TW202411231A - Substituted purinone derivative used as ubiquitin-specific protease inhibitor - Google Patents
Substituted purinone derivative used as ubiquitin-specific protease inhibitor Download PDFInfo
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- TW202411231A TW202411231A TW112134309A TW112134309A TW202411231A TW 202411231 A TW202411231 A TW 202411231A TW 112134309 A TW112134309 A TW 112134309A TW 112134309 A TW112134309 A TW 112134309A TW 202411231 A TW202411231 A TW 202411231A
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- alkyl
- nhc
- cycloalkenyl
- cycloalkyl
- alkoxy
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- UFZNZKGKBWOSJG-UHFFFAOYSA-N purin-2-one Chemical class O=C1N=CC2=NC=NC2=N1 UFZNZKGKBWOSJG-UHFFFAOYSA-N 0.000 title abstract description 3
- 229940095049 Ubiquitin-specific protease inhibitor Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
本發明涉及用作泛素-特異性蛋白酶抑制劑的取代嘌呤酮衍生物,具體涉及式(I)所示化合物、其異構物或其藥學上可接受的鹽。The present invention relates to substituted purinone derivatives used as ubiquitin-specific protease inhibitors, and specifically to compounds represented by formula (I), isomers thereof or pharmaceutically acceptable salts thereof.
USP1 (ubiquitin specific peptidase 1)全稱泛素特異性肽酶1,是去泛素化酶家族的一員。USP1與其輔因子UAF1 (USP1-associated factor 1)形成USP1-UAF1複合物,對FA和TLS途徑中的2個關鍵蛋白Ub-FANCD2和Ub-PCNA去泛素化,進而起始DNA交聯損傷修復,促進癌細胞存活。USP1在多種人類腫瘤中高表現,與腫瘤的發生發展密切相關,其作為腫瘤治療標的受到廣泛關注。USP1 (ubiquitin specific peptidase 1) is a member of the deubiquitinase family. USP1 and its cofactor UAF1 (USP1-associated factor 1) form the USP1-UAF1 complex, which deubiquitinates two key proteins in the FA and TLS pathways, Ub-FANCD2 and Ub-PCNA, thereby initiating DNA cross-link damage repair and promoting cancer cell survival. USP1 is highly expressed in many human tumors and is closely related to the occurrence and development of tumors. It has received widespread attention as a target for tumor treatment.
基於CRISPR技術的全基因組標的剔除研究顯示,USP1與BRCA1/2突變或其它同源重組修復缺陷(HRD)存在合成致死效應。從作用機制來看,USP1和PARP分屬DNA交聯損傷和單鏈損傷修復途徑中的關鍵調控蛋白,兩者互為補充促進DNA損傷修復以免產生具有細胞致死毒性的DNA雙鏈斷裂。因此,USP1是DNA損傷修復領域極具臨床價值的重要標的。The genome-wide knockout study based on CRISPR technology showed that USP1 and BRCA1/2 mutations or other homologous recombination repair defects (HRD) have synthetic lethal effects. From the perspective of mechanism of action, USP1 and PARP are key regulatory proteins in the DNA cross-link damage and single-strand damage repair pathways, respectively. The two complement each other to promote DNA damage repair to avoid the production of DNA double-strand breaks with cell-lethal toxicity. Therefore, USP1 is an important target with great clinical value in the field of DNA damage repair.
本發明提供了式(I)所示化合物、其異構物或其藥學上可接受的鹽, 其中, X 1和X 2分別獨立地選自C(R 1)或N; X 3、X 4、X 5和X 6分別獨立地選自C(R 5)或N; 每個R 1和R 5分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基或3-12員雜環基,所述-OH、-SH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基和3-12員雜環基任選獨立地被一個或多個取代基取代; 或者相鄰兩個碳原子上的R 5和其所連接的碳原子一起形成任選被一個或多個取代基取代的C 5-7環烯基、5-7員雜環烯基、苯基或5-6員雜芳基; L選自-(C(R 3R 4)) m-、-O-、-S-、-N(R 9)-、-S(O)-或-S(O) 2-; R 2選自C 3-12環烷基、C 6-10芳基、5-10員雜芳基、3-12員雜環基或C 5-7環烯基,所述C 3-12環烷基、C 6-10芳基、5-10員雜芳基、3-12員雜環基和C 5-7環烯基任選獨立地被一個或多個R 2a取代; 每個R 3和R 4分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基或3-12員雜環基,所述-OH、-SH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基和3-12員雜環基任選獨立地被一個或多個取代基取代; 或R 3和R 4以及其共同連接的碳原子一起形成羰基; 或R 3和R 4以及其共同連接的碳原子一起形成任選被一個或多個取代基取代的C 3-6環烷基或3-6員雜環烷基; 或相鄰兩個碳原子上的R 3和R 3、R 3和R 4、R 4和R 3、R 4和R 4和其所連接的碳原子一起形成任選被一個或多個取代基取代的C 3-6環烷基或3-6員雜環烷基; R 6選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基或3-12員雜環基,所述-OH、-SH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基和3-12員雜環基任選獨立地被一個或多個R 6a取代; R 7和R 8分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基或3-12員雜環基,所述-OH、-SH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基和3-12員雜環基任選獨立地被一個或多個取代基取代; 或者R 7和R 8以及其共同連接的碳原子一起形成任選被一個或多個取代基取代的C 3-8環烷基、3-8員雜環基或C 3-8環烯基; R 9選自氫或C 1-12烷基,所述C 1-12烷基任選地被一個或多個取代基取代; 每個R 2a和R 6a分別獨立地選自鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基或3-12員雜環基,所述-OH、-SH、-NH 2、-NHC 1-12烷基、-N(C 1-12烷基) 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、C 1-12烷硫基、-COC 1-12烷基、-OC(O)C 1-12烷基、-C(O)OC 1-12烷基、-OC(O)OC 1-12烷基、-SO 2C 1-12烷基、-NHSO 2C 1-12烷基、-N(C 1-12烷基)SO 2C 1-12烷基、-SO 2NH 2、-SO 2NHC 1-12烷基、-SO 2N(C 1-12烷基) 2、-CONH 2、-CONHC 1-12烷基、-CON(C 1-12烷基) 2、-NHCOC 1-12烷基、-N(C 1-12烷基)COC 1-12烷基、C 3-12環烷基、C 3-12環烯基、C 6-10芳基、5-10員雜芳基和3-12員雜環基任選獨立地被一個或多個取代基取代; m選自1、2或3。 The present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from C( R1 ) or N; X3 , X4 , X5 and X6 are independently selected from C( R5 ) or N; each R1 and R5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2 , -NHC1-12alkyl, -N( C1-12alkyl ) 2 , C1-12alkyl , C2-12alkenyl , C2-12alkynyl , C1-12alkoxy , C1-12alkylthio , -COC1-12alkyl, -OC(O) C1-12alkyl , -C (O) OC1-12alkyl , -OC(O) OC1-12alkyl , -SO2C1-12alkyl , -NHSO2C1-12alkyl -12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; the -OH, -SH, -NH 2 , -NHC 1-12 alkyl, -N(C 1-12 alkyl) 2 , C 1-12 alkyl, C 2-12 alkenyl, C C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylthio, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 3-12 wherein R 5 on two adjacent carbon atoms and the carbon atom to which they are connected together form a C 5-7 cycloalkenyl, 5-7 heterocycloalkenyl, phenyl or 5-6 heteroaryl which is optionally substituted by one or more substituents; L is selected from -(C(R 3 R 4 )) m -, -O-, -S-, -N(R 9 )-, -S(O)- or -S(O) 2 -; R 2 is selected from C 3-12 cycloalkyl, C 6-10 aryl, 5-10 heteroaryl, 3-12 heterocyclo or C 5-7 cycloalkenyl, wherein the C 3-12 cycloalkyl, C 6-10 aryl, 5-10 heteroaryl, 3-12 heterocyclo or C 5-7 cycloalkenyl R 3 and R 4 are each independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-12 alkyl, -N(C 1-12 alkyl) 2 , C 1-12 alkyl, C 2-12 alkenyl , C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylthio, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl , -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl ) 2 -12 alkyl) SO2 C1-12 alkyl , -SO2 NH2 , -SO2 NHC1-12 alkyl, -SO2 N( C1-12 alkyl) 2 , -CONH2 , -CONHC1-12 alkyl , -CON(C1-12 alkyl)2, -NHCOC1-12 alkyl, -N(C1-12 alkyl)COC1-12 alkyl, C3-12 cycloalkyl , C3-12 cycloalkenyl , C6-10 aryl , 5-10 membered heteroaryl or 3-12 membered heterocyclic group; the -OH, -SH, -NH2 , -NHC1-12 alkyl, -N(C1-12 alkyl)2, C1-12 alkyl, C2-12 alkenyl , C2-12 alkynyl , C C 1-12 alkoxy, C 1-12 alkylthio, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 6-10 membered aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group are optionally independently substituted by one or more substituents; or R3 and R4 and the carbon atom to which they are commonly connected together form a carbonyl group; or R3 and R4 and the carbon atom to which they are commonly connected together form a C3-6 cycloalkyl or 3-6 membered heterocycloalkyl group optionally substituted by one or more substituents; or R3 and R3 , R3 and R4 , R4 and R3 , R4 and R4 on two adjacent carbon atoms and the carbon atom to which they are connected together form a C3-6 cycloalkyl or 3-6 membered heterocycloalkyl group optionally substituted by one or more substituents; R6 is selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2 , -NHC C 1-12 alkyl, -N(C 1-12 alkyl) 2 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylthio, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl) C 1-12 alkyl)COC 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-12 alkyl, -N(C 1-12 alkyl) 2 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylthio, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C (O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl) 2 R 7 and