2 are substituted;每一个R 5各自相同或不同，其各自独立地选自H、F、Cl、Br、I、C 1-C 6烷基、-OC 1-C 6烷基、-CN、-NH 2、-NO 2、-COOH、-CHO、-OH、、C 3-C 6环烷基、3-6元杂环基、6-10元芳基和5-10元杂芳基；其中，所述C 1-C 6烷基、-OC 1-C 6烷基、C 3-C 6环烷基、3-6元杂环基、6-10元芳基和5-10元杂芳基各自独立地任选被选自C 1-C 3烷基、F、Cl、Br、I、-CN、-NH 2、-NO 2、-OH、羟基C 1-C 3烷基、-OC 1-C 3烷氧基、卤代的C 1-C 3烷氧基、C 3-C 6环烷基、3-6元杂环基、6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Each R 5 is the same or different and each is independently selected from H, F, Cl, Br, I, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -CN, -NH 2 , - NO 2 , -COOH, -CHO, -OH, , C 3 -C 6 cycloalkyl, 3-6-membered heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl; wherein, the C 1 - C6 alkyl, -OC1 - C6 alkyl, C3 - C6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally selected from C 1 -C 3 alkyl, F, Cl, Br, I, -CN, -NH 2 , -NO 2 , -OH, hydroxy C 1 -C 3 alkyl, -OC 1 -C 3 One of alkoxy, halogenated C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 aryl and 5-10 membered heteroaryl or replaced by multiple substituents;R 7是H、F、Cl、Br、I、OH或NH 2； R7 is H, F, Cl, Br, I, OH or NH2 ;R 8是H、F或CN； R8 is H, F or CN;当D选自CR 9或N时，E选自CR 10，R 9选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基，R 10选自卤代的C 1-C 6烷氧基；或 When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo of C 1 -C 6 alkoxy; or当E选自CR 10或N时，D选自CR 9，R 9选自卤代的C 1-C 6烷氧基，R 10选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基； When E is selected from CR 10 or N, D is selected from CR 9 , R 9 is selected from halogenated C 1 -C 6 alkoxy, R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated of C 1 -C 6 alkoxy;R a选自H、C 1-C 6烷基、C 2-C 8烯基、炔丙基、C 3-C 6环烷基和3-6元杂环基，所述C 1-C 6烷基、C 2-C 8烯基、炔丙基、C 3-C 6环烷基和3-6元杂环基任选地被一个或多个独立选自以下的基团：F、CI、Br、I、CN、OH、OCH 3和SO 2CH 3取代； R a is selected from H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl, said C 1 -C 6 Alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl, and 3-6 membered heterocyclyl are optionally selected by one or more groups independently selected from the following: F, CI , Br, I, CN, OH, OCH 3 and SO 2 CH 3 substituted;R b独立选自H、OH、-O(C 1-C 3烷基)、C 1-C 6烷基、C 2-C 8烯基、炔丙基、-(C 1-C 6亚烷基)-(C 3-C 6环烷基)、C 3-C 6环烷基和3-6元杂环基，其中，所述C 1-C 3烷基、C 1-C 6烷基、C 2-C 8烯基、炔丙基、-(C 1-C 6亚烷基)-(C 3-C 6环烷基)、C 3-C 6环烷基和3-6元杂环基任选地被一个或多个独立选自以下的基团：F、Cl、Br、I、CN、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-CH 2CHF 2、-CH 2CH 2F、-OH、-OCH 3和-SO 2CH 3 取代； R b is independently selected from H, OH, -O(C 1 -C 3 alkyl), C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkylene base)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl, wherein the C 1 -C 3 alkyl, C 1 -C 6 alkyl , C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl and 3-6 membered heteroalkyl The cyclyl group is optionally by one or more groups independently selected from: F, Cl , Br, I, CN, -CH2F , -CHF2 , -CF3 , -CH2CF3 , -CH2 CHF 2 , -CH 2 CH 2 F, -OH, -OCH 3 and -SO 2 CH 3 substituted;m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;r为0、1、2或3；r is 0, 1, 2 or 3;s为1、2或3。s is 1, 2 or 3. - 根据权利要求1所述的化合物，其特征在于，所述化合物为式(Ⅰa)所示化合物：The compound according to claim 1, wherein the compound is a compound represented by formula (Ia):