R 8 are independently selected from hydrogen , halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-12 alkyl , -N(C 1-12 alkyl) 2 , C 3-12 cycloalkyl , C 3-12 cycloalkenyl , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic groups, and are optionally substituted with one or more R 6a ; R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-12 alkyl, -N(C 1-12 alkyl) 2 , C 3-12 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic groups, respectively. C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylthio, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl , -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, C 1-12 The -OH, -SH, -NH 2 , -NHC 1-12 alkyl, -N(C 1-12 alkyl) 2 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylthio, -COC 1-12 alkyl, -OC(O )C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl , -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl )SO 2 C 1-12 alkyl , -SO 2 NH 2 , -SO 2 NHC R7 and R8, together with the carbon atoms to which they are commonly attached, form a C3-8 cycloalkyl, a 3-8 membered heterocyclic group or a C3-8 cycloalkenyl group which is optionally substituted with one or more substituents; R9 is selected from hydrogen or C1-12 alkyl, and the C3-12 cycloalkyl , C3-12 cycloalkenyl, C6-10 aryl, a 5-10 membered heteroaryl and a 3-12 membered heterocyclic group. R 2a and R 6a are each independently selected from halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-12 alkyl, -N(C 1-12 alkyl) 2 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylthio, -COC 1-12 alkyl , -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl , -OC(O) OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC -1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-12 alkyl, -N(C 1-12 alkyl) 2 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylthio , -COC 1-12 alkyl, -OC(O)C C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C The 6-10 membered aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group are optionally and independently substituted with one or more substituents; m is selected from 1, 2 or 3.
在本發明的一些實施方案中,所述“被1個或多個取代”各自獨立地選自被1、2、3、4、5或6個取代。In some embodiments of the invention, the "substituted by 1 or more" is each independently selected from substituted by 1, 2, 3, 4, 5 or 6.
在本發明的一些實施方案中,所述“被1個或多個取代”各自獨立地選自被1、2、3、4或5個取代。In some embodiments of the invention, the "substituted by 1 or more" is each independently selected from substituted by 1, 2, 3, 4 or 5.
在本發明的一些實施方案中,所述“被1個或多個取代”各自獨立地選自被1、2、3或4個取代。In some embodiments of the present invention, the "substituted by 1 or more" is each independently selected from substituted by 1, 2, 3 or 4.
在本發明的一些實施方案中,所述“被1個或多個取代”各自獨立地選自被1、2或3個取代。In some embodiments of the present invention, the "substituted by 1 or more" is each independently selected from substituted by 1, 2 or 3.
在本發明的一些實施方案中,所述“被1個或多個取代”各自獨立地選自被1或2個取代。In some embodiments of the present invention, the "substituted by 1 or more" are each independently selected from substituted by 1 or 2.
在本發明的一些實施方案中,X 1和X 2中至少有一個選自C(R 1)。 In some embodiments of the present invention, at least one of X 1 and X 2 is selected from C(R 1 ).
在本發明的一些實施方案中,X 1和X 2中一個選自C(R 1),另一個選自N。 In some embodiments of the present invention, one of X1 and X2 is selected from C( R1 ), and the other is selected from N.
在本發明的一些實施方案中,X 2選自C(R 1)。 In some embodiments of the present invention, X 2 is selected from C(R 1 ).
在本發明的一些實施方案中,X 1選自N。 In some embodiments of the present invention, X1 is selected from N.
在本發明的一些實施方案中,X 1選自C(R 1),X 2選自C(R 1)。 In some embodiments of the present invention, X1 is selected from C( R1 ), and X2 is selected from C( R1 ).
在本發明的一些實施方案中,X 1選自N,X 2選自C(R 1)。 In some embodiments of the present invention, X 1 is selected from N, and X 2 is selected from C(R 1 ).
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基或3-8員雜環基,所述-OH、-SH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基和3-8員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl) 2 -C 1-6 alkyl ) 2 , -NHCOC 1-6 alkyl , -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl , phenyl , 5-10 membered heteroaryl and 3-8 membered heterocyclic group are optionally substituted independently with one or more substituents.
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-SH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -COC 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -NHSO 2 C 1-3 alkyl, -N(C 1-3 alkyl)SO 2 C 1-3 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-3 alkyl, -SO 2 N(C 1-3 alkyl) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl, -N(C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -COC 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -NHSO 2 C 1-3 alkyl, -N(C 1-3 alkyl) 2 -C 1-3 alkyl ) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl , -N (C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently by one or more substituents.
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -SO 2 NH 2 , -CONH 2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -SO 2 NH 2 2 , -CONH 2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more substituents.
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基或3-6員雜環基,所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 1 and R 5 is independently selected from hydrogen, halogen, -CN, -OH, -NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, and the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more substituents.
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、環戊基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基,所述甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、環戊基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, the methyl, ethyl, Isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl are optionally substituted independently with one or more substituents.
在本發明的一些實施方案中,每個R 1和R 5分別任選獨立地被一個或多個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, each R 1 and R 5 is optionally and independently substituted by one or more groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,每個R 1和R 5分別任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, each R 1 and R 5 is optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、環戊基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基,所述甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、環戊基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, the methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, cyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, the methyl, ethyl, isopropyl, Methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2 .
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、-F、-Cl、-Br、-I、-CN、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、氧雜環丁基、硫雜環丁基或氮雜環丁基,所述甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、氧雜環丁基、硫雜環丁基或氮雜環丁基任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the invention, each R 1 and R 5 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azidocyclobutyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azidocyclobutyl are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、-F、-Cl、-Br、-I、-CN、甲基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基。 In some embodiments of the invention, each R 1 and R 5 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、-F、-CN、甲基、甲氧基、三氟甲基或三氟甲氧基。 In some embodiments of the invention, each R 1 and R 5 is independently selected from hydrogen, -F, -CN, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
在本發明的一些實施方案中,每個R 1和R 5分別獨立地選自氫、-F或CN。 In some embodiments of the present invention, each R 1 and R 5 are independently selected from hydrogen, -F or CN.
在本發明的一些實施方案中,每個R 1分別獨立地選自-F。 In some embodiments of the invention, each R 1 is independently selected from -F.