其中，in,D是CR 9或N； D is CR 9 or N;E是CR 10或N； E is CR 10 or N;L 1选自-O-或-NH-； L 1 is selected from -O- or -NH-;L 2选自-NH-或C 3-C 8杂环基；所述C 3-C 8杂环基任选地被一个或多个R 7取代； L 2 is selected from -NH- or C 3 -C 8 heterocyclyl; the C 3 -C 8 heterocyclyl is optionally substituted with one or more R 7 ;R 1、R 1 ’分别独立地选自H、卤素、C 1-C 3烷基； R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl;R 7是H、F、Cl、Br、I、OH或NH 2； R7 is H, F, Cl, Br, I, OH or NH2 ;R 8是H、F或CN； R8 is H, F or CN;当D选自CR 9或N时，E选自CR 10，R 9选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基，R 10选自卤代的C 1-C 6烷氧基；或 When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo of C 1 -C 6 alkoxy; or当E选自CR 10或N时，D选自CR 9，R 9选自卤代的C 1-C 6烷氧基，R 10选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基； When E is selected from CR 10 or N, D is selected from CR 9 , R 9 is selected from halogenated C 1 -C 6 alkoxy, R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated of C 1 -C 6 alkoxy;R 11选自H、卤素、C 1-C 3烷基；所述C 1-C 3烷基任选地被一个或多个卤素取代； R 11 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted with one or more halogens;R 12选自H、卤素、C 1-C 3烷基；所述C 1-C 3烷基任选地被-OH、卤素、C 1-C 3 烷氧基中的一个或多个取代基所取代； R 12 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted by one or more of -OH, halogen, C 1 -C 3 alkoxy replaced;R 13是H或卤素；或者 R 13 is H or halogen; orR 12和R 13连同它们附接至其上的碳原子一起形成C 3-C 8环烷基、C 3-C 8杂环基； R 12 and R 13 together with the carbon atom to which they are attached form C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl;r为0、1、2或3；r is 0, 1, 2 or 3;s为1、2或3。s is 1, 2 or 3. - 根据权利要求2或3所述的化合物，其特征在于，，所述化合物为式(Ⅰb)所示化合物：The compound according to claim 2 or 3, characterized in that, the compound is a compound represented by formula (Ib):
其中，环A选自C 3-C 8杂环基； wherein Ring A is selected from C 3 -C 8 heterocyclyl;D是CR 9或N； D is CR 9 or N;E是CR 10或N； E is CR 10 or N;L 1选自-O-或-NH-； L 1 is selected from -O- or -NH-;R 1、R 1 ’分别独立地选自H、卤素、C 1-C 3烷基； R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl;R 7是H、F、Cl、Br、I、OH或NH 2； R7 is H, F, Cl, Br, I, OH or NH2 ;R 8是H、F或CN； R8 is H, F or CN;当D选自CR 9或N时，E选自CR 10，R 9选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基，R 10选自卤代的C 1-C 6烷氧基；或 When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo of C 1 -C 6 alkoxy; or当E选自CR 10或N时，D选自CR 9，R 9选自卤代的C 1-C 6烷氧基，R 10选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基； When E is selected from CR 10 or N, D is selected from CR 9 , R 9 is selected from halogenated C 1 -C 6 alkoxy, R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated of C 1 -C 6 alkoxy;R 11选自H、卤素、C 1-C 3烷基；所述C 1-C 3烷基任选地被一个或多个卤素取代； R 11 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted with one or more halogens;R 12选自H、卤素、C 1-C 3烷基；所述C 1-C 3烷基任选地被-OH、卤素、C 1-C 3烷氧基中的一个或多个取代基所取代； R 12 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted by one or more of -OH, halogen, C 1 -C 3 alkoxy replaced;R 13是H或卤素；或者 R 13 is H or halogen; orR 12和R 13连同它们附接至其上的碳原子一起形成C 3-C 8环烷基、C 3-C 8杂环基； R 12 and R 13 together with the carbon atom to which they are attached form C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl;r为0、1、2或3；r is 0, 1, 2 or 3;s为1、2或3。s is 1, 2 or 3. - 根据权利要求1-3任一项所述的化合物，其特征在于，所述化合物为式(Ⅰc)所示化合物：The compound according to any one of claims 1-3, wherein the compound is a compound represented by formula (Ic):
其中，in,D是CR 9或N； D is CR 9 or N;E是CR 10或N； E is CR 10 or N;L 1选自-O-或-NH-； L 1 is selected from -O- or -NH-;R 1选自H、卤素、C 1-C 3烷基； R 1 is selected from H, halogen, C 1 -C 3 alkyl;R 7是H、F、Cl、Br、I、OH或NH 2； R7 is H, F, Cl, Br, I, OH or NH2 ;R 8是H、F或CN； R8 is H, F or CN;当D选自CR 9或N时，E选自CR 10，R 9选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基，R 10选自卤代的C 1-C 6烷氧基；或 When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo of C 1 -C 6 alkoxy; or当E选自CR 10或N时，D选自CR 9，R 9选自卤代的C 1-C 6烷氧基，R 10选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基； When E is selected from CR 10 or N, D is selected from CR 9 , R 9 is selected from halogenated C 1 -C 6 alkoxy, R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated of C 1 -C 6 alkoxy;R 11是Me、F或CH 2F； R 11 is Me, F or CH 2 F;R 12是Me、F、CH 2F、CHF 2、CF 3、CH 2OMe或CH 2OH； R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH;R 13是H或F；或者 R 13 is H or F; orR 12和R 13连同它们附接至其上的碳原子一起形成环丙基、环丁基或氧杂环丁基； R 12 and R 13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl;p为1、2或3。p is 1, 2 or 3. - 根据权利要求1-4任一项所述的化合物，其特征在于，所述化合物为式(Ⅰd)所示化合物：The compound according to any one of claims 1-4, wherein the compound is a compound represented by formula (Id):
其中，in,D是CR 9或N； D is CR 9 or N;E是CR 10或N； E is CR 10 or N;R 1选自H、卤素、C 1-C 3烷基； R 1 is selected from H, halogen, C 1 -C 3 alkyl;R 7是H、F、Cl、Br、I、OH或NH 2； R7 is H, F, Cl, Br, I, OH or NH2 ;R 8是H、F或CN； R8 is H, F or CN;当D选自CR 9或N时，E选自CR 10，R 9选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基，R 10选自卤代的C 1-C 6烷氧基；或 When D is selected from CR 9 or N, E is selected from CR 10 , R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy, and R 10 is selected from halo of C 1 -C 6 alkoxy; or当E选自CR 10或N时，D选自CR 9，R 9选自卤代的C 1-C 6烷氧基，R 10选自H、卤素、C 1-C 3烷基、卤代的C 1-C 6烷氧基； When E is selected from CR 10 or N, D is selected from CR 9 , R 9 is selected from halogenated C 1 -C 6 alkoxy, R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated of C 1 -C 6 alkoxy;R 11是Me、F或CH 2F； R 11 is Me, F or CH 2 F;R 12是Me、F、CH 2F、CHF 2、CF 3、CH 2OMe或CH 2OH； R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH;R 13是H或F；或者 R 13 is H or F; orR 12和R 13连同它们附接至其上的碳原子一起形成环丙基、环丁基或氧杂环丁基； R 12 and R 13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl;p为1、2或3。p is 1, 2 or 3. - 根据权利要求1-5任一项所述的化合物，其特征在于，所述化合物为式(Ⅰe)或式(Ⅰf)或式(Ⅰg)所示化合物：The compound according to any one of claims 1-5, wherein the compound is a compound represented by formula (Ie) or formula (If) or formula (Ig):
- 根据权利要求1-6任一项所述的化合物，其特征在于，所述化合物为式(Ⅰh)或式(Ⅰi)或式(Ⅰj)所示化合物：The compound according to any one of claims 1-6, wherein the compound is a compound represented by formula (Ih) or formula (Ii) or formula (Ij):
- 根据权利要求1-3任一项所述的化合物，其特征在于，R 1、R 1 ’相同或不同，独立地选自H、-CH 3。 The compound according to any one of claims 1-3, wherein R 1 and R 1 ' are the same or different, and are independently selected from H and -CH 3 .
- 根据权利要求1-8任一项所述的化合物，其特征在于，D是CR 9，E是 CR 10；R 9选自H、Cl、F、卤代的C 1-C 6烷氧基，R 10选自卤代的C 1-C 6烷氧基；进一步地，R 9选自H、Cl、F、-OCH 2F、-OCHF 2或-OCF 3，R 10选自-OCH 2F、-OCHF 2或-OCF 3。 The compound according to any one of claims 1-8, wherein D is CR 9 , E is CR 10 ; R 9 is selected from H, Cl, F, halogenated C 1 -C 6 alkoxy, R 10 is selected from halogenated C 1 -C 6 alkoxy; further, R 9 is selected from H, Cl, F, -OCH 2 F, -OCHF 2 or -OCF 3 , and R 10 is selected from -OCH 2 F , -OCHF 2 or -OCF 3 .