在本發明的一些實施方案中,每個R 1分別獨立地選自氫。 In some embodiments of the invention, each R 1 is independently selected from hydrogen.
在本發明的一些實施方案中,X 1選自CH,X 2選自CH。 In some embodiments of the present invention, X1 is selected from CH, and X2 is selected from CH.
在本發明的一些實施方案中,X 1選自N,X 2選自CH。 In some embodiments of the present invention, X1 is selected from N, and X2 is selected from CH.
在本發明的一些實施方案中,X 1選自C(F),X 2選自CH。 In some embodiments of the present invention, X1 is selected from C(F), and X2 is selected from CH.
在本發明的一些實施方案中,X 1選自C(CN),X 2選自CH。 In some embodiments of the present invention, X1 is selected from C(CN), and X2 is selected from CH.
在本發明的一些實施方案中,X 3、X 4、X 5和X 6中至少有2個選自C(R 5)。 In some embodiments of the present invention, at least two of X 3 , X 4 , X 5 and X 6 are selected from C(R 5 ).
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自C(R 5)。 In some embodiments of the present invention, X 3 is selected from C(R 5 ), and X 4 is selected from C(R 5 ).
在本發明的一些實施方案中,X 5選自C(R 5),X 6選自C(R 5)。 In some embodiments of the present invention, X5 is selected from C( R5 ), and X6 is selected from C( R5 ).
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自C(R 5),X 5選自C(R 5),X 6選自C(R 5)。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from C( R5 ), X5 is selected from C( R5 ), and X6 is selected from C( R5 ).
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自N,X 5選自C(R 5),X 6選自C(R 5)。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from N, X5 is selected from C( R5 ), and X6 is selected from C( R5 ).
在本發明的一些實施方案中,X 3選自N,X 4選自C(R 5),X 5選自C(R 5),X 6選自C(R 5)。 In some embodiments of the present invention, X3 is selected from N, X4 is selected from C( R5 ), X5 is selected from C( R5 ), and X6 is selected from C( R5 ).
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自C(R 5),X 5選自N,X 6選自C(R 5)。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from C( R5 ), X5 is selected from N, and X6 is selected from C( R5 ).
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自C(R 5),X 5選自C(R 5),X 6選自N。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from C( R5 ), X5 is selected from C( R5 ), and X6 is selected from N.
在本發明的一些實施方案中,X 3選自N,X 4選自C(R 5),X 5選自N,X 6選自C(R 5)。 In some embodiments of the present invention, X3 is selected from N, X4 is selected from C( R5 ), X5 is selected from N, and X6 is selected from C( R5 ).
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自N,X 5選自C(R 5),X 6選自N。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from N, X5 is selected from C( R5 ), and X6 is selected from N.
在本發明的一些實施方案中,每個R 5分別獨立地選自氫或-F。 In some embodiments of the invention, each R 5 is independently selected from hydrogen or -F.
在本發明的一些實施方案中,每個R 5分別獨立地選自H。 In some embodiments of the present invention, each R 5 is independently selected from H.
在本發明的一些實施方案中,X 3選自CH,X 4選自CH。 In some embodiments of the present invention, X3 is selected from CH, and X4 is selected from CH.
在本發明的一些實施方案中,X 5選自CH,X 6選自CH。 In some embodiments of the present invention, X5 is selected from CH, and X6 is selected from CH.
在本發明的一些實施方案中,X 3選自CH,X 4選自CH,X 5選自CH,X 6選自CH。 In some embodiments of the present invention, X3 is selected from CH, X4 is selected from CH, X5 is selected from CH, and X6 is selected from CH.
在本發明的一些實施方案中,X 3選自CH,X 4選自N,X 5選自CH,X 6選自CH。 In some embodiments of the present invention, X3 is selected from CH, X4 is selected from N, X5 is selected from CH, and X6 is selected from CH.
在本發明的一些實施方案中,X 3選自CH,X 4選自CH,X 5選自CH,X 6選自C(F)。 In some embodiments of the present invention, X3 is selected from CH, X4 is selected from CH, X5 is selected from CH, and X6 is selected from C(F).
在本發明的一些實施方案中,X 3選自N,X 4選自CH,X 5選自CH,X 6選自CH。 In some embodiments of the present invention, X3 is selected from N, X4 is selected from CH, X5 is selected from CH, and X6 is selected from CH.
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自C(R 5),且X 3和X 4兩個碳原子上的R 5和其所連接的碳原子一起形成任選被一個或多個取代基取代的C 5-6環烯基、5-6員雜環烯基、苯基或5-6員雜芳基。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from C( R5 ), and R5 on the two carbon atoms of X3 and X4 and the carbon atom to which they are attached together form a C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted with one or more substituents.
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自C(R 5),且X 3和X 4兩個碳原子上的R 5和其所連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的C 5-6環烯基、5-6員雜環烯基、苯基或5-6員雜芳基。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from C( R5 ), and R5 on the two carbon atoms of X3 and X4 and the carbon atom to which they are attached together form a C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2 .
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自C(R 5),且X 3和X 4兩個碳原子上的R 5和其所連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環戊烯基、環己烯基、2,5-二氫-吡咯基、2,3-二氫-吡咯基、2,5-二氫-呋喃基、2,3-二氫-呋喃基、2,5-二氫-噻吩基、2,3-二氫-噻吩基、1,2,3,4-四氫吡啶基、1,2,3,6-四氫吡啶基、3,4-二氫-2H-吡喃基、3,6-二氫-2H-吡喃基、3,4-二氫-2H-硫吡喃基、3,6-二氫-2H-硫吡喃基、3,4-二氫-2H-1,4-噁嗪基、3,4-二氫-2H-1,4-噻嗪基、苯基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、異噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基或噠嗪基。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from C( R5 ), and R5 on the two carbon atoms of X3 and X4 and the carbon atom to which they are attached together form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, 2,5-dihydro-furanyl, 2,3-dihydro-furanyl, 2,5-dihydro-thienyl, 2,3-dihydro-thienyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2 The invention may be any of the following: 1,4-dihydro-2H-1,4-thiopyranyl, 3,6-dihydro-2H-thiopyranyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl.
在本發明的一些實施方案中,X 3選自C(R 5),X 4選自C(R 5),且X 3和X 4兩個碳原子上的R 5和其所連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環戊烯基、環己烯基、2,5-二氫-吡咯基、2,3-二氫-吡咯基、苯基、吡咯基、吡唑基、吡啶基或嘧啶基。 In some embodiments of the present invention, X3 is selected from C( R5 ), X4 is selected from C( R5 ), and R5 on the two carbon atoms of X3 and X4 and the carbon atom to which they are attached together form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl group optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2 .
在本發明的一些實施方案中,X 5選自C(R 5),X 6選自C(R 5),且X 5和X 6兩個碳原子上的R 5和其所連接的碳原子一起形成任選被一個或多個取代基取代的C 5-6環烯基、5-6員雜環烯基、苯基或5-6員雜芳基。 In some embodiments of the present invention, X5 is selected from C( R5 ), X6 is selected from C( R5 ), and R5 on the two carbon atoms of X5 and X6 and the carbon atom to which they are attached together form a C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted with one or more substituents.
在本發明的一些實施方案中,X 5選自C(R 5),X 6選自C(R 5),且X 5和X 6兩個碳原子上的R 5和其所連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的C 5-6環烯基、5-6員雜環烯基、苯基或5-6員雜芳基。 In some embodiments of the present invention, X5 is selected from C( R5 ), X6 is selected from C( R5 ), and R5 on the two carbon atoms of X5 and X6 and the carbon atom to which they are attached together form a C5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2 .
在本發明的一些實施方案中,X 5選自C(R 5),X 6選自C(R 5),且X 5和X 6兩個碳原子上的R 5和其所連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環戊烯基、環己烯基、2,5-二氫-吡咯基、2,3-二氫-吡咯基、2,5-二氫-呋喃基、2,3-二氫-呋喃基、2,5-二氫-噻吩基、2,3-二氫-噻吩基、1,2,3,4-四氫吡啶基、1,2,3,6-四氫吡啶基、3,4-二氫-2H-吡喃基、3,6-二氫-2H-吡喃基、3,4-二氫-2H-硫吡喃基、3,6-二氫-2H-硫吡喃基、3,4-二氫-2H-1,4-噁嗪基、3,4-二氫-2H-1,4-噻嗪基、苯基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、異噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基或噠嗪基。 In some embodiments of the present invention, X5 is selected from C( R5 ), X6 is selected from C( R5 ), and R5 on the two carbon atoms of X5 and X6 and the carbon atom to which they are attached together form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, 2,5-dihydro-furanyl, 2,3-dihydro-furanyl, 2,5-dihydro-thienyl, 2,3-dihydro-thienyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2 The invention may be any of the following: 1,4-dihydro-2H-1,4-thiopyranyl, 3,6-dihydro-2H-thiopyranyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl.
在本發明的一些實施方案中,X 5選自C(R 5),X 6選自C(R 5),且X 5和X 6兩個碳原子上的R 5和其所連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環戊烯基、環己烯基、2,5-二氫-吡咯基、2,3-二氫-吡咯基、苯基、吡咯基、吡唑基、吡啶基或嘧啶基。 In some embodiments of the present invention, X 5 is selected from C(R 5 ), X 6 is selected from C(R 5 ), and R 5 on the two carbon atoms of X 5 and X 6 and the carbon atom to which they are attached together form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl group optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2.
在本發明的一些實施方案中,L選自-(C(R 3R 4)) m-、-O-、-S-或-N(R 9)-。 In some embodiments of the invention, L is selected from -(C(R 3 R 4 )) m -, -O-, -S-, or -N(R 9 )-.
在本發明的一些實施方案中,R 9選自氫、甲基、乙基或異丙基。 In some embodiments of the invention, R 9 is selected from hydrogen, methyl, ethyl or isopropyl.
在本發明的一些實施方案中,R 9選自氫。 In some embodiments of the present invention, R 9 is selected from hydrogen.
在本發明的一些實施方案中,L選自-(C(R 3R 4)) m-、-O-、-S-或-NH-。 In some embodiments of the invention, L is selected from -(C(R 3 R 4 )) m -, -O-, -S- or -NH-.
在本發明的一些實施方案中,L選自-C(R 3R 4)-或-C(R 3R 4)-C(R 3R 4)-。 In some embodiments of the invention, L is selected from -C(R 3 R 4 )- or -C(R 3 R 4 )-C(R 3 R 4 )-.
在本發明的一些實施方案中,每個R 3和R 4分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基或3-8員雜環基,所述-OH、-SH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基和3-8員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 3 and R 4 is independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl) 2 -C 1-6 alkyl ) 2 , -NHCOC 1-6 alkyl , -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl , phenyl , 5-10 membered heteroaryl and 3-8 membered heterocyclic group are optionally substituted independently with one or more substituents.
在本發明的一些實施方案中,每個R 3和R 4分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-SH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 3 and R 4 is independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -COC 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -NHSO 2 C 1-3 alkyl, -N(C 1-3 alkyl)SO 2 C 1-3 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-3 alkyl, -SO 2 N(C 1-3 alkyl) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl, -N(C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -COC 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -NHSO 2 C 1-3 alkyl, -N(C 1-3 alkyl) 2 -C 1-3 alkyl ) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl , -N (C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently by one or more substituents.
在本發明的一些實施方案中,每個R 3和R 4分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -SO 2 NH 2 , -CONH 2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -SO 2 NH 2 2 , -CONH 2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more substituents.
在本發明的一些實施方案中,每個R 3和R 4分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、C 1-3烷基或C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 3 and R 4 is independently selected from hydrogen, halogen, -CN, -OH, -NH 2 , C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally and independently substituted with one or more substituents.
在本發明的一些實施方案中,每個R 3和R 4分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基,所述甲基、乙基、異丙基、甲氧基、乙氧基和異丙氧基任選獨立地被一個或多個取代基取代。 In some embodiments of the invention, each R 3 and R 4 is independently selected from hydrogen, halogen, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally and independently substituted with one or more substituents.
在本發明的一些實施方案中,每個R 3和R 4任選獨立地被一個或多個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, each R 3 and R 4 is optionally and independently substituted with one or more groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,每個R 3和R 4分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基,所述甲基、乙基、異丙基、甲氧基、乙氧基和異丙氧基任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, each R 3 and R 4 is independently selected from hydrogen, halogen, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,每個R 3和R 4分別獨立地選自氫、-F、-Cl、-Br、-I、-CN、甲基或乙基。 In some embodiments of the invention, each R 3 and R 4 is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl.
在本發明的一些實施方案中,每個R 3分別獨立地選自氫,每個R 4分別獨立地選自氫、-F、-Cl、-Br、-I、-CN、甲基或乙基。 In some embodiments of the invention, each R 3 is independently selected from hydrogen, and each R 4 is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl.
在本發明的一些實施方案中,每個R 3分別獨立地選自氫、-F、-Cl、-Br、-I、-CN、甲基或乙基,每個R 4分別獨立地選自氫。 In some embodiments of the invention, each R 3 is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl, and each R 4 is independently selected from hydrogen.
在本發明的一些實施方案中,每個R 3分別獨立地選自氫,每個R 4分別獨立地選自氫、甲基或乙基。 In some embodiments of the present invention, each R 3 is independently selected from hydrogen, and each R 4 is independently selected from hydrogen, methyl or ethyl.
在本發明的一些實施方案中,每個R 3分別獨立地選自氫、甲基或乙基,每個R 4分別獨立地選自氫。 In some embodiments of the present invention, each R 3 is independently selected from hydrogen, methyl or ethyl, and each R 4 is independently selected from hydrogen.
在本發明的一些實施方案中,每個R 3分別獨立地選自甲基,每個R 4分別獨立地選自甲基;或每個R 3分別獨立地選自氫,每個R 4分別獨立地選自氫;或每個R 3分別獨立地選自氫,每個分別獨立地R 4選自甲基;每個R 3分別獨立地選自甲基,每個R 4分別獨立地選自氫;或每個R 3分別獨立地選自氫,每個R 4分別獨立地選自乙基;或每個R 3分別獨立地選自乙基,每個R 4分別獨立地選自氫。 In some embodiments of the present invention, each R3 is independently selected from methyl, and each R4 is independently selected from methyl; or each R3 is independently selected from hydrogen, and each R4 is independently selected from hydrogen; or each R3 is independently selected from hydrogen, and each R4 is independently selected from methyl; each R3 is independently selected from methyl, and each R4 is independently selected from hydrogen; or each R3 is independently selected from hydrogen, and each R4 is independently selected from ethyl; or each R3 is independently selected from ethyl, and each R4 is independently selected from hydrogen.
在本發明的一些實施方案中,R 3和R 4以及其共同連接的碳原子一起形成任選被一個或多個取代基取代的環丙基、環丁基、環戊基、環己基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基、呱啶基、呱嗪基或嗎啉基。 In some embodiments of the invention, R3 and R4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, azacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or oxolinyl, which may be optionally substituted with one or more substituents.
在本發明的一些實施方案中,R 3和R 4以及其共同連接的碳原子一起形成任選被一個或多個取代基取代的環丙基、環丁基、氧雜環丁基、硫雜環丁基或氮雜環丁基。 In some embodiments of the present invention, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azacyclobutyl group which is optionally substituted with one or more substituents.