- 根据权利要求1-8任一项所述的化合物，其特征在于，D是N，E是CR 10；R 10选自卤代的C 1-C 6烷氧基；进一步地R 10选自-OCH 2F、-OCHF 2或-OCF 3。 The compound according to any one of claims 1-8, wherein D is N, E is CR 10 ; R 10 is selected from halogenated C 1 -C 6 alkoxy; further R 10 is selected from- OCH 2 F, -OCHF 2 or -OCF 3 .
- 根据权利要求1-8任一项所述的化合物，其特征在于，D是CR 9，E是CR 10；R 9选自卤代的C 1-C 6烷氧基，R 10选自H、Cl、F、卤代的C 1-C 6烷氧基；进一步地，R 9选自-OCH 2F、-OCHF 2或-OCF 3，R 10选自H、Cl、F、-OCH 2F、-OCHF 2或-OCF 3。 The compound according to any one of claims 1-8, wherein D is CR 9 , E is CR 10 ; R 9 is selected from halogenated C 1 -C 6 alkoxy, and R 10 is selected from H, Cl, F, halogenated C 1 -C 6 alkoxy; further, R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 , R 10 is selected from H, Cl, F, -OCH 2 F , -OCHF 2 or -OCF 3 .
- 根据权利要求1-8任一项所述的化合物，其特征在于，D是CR 9，E是N；R 9选自卤代的C 1-C 6烷氧基；进一步地，R 9选自-OCH 2F、-OCHF 2或-OCF 3。 The compound according to any one of claims 1-8, wherein D is CR 9 , E is N; R 9 is selected from halogenated C 1 -C 6 alkoxy; further, R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
- 根据权利要求12所述的化合物，其特征在于，D是CR 9，E是N；R 9选自-OCH 2F、-OCHF 2或-OCF 3。 The compound of claim 12, wherein D is CR 9 , E is N; R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
- 根据权利要求10所述的化合物，其特征在于，D是CR 9，E是CR 10；R 9选自H、Cl、F；R 10选自-OCH 2F、-OCHF 2或-OCF 3。 The compound of claim 10, wherein D is CR 9 , E is CR 10 ; R 9 is selected from H, Cl, F; R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
- 根据权利要求2-14任一项所述的化合物，其特征在于，R 11是Me、F或CH 2F。 The compound of any one of claims 2-14, wherein R 11 is Me, F or CH 2 F.
- 根据权利要求2-14任一项所述的化合物，其特征在于，R 12是Me、F、CH 2F、CHF 2、CF 3、CH 2OMe或CH 2OH。 The compound of any one of claims 2-14, wherein R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH.
- 根据权利要求2-14任一项所述的化合物，其特征在于，R 13是H或F。 The compound of any one of claims 2-14, wherein R 13 is H or F.
- 根据权利要求2-14任一项所述的化合物，其特征在于，R 12和R 13连同它们附接至其上的碳原子一起形成环丙基、环丁基或氧杂环丁基。 15. The compound of any one of claims 2-14, wherein R12 and R13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl.
- 根据权利要求2-14任一项所述的化合物，其特征在于，R 11为F，R 12为F，且R 13为F。 The compound of any one of claims 2-14, wherein R 11 is F, R 12 is F, and R 13 is F.
- 根据权利要求2-14任一项所述的化合物，其特征在于，R 11为F，R 12为CH 2OH，且R 13为F。 The compound of any one of claims 2-14, wherein R 11 is F, R 12 is CH 2 OH, and R 13 is F.
- 根据权利要求2-14任一项所述的化合物，其特征在于，R 11为F，R 12和R 13连同它们附接至其上的碳原子一起形成氧杂环丁基。 The compound of any one of claims 2-14, wherein R11 is F, and R12 and R13 together with the carbon atom to which they are attached form an oxetanyl group.
- 根据权利要求1-21任一项所述的化合物，其特征在于，R 8是H。 The compound of any one of claims 1-21, wherein R8 is H.
- 根据权利要求1-21任一项所述的化合物，其特征在于，R 8是F。 The compound of any one of claims 1-21, wherein R8 is F.
- 根据权利要求1-21任一项所述的化合物，其特征在于，R 8是CN。 The compound of any one of claims 1-21, wherein R8 is CN.
- 根据权利要求1-3任一项所述的化合物，其特征在于，r为0；s为3。The compound according to any one of claims 1-3, wherein r is 0; s is 3.
- 根据权利要求1-3任一项所述的化合物，其特征在于，r为2；s为2。The compound according to any one of claims 1-3, wherein r is 2; s is 2.
- 根据权利要求1-3任一项所述的化合物，其特征在于，r为2；s为1。The compound according to any one of claims 1-3, wherein r is 2; s is 1.