在本發明的一些實施方案中,R 3和R 4以及其共同連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環丙基、環丁基、氧雜環丁基、硫雜環丁基或氮雜環丁基。 In some embodiments of the present invention, R 3 and R 4 together with the carbon atom to which they are commonly attached form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azacyclobutyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,R 3和R 4以及其共同連接的碳原子一起形成的取代基任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, R 3 and R 4 together with the carbon atom to which they are commonly attached form a substituent group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,R 3和R 4以及其共同連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環丙基、氧雜環丁基或氮雜環丁基。 In some embodiments of the present invention, R 3 and R 4 together with the carbon atom to which they are commonly attached form a cyclopropyl, oxacyclobutyl or azacyclobutyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,L選自-C(R 3R 4)-C(R 3R 4)-,相鄰兩個碳原子上的R 3和R 3、R 3和R 4、R 4和R 3、R 4和R 4和其所連接的碳原子一起形成任選被一個或多個取代基取代的環丙基、環丁基、環戊基、環己基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基或異噁唑烷基。 In some embodiments of the present invention , L is selected from -C( R3R4 )-C ( R3R4 )-, R3 and R3 , R3 and R4 , R4 and R3 , R4 and R4 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl , imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl or isoxazolidinyl group, which is optionally substituted with one or more substituents.
在本發明的一些實施方案中,L選自-C(R 3R 4)-C(R 3R 4)-,相鄰兩個碳原子上的R 3和R 3、R 3和R 4、R 4和R 3、R 4和R 4和其所連接的碳原子一起形成任選被一個或多個取代基取代的環丙基、環丁基、氧雜環丁基、硫雜環丁基或氮雜環丁基。 In some embodiments of the present invention , L is selected from -C( R3R4 )-C ( R3R4 )-, and R3 and R3 , R3 and R4 , R4 and R3 , R4 and R4 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azacyclobutyl group which is optionally substituted with one or more substituents.
在本發明的一些實施方案中,L選自-C(R 3R 4)-C(R 3R 4)-,相鄰兩個碳原子上的R 3和R 3、R 3和R 4、R 4和R 3、R 4和R 4和其所連接的碳原子一起形成的取代基任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention , L is selected from -C( R3R4 )-C( R3R4 )-, and the substituents formed by R3 and R3 , R3 and R4 , R4 and R3 , R4 and R4 on two adjacent carbon atoms and the carbon atoms to which they are connected are optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2 .
在本發明的一些實施方案中,L選自-C(R 3R 4)-C(R 3R 4)-,相鄰兩個碳原子上的R 3和R 3、R 3和R 4、R 4和R 3、R 4和R 4和其所連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環丙基、環丁基、氧雜環丁基、硫雜環丁基或氮雜環丁基。 In some embodiments of the present invention , L is selected from -C( R3R4 )-C ( R3R4 )-, and R3 and R3 , R3 and R4 , R4 and R3 , R4 and R4 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, oxacyclobutyl, thiacyclobutyl or azocyclobutyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.
在本發明的一些實施方案中,L選自-C(R 3R 4)-C(R 3R 4)-,相鄰兩個碳原子上的R 3和R 3、R 3和R 4、R 4和R 3、R 4和R 4和其所連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環丁基、氧雜環丁基或氮雜環丁基。 In some embodiments of the present invention , L is selected from -C( R3R4 )-C ( R3R4 )-, and R3 and R3 , R3 and R4 , R4 and R3 , R4 and R4 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a cyclobutyl, oxacyclobutyl or azocyclobutyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2 .
在本發明的一些實施方案中,L選自-O-、-S-、-NH-、-CH 2-、-CH(CH 3)-、-CH 2CH 2-、-CH(F)-、-CH(Cl)-、-CH(Br)-、-CH(I)-、-CH(CN)-、-CH(CF 3)-、-CH(OH)-、-CH(NH 2)-、-C(O)-、 、 、 、 、 、 、-CH(CH 3)CH 2-、-CH(F)CH 2-、-CH(Cl)CH 2-、-CH(Br)CH 2-、-CH(I)CH 2-、-CH(CN)CH 2-、-CH(CF 3)CH 2-、-CH(OH)CH 2-、-CH(NH 2)CH 2-、 、 、 、 、 或 。 In some embodiments of the invention, L is selected from -O-, -S-, -NH-, -CH2-, -CH( CH3 )-, -CH2CH2- , -CH(F)-, -CH ( Cl ) -, -CH(Br)-, -CH(I)-, -CH(CN)-, -CH( CF3 )-, -CH(OH)-, -CH( NH2 )-, -C(O)-, , , , , , , -CH(CH 3 )CH 2 -, -CH(F)CH 2 -, -CH(Cl)CH 2 -, -CH(Br)CH 2 -, -CH(I)CH 2 -, -CH(CN)CH 2 -, -CH(CF 3 )CH 2 -, -CH(OH)CH 2 -, -CH(NH 2 )CH 2 -, , , , , or .
在本發明的一些實施方案中,L選自-O-、-S-、-NH-、-CH 2-、-CH(CH 3)-、-CH 2CH 2-、-C(O)-、 、 、 、 、 、 、 或 。 In some embodiments of the present invention, L is selected from -O-, -S-, -NH-, -CH2- , -CH( CH3 )-, -CH2CH2- , -C(O)-, , , , , , , or .
在本發明的一些實施方案中,L選自-CH 2-、-CH(CH 3)-或 。 In some embodiments of the invention, L is selected from -CH2- , -CH( CH3 )- or .
在本發明的一些實施方案中,L選自-CH 2-。 In some embodiments of the invention, L is selected from -CH 2 -.
在本發明的一些實施方案中,L選自-C(R 3R 4)-或-C(R 3R 4)-C(R 3R 4)-時,所述各個碳原子可以為掌性碳原子,以(R)或(S)單一鏡像異構物形式或富含一種鏡像異構物形式存在。 In some embodiments of the present invention, when L is selected from -C(R 3 R 4 )- or -C(R 3 R 4 )-C(R 3 R 4 )-, each carbon atom may be a chiral carbon atom, existing in the form of (R) or (S) single mirror image isomer or in the form enriched in one mirror image isomer.
在本發明的一些實施方案中,R 2選自C 3-8環烷基、苯基、萘基、5-10員雜芳基、3-8員雜環基或C 5-6環烯基,所述C 3-8環烷基、苯基、萘基、5-10員雜芳基、3-8員雜環基和C 5-6環烯基任選獨立地被一個或多個R 2a取代。 In some embodiments of the present invention, R 2 is selected from C 3-8 cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group or C 5-6 cycloalkenyl, and the C 3-8 cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group and C 5-6 cycloalkenyl are optionally and independently substituted by one or more R 2a .
在本發明的一些實施方案中,R 2選自C 3-6環烷基、苯基、萘基、5-9員雜芳基、3-6員雜環基或C 5-6環烯基,所述C 3-6環烷基、苯基、萘基、5-9員雜芳基、3-6員雜環基和C 5-6環烯基任選獨立地被一個或多個R 2a取代。 In some embodiments of the present invention, R 2 is selected from C 3-6 cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group or C 5-6 cycloalkenyl, and the C 3-6 cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group and C 5-6 cycloalkenyl are optionally and independently substituted by one or more R 2a .
在本發明的一些實施方案中,R 2選自C 5-6環烷基、苯基、5-6員雜芳基、5-6員雜環基或C 5-6環烯基,所述C 5-6環烷基、苯基、5-6員雜芳基、5-6員雜環基和C 5-6環烯基任選獨立地被一個或多個R 2a取代。 In some embodiments of the present invention, R 2 is selected from C 5-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group or C 5-6 cycloalkenyl, and the C 5-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group and C 5-6 cycloalkenyl are optionally and independently substituted by one or more R 2a .
在本發明的一些實施方案中,R 2選自C 5-6環烷基、苯基、含1-3個N原子的5-6員雜芳基、含1-3個N原子的5-6員雜環基或C 5-6環烯基,所述C 5-6環烷基、苯基、含1-3個N原子的5-6員雜芳基、含1-3個N原子的5-6員雜環基和C 5-6環烯基任選獨立地被一個或多個R 2a取代。 In some embodiments of the present invention, R 2 is selected from C 5-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms, 5-6 membered heterocyclic group containing 1-3 N atoms or C 5-6 cycloalkenyl, and the C 5-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms, 5-6 membered heterocyclic group containing 1-3 N atoms and C 5-6 cycloalkenyl are optionally and independently substituted by one or more R 2a .
在本發明的一些實施方案中,R 2選自環戊基、環己基、苯基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基、呱啶基、呱嗪基、嗎啉基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑環、異噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、噠嗪基、環戊烯基或環己烯基,所述環戊基、環己基、苯基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基、呱啶基、呱嗪基、嗎啉基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑環、異噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、噠嗪基、環戊烯基和環己烯基任選獨立地被一個或多個R 2a取代。 In some embodiments of the invention, R is selected from cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl, oxazinyl, cyclopentenyl or cyclohexenyl, wherein the cyclopentyl R , cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, fluorenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, oxazinyl, cyclopentenyl and cyclohexenyl are optionally and independently substituted with one or more R 2a .
在本發明的一些實施方案中,R 2選自苯基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑環、異噻唑基、吡啶基、吡嗪基、嘧啶基或噠嗪基,所述苯基、吡咯基、吡唑基、噁唑基、異噁唑基、噻唑環、異噻唑基吡啶基、吡嗪基、嘧啶基和噠嗪基任選獨立地被一個或多個R 2a取代。 In some embodiments of the invention, R is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl, and the phenyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl pyridinyl, pyrazinyl, pyrimidinyl and oxazinyl are optionally and independently substituted with one or more R.
在本發明的一些實施方案中,R 2選自苯基、吡咯基、吡唑基、咪唑基、吡啶基或嘧啶基,所述苯基、吡咯基、吡唑基、咪唑基、吡啶基和嘧啶基任選獨立地被一個或多個R 2a取代。 In some embodiments of the present invention, R 2 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl and pyrimidinyl are optionally and independently substituted with one or more R 2a .
在本發明的一些實施方案中,R 2選自苯基、吡唑基、吡啶基或嘧啶基,所述苯基、吡唑基、吡啶基和嘧啶基任選獨立地被一個或多個R 2a取代。 In some embodiments of the present invention, R 2 is selected from phenyl, pyrazolyl, pyridinyl or pyrimidinyl, and the phenyl, pyrazolyl, pyridinyl and pyrimidinyl are optionally and independently substituted with one or more R 2a .
在本發明的一些實施方案中,R 2選自嘧啶基,所述嘧啶基任選地被一個或多個R 2a取代。 In some embodiments of the invention, R 2 is selected from pyrimidinyl, which is optionally substituted with one or more R 2a .
在本發明的一些實施方案中,R 2選自 、 、 、 、 、 、 、 或 ,所述R 2任選獨立地被一個或多個R 2a取代。 In some embodiments of the present invention, R is selected from , , , , , , , or , said R 2 is optionally independently substituted by one or more R 2a .
在本發明的一些實施方案中,R 2選自 、 、 或 ,所述R 2任選獨立地被一個或多個R 2a取代。 In some embodiments of the present invention, R is selected from , , or , said R 2 is optionally independently substituted by one or more R 2a .
在本發明的一些實施方案中,R 2選自 ,所述R 2任選地被一個或多個R 2a取代。 In some embodiments of the present invention, R is selected from , said R 2 is optionally substituted by one or more R 2a .
在本發明的一些實施方案中,每個R 2a和R 6a分別獨立地選自鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基或3-8員雜環基,所述-OH、-SH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基和3-8員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 2a and R 6a is independently selected from halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl) 2 -C 1-6 alkyl ) 2 , -NHCOC 1-6 alkyl , -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl , phenyl , 5-10 membered heteroaryl and 3-8 membered heterocyclic group are optionally substituted independently with one or more substituents.
在本發明的一些實施方案中,每個R 2a和R 6a分別獨立地選自鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-SH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 2a and R 6a is independently selected from halogen, -CN, -OH, -SH, -COOH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -COC 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -NHSO 2 C 1-3 alkyl, -N(C 1-3 alkyl)SO 2 C 1-3 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-3 alkyl, -SO 2 N(C 1-3 alkyl) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl, -N(C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -COC 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -NHSO 2 C 1-3 alkyl, -N(C 1-3 alkyl) 2 -C 1-3 alkyl ) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl , -N(C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl , phenyl , 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently by one or more substituents.
在本發明的一些實施方案中,每個R 2a和R 6a分別獨立地選自鹵素、-CN、-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 2a and R 6a is independently selected from halogen, -CN, -OH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -SO 2 NH 2 , -CONH 2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio , -SO 2 NH 2 , -CONH 2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more substituents.
在本發明的一些實施方案中,每個R 2a和R 6a分別獨立地選自鹵素、-CN、-OH、-NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基或3-6員雜環基,所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 2a and R 6a is independently selected from halogen, -CN, -OH, -NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, and the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more substituents.
在本發明的一些實施方案中,每個R 2a和R 6a分別獨立地選自鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、環戊基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基或異噁唑烷基,所述甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、環戊基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基和異噁唑烷基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 2a and R 6a is independently selected from halogen, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl or isoxazolidinyl, wherein the methyl, ethyl, Isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiacyclobutyl, azacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl and isoxazolidinyl are optionally and independently substituted with one or more substituents.
在本發明的一些實施方案中,每個R 2a和R 6a分別獨立地選自鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、氧雜環丁基或氮雜環丁基,所述甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、氧雜環丁基和氮雜環丁基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, each R 2a and R 6a is independently selected from halogen, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl or azocyclobutyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl and azocyclobutyl are optionally and independently substituted with one or more substituents.
在本發明的一些實施方案中,R 2a和R 6a分別任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, R 2a and R 6a are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,每個R 2a和R 6a分別獨立地選自鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、氧雜環丁基或氮雜環丁基,所述甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、氧雜環丁基和氮雜環丁基任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, each R 2a and R 6a is independently selected from halogen, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl or azidocyclobutyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxacyclobutyl and azidocyclobutyl are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,每個R 2a和R 6a分別獨立地選自鹵素、甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基或環丙基,所述甲基、乙基、異丙基、甲氧基、乙氧基、異丙氧基和環丙基任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, each R 2a and R 6a are independently selected from halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy and cyclopropyl are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,R 2a選自-F、-Cl、-Br、-I、甲基、異丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、 、 、 、 、 或 。 In some embodiments of the present invention, R 2a is selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, , , , , or .
在本發明的一些實施方案中,R 2a選自甲基、異丙基、甲氧基或 。 In some embodiments of the present invention, R 2a is selected from methyl, isopropyl, methoxy or .
在本發明的一些實施方案中,R 2a選自異丙基、甲氧基或 。 In some embodiments of the present invention, R 2a is selected from isopropyl, methoxy or .
在本發明的一些實施方案中,R 2選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments of the present invention, R is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在本發明的一些實施方案中,R 2選自 、 、 或 。 In some embodiments of the present invention, R is selected from , , or .
在本發明的一些實施方案中,R 2選自 。 In some embodiments of the present invention, R is selected from .
在本發明的一些實施方案中,R 6選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基或3-8員雜環基,所述-OH、-SH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基和3-8員雜環基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R6 is selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2 , C1-6alkyl , C2-6alkenyl , C2-6alkynyl, C1-6alkoxy, C1-6alkylthio, -COC1-6alkyl, -OC(O)C1-6alkyl, -C(O)OC1-6alkyl , -OC ( O ) OC1-6alkyl , -SO2C1-6alkyl , -NHSO2C1-6alkyl , -N( C1-6alkyl ) SO2C1-6alkyl , -SO2NH2 , -SO2NHC1-6alkyl , -SO2N ( C1-6alkyl ) 2 , -CONH2 , -CONHC -1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic are optionally and independently substituted by one or more R 6a .