- 根据权利要求2所述的化合物，其特征在于，环A选自C 4-C 6杂环基；进一步地，环A为氮杂环丁烷基、吡咯烷基或哌啶基。 The compound according to claim 2, wherein ring A is selected from C 4 -C 6 heterocyclyl; further, ring A is azetidinyl, pyrrolidinyl or piperidinyl.
- 根据权利要求4-28任一项所述的化合物，其特征在于，p为1。The compound of any one of claims 4-28, wherein p is 1.
- 根据权利要求4-28任一项所述的化合物，其特征在于，p为2。The compound of any one of claims 4-28, wherein p is 2.
- 根据权利要求1-30任一项所述的化合物或其药学上可接受的盐，其特征在于，所述化合物选自：The compound according to any one of claims 1-30 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;4-((3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氨基)-1-(3-氟丙基)吡咯烷-3-醇；4-((3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyrido[3,4-b]indol-1-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;4-((4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)氨基)-1-(3-氟丙基)吡咯烷-3-醇；4-((4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole- 1-yl)-3-(difluoromethoxy)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;6-((2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-(二氟甲氧基)-N-(1-(3-氟丙基)氮杂环丁烷-3-基)吡啶-3-胺；6-((2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl )-5-(difluoromethoxy)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine;N-(3-(二氟甲氧基)-4-(2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;N-(3-(二氟甲氧基)-4-(2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((1-fluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;1-(3-氟丙基)-N-(4-((3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)氮杂环丁烷-3-胺；1-(3-Fluoropropyl)-N-(4-((3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)azetidin-3-amine;1-(3-氟丙基)-N-(4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺；1-(3-Fluoropropyl)-N-(4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;3-(1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇；3-(1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-Tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;N-(3-(二氟甲氧基)-4-(2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;2,2-二氟-3-(1-(4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)-2-(三氟甲氧基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙-1-醇；2,2-Difluoro-3-(1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-(trifluoromethoxy)phenyl )-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propan-1-ol;N-(3-(二氟甲氧基)-4-(2-((3-氟代氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;N-(3-(二氟甲氧基)-4-(2-((3-氟氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrakis Hydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;6-((2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-(二氟甲氧基)-N-(1-(3-氟丙基)吡咯烷-3-基)吡啶-3-胺；6-((2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl )-5-(difluoromethoxy)-N-(1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;5-(二氟甲氧基)-N-(1-(3-氟丙基)氮杂环丁烷-3-基)-6-((3-甲基-2-(2,2,2-三氟乙基)-2，3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)吡啶-3-胺；5-(Difluoromethoxy)-N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((3-methyl-2-(2,2,2 - trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)pyridin-3-amine;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;N1-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-N2-(3-氟丙基)乙烷-1,2-二胺；N1-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-propylazetidine-3-amine;N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;1-(3-氟丙基)-N-(4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺；1-(3-Fluoropropyl)-N-(4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine;N1-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-N2-(3-氟丙基)乙烷-1,2-二胺；N1-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;N1-(3-氟丙基)-N2-(4-((3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)乙烷-1,2-二胺；N1-(3-Fluoropropyl)-N2-(4-((3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)ethane-1,2-diamine;N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) yl[3,4-b]indol-1-yl)phenyl)-1-propylazetidine-3-amine;N-(4-((3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(4-((3-Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridinyl[3,4-b]indole dol-1-yl)-3-(trifluoromethoxy)phenyl)-1-propylazetidine-3-amine;N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;1-(3-氟丙基)-N-(4-((3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)哌啶-4-胺；1-(3-Fluoropropyl)-N-(4-((3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)piperidin-4-amine;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4-b]indole-1 -yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-N-(2-(3-(氟甲基)氮杂环丁烷-1-基)乙基)-3-(三氟甲氧基)苯胺；4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl) -N-(2-(3-(fluoromethyl)azetidin-1-yl)ethyl)-3-(trifluoromethoxy)aniline;N-(2-(3-(氟甲基)氮杂环丁烷-1-基)乙基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4，9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯胺；N-(2-(3-(Fluoromethyl)azetidine-1-yl)ethyl)-4-(3-methyl-2-(2,2,2-trifluoroethyl)- 2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)aniline;1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2- (2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;1-(3-(二氟甲氧基)-5-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)吡 啶-2-基)-3-甲基-2-(2，2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；1-(3-(Difluoromethoxy)-5-((1-(3-fluoropropyl)azetidin-3-yl)oxy)pyridin-2-yl)-3-methyl -2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;5-(二氟甲氧基)-N-(1-(3-氟丙基)吡咯烷-3-基)-6-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)吡啶-3-胺；5-(Difluoromethoxy)-N-(1-(3-fluoropropyl)pyrrolidin-3-yl)-6-(3-methyl-2-(2,2,2-trifluoroethyl) yl)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)pyridin-3-amine;1-(3-(二氟甲氧基)-5-(((1-(3-氟丙基)吡咯烷-3-基)氧基)吡啶-2-基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；1-(3-(Difluoromethoxy)-5-(((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2 -(2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)吡咯烷-3-基)氧基)苯基)-3-甲基-2-(2，2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2, 2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;N-(3-(二氟甲氧基)-4-(2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;N-(3-(二氟甲氧基)-4-(2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;N-(3-(二氟甲氧基)-4-(2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((1-fluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;3-(1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)吡咯烷-3-基)氨基)苯基)-3-甲基-1，3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇；3-(1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-1,3 ,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;2,2-二氟-3-((1-(4-((1-(3-氟丙基)吡咯烷-3-基)氨基)-2-(三氟甲氧基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙-1-醇；2,2-Difluoro-3-((1-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2-(trifluoromethoxy)phenyl)- 3-Methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propan-1-ol;N-(4-(2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-(2-(2,2-Difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-1- yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;3-(1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)吡咯烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇；3-(1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-1,3 ,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;N-(3-(二氟甲氧基)-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine) [3,4-b]Indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;1-(4-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)-2-(三氟甲氧基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚；1-(4-((1-(3-Fluoropropyl)azetidine-3-yl)oxy)-2-(trifluoromethoxy)phenyl)-3-methyl-2- (2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole;1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-6-甲腈；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-( 2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-6-carbonitrile;N-(3-(二氟甲氧基)-4-(3-甲基-2-((3-甲基氧杂环丁-3-基)甲 基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(3-methyl-2-((3-methyloxetan-3-yl)methyl)-2,3,4,9- Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;N-(4-(2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-(2-(2-Fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole -1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;N-(3-(二氟甲氧基)-5-氟-4-(2-((3-氟代氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-5-fluoro-4-(2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-7-甲腈；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-( 2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-7-carbonitrile;1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-8-甲腈；1-(2-(Difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-( 2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-8-carbonitrile;N-(3-(二氟甲氧基)-4-(2-((3-氟氧代环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-(2-((3-fluorooxocyclobutan-3-yl)methyl)-3-methyl-2,3,4,9-tetra Hydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;N-(3-(二氟甲氧基)-4-(2-((3-氟氮杂环丁烷-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；或N-(3-(Difluoromethoxy)-4-(2-((3-fluoroazetidin-3-yl)methyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine; or4-(3-((3,5-二氟-4-(3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氨基)氮杂环丁烷-1-基)丁腈。4-(3-((3,5-Difluoro-4-(3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H- Pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidin-1-yl)butyronitrile.
- 根据权利要求1-31任一项所述的化合物或其药学上可接受的盐，其特征在于，所述化合物选自：The compound according to any one of claims 1-31 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;N-(3-(二氟甲氧基)-4-((1R,3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;(3R，4R)-4-((3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氨基)-1-(3-氟丙基)吡咯烷-3-醇；(3R,4R)-4-((3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2 ,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;(3R，4R)-4-((4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)氨基)-1-(3- 氟丙基)吡咯烷-3-醇；(3R,4R)-4-((4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(difluoromethoxy)phenyl)amino)-1-(3-fluoropropyl)pyrrolidin-3-ol;6-(((1S，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-(二氟甲氧基)-N-(1-(3-氟丙基)氮杂环丁烷-3-基)吡啶-3-胺；6-(((1S,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-1-yl)-5-(difluoromethoxy)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine;N-(3-(二氟甲氧基)-4-((1R，3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;N-(3-(二氟甲氧基)-4-((1R，3R)-2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((1-fluorocyclobutyl)methyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;1-(3-氟丙基)-N-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)氮杂环丁烷-3-胺；1-(3-Fluoropropyl)-N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 - Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)azetidine-3-amine;(S)-1-(3-氟丙基)-N-(4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺；(S)-1-(3-Fluoropropyl)-N-(4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine;N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;(S)-N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[ 