在本發明的一些實施方案中,R 6選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-SH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R6 is selected from hydrogen, halogen , -CN, -OH, -SH, -COOH, -NH2, -NHC1-3 alkyl, -N( C1-3 alkyl) 2 , C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio, -COC1-3 alkyl, -OC(O) C1-3 alkyl , -C(O) OC1-3 alkyl, -OC(O ) OC1-3 alkyl , -SO2C1-3 alkyl , -NHSO2C1-3 alkyl, -N( C1-3 alkyl) SO2C1-3 alkyl , -SO2NH2 , -SO2NHC1-3 alkyl , -SO2N ( C1-3 alkyl) 2 , -CONH2, -CONHC -1-3 alkyl, -CON( C1-3 alkyl) 2 , -NHCOC1-3 alkyl, -N( C1-3 alkyl) COC1-3 alkyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2 , -NHC1-3 alkyl, -N( C1-3 alkyl) 2 , C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio, -COC1-3 alkyl, -OC(O) C1-3 alkyl, -C(O ) OC1-3 alkyl, -OC(O) OC1-3 alkyl, -SO2C1-3 alkyl, -NHSO2C1-3 alkyl, -N ( C1-3 alkyl) SO2C1-3 alkyl R 6a is optionally substituted with one or more R 6a in the following examples: -SO 2 NH 2 , -SO 2 NHC 1-3 alkyl, -SO 2 N(C 1-3 alkyl) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl, -N(C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally and independently substituted with one or more R 6a .
在本發明的一些實施方案中,R 6選自氫、鹵素、-CN、-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R6 is selected from hydrogen, halogen, -CN, -OH, -NH2 , -NHC1-3 alkyl, -N( C1-3 alkyl) 2 , C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio, -SO2NH2 , -CONH2 , C3-6 cycloalkyl, C3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, -NH2 , -NHC1-3 alkyl, -N( C1-3 alkyl) 2 , C1-3 alkyl, C2-3 alkenyl , C2-3 alkynyl, C1-3 alkoxy , C1-3 alkylthio , -SO2NH2 , -CONH2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more R 6a .
在本發明的一些實施方案中,R 6選自氫、鹵素、-CN、-OH、-NH 2、C 1-3烷基、C 1-3烷氧基、C 3-6環烷基、苯基、5-6員雜芳基或3-6員雜環基,所述C 1-3烷基、C 1-3烷氧基、C 3-6環烷基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R 6 is selected from hydrogen, halogen, -CN, -OH, -NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, and the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more R 6a .
在本發明的一些實施方案中,R 6選自C 3-6環烷基、苯基、5-6員雜芳基或3-6員雜環基,所述C 3-6環烷基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R 6 is selected from C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, and the C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally and independently substituted by one or more R 6a .
在本發明的一些實施方案中,R 6選自C 3-6環烷基、苯基、含1-3個N原子的5-6員雜芳基或含1-3個N原子的5-6員雜環基,所述C 3-6環烷基、苯基、含1-3個N原子的5-6員雜芳基和含1-3個N原子的5-6員雜環基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R6 is selected from C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms or 5-6 membered heterocyclic group containing 1-3 N atoms, and the C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms and 5-6 membered heterocyclic group containing 1-3 N atoms are optionally and independently substituted by one or more R6a .
在本發明的一些實施方案中,R 6選自環丙基、環丁基、環戊基、環己基、苯基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基、呱啶基、呱嗪基、嗎啉基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑環、異噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基或噠嗪基,所述環丙基、環丁基、環戊基、環己基、苯基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基、呱啶基、呱嗪基、嗎啉基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑環、異噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基和噠嗪基任選獨立地被一個或多個R 6a取代。 In some embodiments of the invention, R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl, and the cyclopropyl R , cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, fluorenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl and oxazinyl are optionally and independently substituted with one or more R 6a .
在本發明的一些實施方案中,R 6選自苯基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑環、異噻唑基、三唑基、吡啶基、吡嗪基、嘧啶基或噠嗪基,所述苯基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑環、異噻唑基、三唑基、吡啶基、吡嗪基、嘧啶基和噠嗪基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl or oxazinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl ring, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl and oxazinyl are optionally and independently substituted with one or more R.
在本發明的一些實施方案中,R 6選自苯基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基或嘧啶基,所述苯基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基和嘧啶基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R 6 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl or pyrimidinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl and pyrimidinyl are optionally and independently substituted with one or more R 6a .
在本發明的一些實施方案中,R 6選自吡唑基或咪唑基,所述吡唑基和咪唑基任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R 6 is selected from pyrazolyl or imidazolyl, and the pyrazolyl and imidazolyl are optionally and independently substituted with one or more R 6a .
在本發明的一些實施方案中,R 6選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 ,所述R 6任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R is selected from , , , , , , , , , , , , , , , or , said R 6 is optionally independently substituted by one or more R 6a .
在本發明的一些實施方案中,R 6選自 、 、 、 、 或 ,所述R 6任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R is selected from , , , , or , said R 6 is optionally independently substituted by one or more R 6a .
在本發明的一些實施方案中,R 6選自 或 ,所述R 6任選獨立地被一個或多個R 6a取代。 In some embodiments of the present invention, R is selected from or , said R 6 is optionally independently substituted by one or more R 6a .
在本發明的一些實施方案中,R 6a選自-F、-Cl、-Br、-I、甲基、異丙基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、 、 、 、 、 、 或 。 In some embodiments of the present invention, R 6a is selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, , , , , , or .
在本發明的一些實施方案中,R 6a選自甲基、異丙基、三氟甲基、 或 。 In some embodiments of the present invention, R 6a is selected from methyl, isopropyl, trifluoromethyl, or .
在本發明的一些實施方案中,R 6a選自異丙基或三氟甲基。 In some embodiments of the invention, R 6a is selected from isopropyl or trifluoromethyl.
在本發明的一些實施方案中,R 6選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments of the present invention, R is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在本發明的一些實施方案中,R 6選自 、 、 、 、 或 。 In some embodiments of the present invention, R is selected from , , , , or .
在本發明的一些實施方案中,R 6選自 、 或 。 In some embodiments of the present invention, R is selected from , or .
在本發明的一些實施方案中,R 6選自 。 In some embodiments of the present invention, R is selected from .
在本發明的一些實施方案中,R 7和R 8分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基或3-8員雜環基,所述-OH、-SH、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-COC 1-6烷基、-OC(O)C 1-6烷基、-C(O)OC 1-6烷基、-OC(O)OC 1-6烷基、-SO 2C 1-6烷基、-NHSO 2C 1-6烷基、-N(C 1-6烷基)SO 2C 1-6烷基、-SO 2NH 2、-SO 2NHC 1-6烷基、-SO 2N(C 1-6烷基) 2、-CONH 2、-CONHC 1-6烷基、-CON(C 1-6烷基) 2、-NHCOC 1-6烷基、-N(C 1-6烷基)COC 1-6烷基、C 3-8環烷基、C 3-8環烯基、苯基、5-10員雜芳基和3-8員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, R7 and R8 are independently selected from hydrogen, halogen, -CN, -OH , -SH, -COOH, -NH2, -NHC1-6alkyl, -N( C1-6alkyl ) 2 , C1-6alkyl , C2-6alkenyl , C2-6alkynyl , C1-6alkoxy , C1-6alkylthio , -COC1-6alkyl, -OC(O)C1-6alkyl, -C(O)OC1-6alkyl , -OC ( O ) OC1-6alkyl , -SO2C1-6alkyl , -NHSO2C1-6alkyl, -N( C1-6alkyl ) SO2C1-6alkyl , -SO2NH2 , -SO2NHC1-6alkyl , -SO2N ( C1-6alkyl ) 2 , -CONH2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl) 2 -C 1-6 alkyl ) 2 , -NHCOC 1-6 alkyl , -N(C 1-6 alkyl)COC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl , phenyl , 5-10 membered heteroaryl and 3-8 membered heterocyclic group are optionally substituted independently with one or more substituents.