3,4-b]indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;(R)-N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(R)-N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[ 3,4-b]indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;3-((1R,3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基) 苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇；3-((1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl) -3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;(S)-N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[ 3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;2,2-二氟-3-((1R,3R)-1-(4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)-2-(三氟甲氧基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙-1-醇；2,2-Difluoro-3-((1R,3R)-1-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-(trifluoro Methoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propan-1-ol;N-(3-(二氟甲氧基)-4-((1R,3R)-2-((3-氟代氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2, 3,4,9-Tetrahydro-1H-pyridinyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-2-((3-氟氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl -2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;6-(((1S，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-(二氟甲氧基)-N-((S)-1-(3-氟丙基)吡咯烷-3-基)吡啶-3-胺；6-(((1S,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-1-yl)-5-(difluoromethoxy)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)pyridin-3-amine;(R)-N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(R)-N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[ 3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;5-(二氟甲氧基)-N-(1-(3-氟丙基)氮杂环丁烷-3-基)-6-(((1S，3R)-3-甲基-2-(2,2,2-三氟乙基)-2，3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)吡啶-3-胺；5-(Difluoromethoxy)-N-(1-(3-fluoropropyl)azetidine-3-yl)-6-(((1S,3R)-3-methyl-2- (2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)pyridin-3-amine;N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;N1-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-N2-(3-氟丙基)乙烷-1,2- 二胺；N1-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridyl[3,4- b] Indol-1-yl)-3-(trifluoromethoxy)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-propylazetidine-3-amine;(R)-N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(R)-N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;(R)-1-(3-氟丙基)-N-(4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)吡咯烷-3-胺；(R)-1-(3-Fluoropropyl)-N-(4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidin-3-amine;N1-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-N2-(3-氟丙基)乙烷-1,2-二胺；N1-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-N2-(3-fluoropropyl)ethane-1,2-diamine;N1-(3-氟丙基)-N2-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)乙烷-1,2-二胺；N1-(3-Fluoropropyl)-N2-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 - Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)ethane-1,2-diamine;N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-propylazetidine-3-amine;N-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-丙基氮杂环丁烷-3-胺；N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridinyl[3 ,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-propylazetidine-3-amine;N-(3-(二氟甲氧基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3，4-b]吲哚-1-基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;1-(3-氟丙基)-N-(4-(((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)哌啶-4-胺；1-(3-Fluoropropyl)-N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 - Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)piperidin-4-amine;N-(4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)哌啶-4-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridinyl[3,4- b] indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)piperidin-4-amine;4-((1R，3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-N-(2-(3-(氟甲基)氮杂环丁烷-1-基)乙基)-3-(三氟甲氧基)苯胺；4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole dol-1-yl)-N-(2-(3-(fluoromethyl)azetidin-1-yl)ethyl)-3-(trifluoromethoxy)aniline;N-(2-(3-(氟甲基)氮杂环丁烷-1-基)乙基)-4-((1R，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4，9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯胺；N-(2-(3-(Fluoromethyl)azetidin-1-yl)ethyl)-4-((1R,3R)-3-methyl-2-(2,2,2- trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)aniline;(1R，3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3- 基)氧基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；(1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3 -methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;(1S，3R)-1-(3-(二氟甲氧基)-5-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)吡啶-2-基)-3-甲基-2-(2，2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；(1S,3R)-1-(3-(difluoromethoxy)-5-((1-(3-fluoropropyl)azetidin-3-yl)oxy)pyridin-2-yl )-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;5-(二氟甲氧基)-N-((S)-1-(3-氟丙基)吡咯烷-3-基)-6-((1S，3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)吡啶-3-胺；5-(Difluoromethoxy)-N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((1S,3R)-3-methyl-2- (2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)pyridin-3-amine;(1S，3R)-1-(3-(二氟甲氧基)-5-((((S)-1-(3-氟丙基)吡咯烷-3-基)氧基)吡啶-2-基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；(1S,3R)-1-(3-(difluoromethoxy)-5-((((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridine-2 -yl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;(1R，3R)-1-(2-(二氟甲氧基)-4-(((S)-1-(3-氟丙基)吡咯烷-3-基)氧基)苯基)-3-甲基-2-(2，2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；(1R,3R)-1-(2-(difluoromethoxy)-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;N-(3-(二氟甲氧基)-4-((1R，3R)-2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-2-((1-氟环丙基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3, 4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;(S)-N-(3-(二氟甲氧基)-4-((1R，3R)-2-((1-氟环丁基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶基[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1R,3R)-2-((1-fluorocyclobutyl)methyl)-3-methyl-2,3, 4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;3-((1R，3R)-1-(2-(二氟甲氧基)-4-(((S)-1-(3-氟丙基)吡咯烷-3-基)氨基)苯基)-3-甲基-1，3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-2,2-二氟丙烷-1-醇；3-((1R,3R)-1-(2-(difluoromethoxy)-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl )-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;2,2-二氟-3-(((1R，3R)-1-(4-(((S)-1-(3-氟丙基)吡咯烷-3-基)氨基)-2-(三氟甲氧基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙-1-醇；2,2-Difluoro-3-(((1R,3R)-1-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2-( trifluoromethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propan-1-ol;N-(4-((1R,3R)-2-(2,2-二氟乙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b] 吲哚-1-基)-3-(二氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridine[3,4-b ] Indol-1-yl)-3-(difluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;3-((1R,3R)-1-(2-(二氟甲氧基)-4-(((S)-1-(3-氟丙基)吡咯烷-3-基)氨基)苯基)-3-甲基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)-2,2-二氟丙-1-醇；3-((1R,3R)-1-(2-(difluoromethoxy)-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl )-3-methyl-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol;(S)-N-(3-(二氟甲氧基)-4-((1S,3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)吡咯烷-3-胺；(S)-N-(3-(difluoromethoxy)-4-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, 4,9-Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine;(1R,3R)-1-(4-((1-(3-氟丙基)氮杂环丁烷-3-基)氧基)-2-(三氟甲氧基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚；(1R,3R)-1-(4-((1-(3-Fluoropropyl)azetidin-3-yl)oxy)-2-(trifluoromethoxy)phenyl)-3 -methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole;(1R,3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-6-甲腈；(1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3- Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-6-carbonitrile;N-(3-(二氟甲氧基)-4-((1R,3R)-3-甲基-2-((3-甲基氧杂环丁-3-基)甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-3-methyl-2-((3-methyloxetan-3-yl)methyl)-2, 3,4,9-Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine;N-(4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3-(三氟甲氧基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]Indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;N-(3-(二氟甲氧基)-5-氟-4-((1R,3R)-2-((3-氟代氧杂环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-5-fluoro-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl yl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine- 3-amine;(1R,3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-7-甲腈；(1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3- Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-7-carbonitrile;(1R,3R)-1-(2-(二氟甲氧基)-4-((1-(3-氟丙基)氮杂环丁烷-3-基)氨基)苯基)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-8-甲腈；(1R,3R)-1-(2-(difluoromethoxy)-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3- Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-8-carbonitrile;N-(3-(二氟甲氧基)-4-((1R,3R)-2-((3-氟氧代环丁-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((3-fluorooxocyclobutan-3-yl)methyl)-3-methyl-2,3 ,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine;N-(3-(二氟甲氧基)-4-((1R,3R)-2-((3-氟氮杂环丁烷-3-基)甲基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)-1-(3-氟丙基)氮杂环丁烷-3-胺；或N-(3-(Difluoromethoxy)-4-((1R,3R)-2-((3-fluoroazetidin-3-yl)methyl)-3-methyl-2, 3,4,9-Tetrahydro-1H-pyridin[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine; or4-(3-((3,5-二氟-4-((1R,3R)-3-甲基-2-(2,2,2-三氟乙基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氨基)氮杂环丁烷-1-基)丁腈。4-(3-((3,5-Difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9 -Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidin-1-yl)butyronitrile.
- 一种药物组合物，其特征在于，所述药物组合物包含治疗有效量的至少一种权利要求1-32任一项所述化合物和至少一种药学上可接受的辅料。A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described in any one of claims 1-32 and at least one pharmaceutically acceptable adjuvant.
- 权利要求1-32任一项所述的化合物或权利要求33所述的药物组合物在制备用于治疗***受体相关疾病的药物中的用途。Use of the compound of any one of claims 1-32 or the pharmaceutical composition of claim 33 in the preparation of a medicament for the treatment of estrogen receptor-related diseases.
- 根据权利要求34所述的用途，其特征在于，所述***受体相关疾病为选自以下的癌症：乳腺癌、肺癌、卵巢癌、子宫内膜癌、***癌和子宫癌。The use according to claim 34, wherein the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer and uterine cancer.
- 一种在患者中治疗***受体相关疾病的方法，其包括向所述患者给予治疗有效量的权利要求1-32任一项所述化合物或权利要求33所述的药物组合物。A method of treating an estrogen receptor-related disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-32 or the pharmaceutical composition of claim 33.
- 根据权利要求36所述的方法，其特征在于，所述***受体相关疾病为选自以下的癌症：乳腺癌、肺癌、卵巢癌、子宫内膜癌、***癌和子宫癌。The method of claim 36, wherein the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
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| WO2024017131A1 (en) * | 2022-07-21 | 2024-01-25 | 贝达药业股份有限公司 | Heteroarylopiperidine derivative, and pharmaceutical composition and use thereof |
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