在本發明的一些實施方案中,R 7和R 8分別獨立地選自氫、鹵素、-CN、-OH、-SH、-COOH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-SH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-COC 1-3烷基、-OC(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)OC 1-3烷基、-SO 2C 1-3烷基、-NHSO 2C 1-3烷基、-N(C 1-3烷基)SO 2C 1-3烷基、-SO 2NH 2、-SO 2NHC 1-3烷基、-SO 2N(C 1-3烷基) 2、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、-NHCOC 1-3烷基、-N(C 1-3烷基)COC 1-3烷基、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, R7 and R8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2 , -NHC1-3 alkyl, -N( C1-3 alkyl) 2 , C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio, -COC1-3 alkyl, -OC(O)C1-3 alkyl , -C(O) OC1-3 alkyl, -OC (O) OC1-3 alkyl, -SO2C1-3 alkyl , -NHSO2C1-3 alkyl, -N ( C1-3 alkyl)SO2C1-3 alkyl , -SO2NH2 , -SO2NHC1-3 alkyl , -SO2N ( C1-3 alkyl) 2 , -CONH2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl, -N(C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, -COC 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -NHSO 2 C 1-3 alkyl, -N(C 1-3 alkyl) 2 -C 1-3 alkyl ) 2 , -CONH 2 , -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHCOC 1-3 alkyl , -N (C 1-3 alkyl)COC 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently by one or more substituents.
在本發明的一些實施方案中,R 7和R 8分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基或3-6員雜環基,所述-OH、-NH 2、-NHC 1-3烷基、-N(C 1-3烷基) 2、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3烷硫基、-SO 2NH 2、-CONH 2、C 3-6環烷基、C 3-6環烯基、苯基、5-6員雜芳基和3-6員雜環基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, R7 and R8 are independently selected from hydrogen, halogen, -CN, -OH, -NH2 , -NHC1-3 alkyl, -N( C1-3 alkyl) 2 , C1-3 alkyl, C2-3 alkenyl , C2-3 alkynyl, C1-3 alkoxy, C1-3 alkylthio , -SO2NH2 , -CONH2 , C3-6 cycloalkyl, C3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein -OH, -NH2 , -NHC1-3 alkyl, -N ( C1-3 alkyl) 2 , C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy , C1-3 alkylthio , -SO2NH2 , -CONH 2 , C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic are optionally and independently substituted by one or more substituents.
在本發明的一些實施方案中,R 7和R 8分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、C 1-3烷基或C 1-3烷氧基,所述C 1-3烷基和C 1-3烷氧基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, R7 and R8 are independently selected from hydrogen, halogen, -CN, -OH, -NH2 , C1-3 alkyl or C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy are optionally and independently substituted with one or more substituents.
在本發明的一些實施方案中,R 7和R 8分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基,所述甲基、乙基、異丙基、甲氧基、乙氧基和異丙氧基任選獨立地被一個或多個取代基取代。 In some embodiments of the present invention, R7 and R8 are independently selected from hydrogen, halogen, -CN, -OH, -NH2 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally and independently substituted with one or more substituents.
在本發明的一些實施方案中,R 7和R 8分別任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, R 7 and R 8 are optionally and independently substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,R 7和R 8分別獨立地選自氫、鹵素、-CN、-OH、-NH 2、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基,所述甲基、乙基、異丙基、甲氧基、乙氧基和異丙氧基任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, R7 and R8 are independently selected from hydrogen, halogen, -CN, -OH, -NH2 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2 .
在本發明的一些實施方案中,R 7和R 8分別獨立地選自氫、-F、-Cl、-Br、-I、-CN、甲基、甲氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基。 In some embodiments of the invention, R 7 and R 8 are each independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
在本發明的一些實施方案中,R 7和R 8分別獨立地選自-F、-Cl、-Br、-I、甲基、甲氧基或三氟甲基。 In some embodiments of the invention, R 7 and R 8 are each independently selected from -F, -Cl, -Br, -I, methyl, methoxy or trifluoromethyl.
在本發明的一些實施方案中,R 7和R 8分別獨立地選自甲基。 In some embodiments of the present invention, R7 and R8 are each independently selected from methyl.
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成任選被一個或多個取代基取代的C 3-6環烷基、3-6員雜環基或C 3-6環烯基。 In some embodiments of the present invention, R 7 and R 8 together with the carbon atom to which they are commonly attached form a C 3-6 cycloalkyl, a 3-6 membered heterocyclic group or a C 3-6 cycloalkenyl group which is optionally substituted with one or more substituents.
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成任選被一個或多個取代基取代的環丙基、環丁基、環戊基、環己基、氧雜環丁基、硫雜環丁基、氮雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、噻唑烷基、異噻唑烷基、噁唑烷基、異噁唑烷基、呱啶基、呱嗪基、嗎啉基、環丙烯基、環丁烯基、環戊烯基或環己烯基。 In some embodiments of the present invention, R and R and the carbon atom to which they are commonly attached together form cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, oxacyclobutyl, thiacyclobutyl, azacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, which is optionally substituted with one or more substituents.
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成任選被一個或多個取代基取代的環丙基、環丁基、氧雜環丁基、氮雜環丁基、吡咯烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、呱啶基、呱嗪基或嗎啉基。 In some embodiments of the present invention, R7 and R8 , together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, oxacyclobutyl, azacyclobutyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl group, which may be optionally substituted with one or more substituents.
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環丙基、環丁基、氧雜環丁基、氮雜環丁基、吡咯烷基、四氫噻吩基、四氫呋喃基、四氫吡喃基、呱啶基、呱嗪基或嗎啉基。 In some embodiments of the present invention, R7 and R8 and the carbon atom to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxacyclobutyl, azacyclobutyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2 .
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的環丙基、環丁基或四氫吡喃基。 In some embodiments of the present invention, R 7 and R 8 together with the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl or tetrahydropyranyl group optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成任選被1、2或3個選自鹵素、OH、CN或NH 2的基團取代的 、 或 。 In some embodiments of the present invention, R7 and R8 together with the carbon atom to which they are attached form a group optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2. , or .
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成的取代基任選獨立地被1、2或3個選自鹵素、OH、CN或NH 2的基團取代。 In some embodiments of the present invention, R 7 and R 8 together with the carbon atom to which they are commonly attached form a substituent group which is optionally and independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH 2 .
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成 、 、 或 。 In some embodiments of the present invention, R7 and R8 together with the carbon atom to which they are attached form , , or .
在本發明的一些實施方案中,R 7和R 8以及其共同連接的碳原子一起形成 。 In some embodiments of the present invention, R7 and R8 together with the carbon atom to which they are attached form .
在本發明的一些實施方案中,所述“雜”各自獨立地選自氧、硫和氮的雜原子,其中氮原子任選地被季銨化或被氧化為N(O),硫原子任選被氧化為S(O)或S(O) 2。 In some embodiments of the present invention, the "impurities" are each independently selected from oxygen, sulfur and nitrogen impurities, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), and the sulfur atom is optionally oxidized to S(O) or S(O) 2 .
在本發明的一些實施方案中,所述“雜”各自獨立地選自氧、硫和氮的雜原子,其中硫雜原子任選被氧化為S(O)或S(O) 2。 In some embodiments of the present invention, the "impurities" are each independently selected from oxygen, sulfur and nitrogen impurity atoms, wherein the sulfur impurity atom is optionally oxidized to S(O) or S(O) 2 .
在本發明的一些實施方案中,m選自1。In some embodiments of the present invention, m is selected from 1.
在本發明的一些實施方案中,所述R 1、R 2、R 3、R 4、R 5、R 6、R 6a、R 7、R 8或R 9任選地被一個或多個選自以下的取代基取代:-OH、-SH、鹵素、-NH 2、硝基、亞硝基、-CN、疊氮基團、亞碸基團、碸基團、磺醯胺基團、羧基、羧醛基團、亞胺基團、烷基、鹵代-烷基、環烷基、鹵代-環烷基、烯基、鹵代-烯基、環烯基、鹵代-環烯基、炔基、鹵代-炔基、環炔基、鹵代-環炔基、雜烷基、鹵代-雜烷基、烷氧基、烷硫基、芳基、芳基氧基、芳基硫基、芳烷基、芳基烷氧基、芳基烷硫基、雜芳基、雜芳基氧基、雜芳基硫基、雜芳烷基、雜芳基烷氧基、雜芳基烷硫基、雜環基、雜環基氧基、雜環基硫基、雜環基烷基、雜環基烷氧基、雜環基烷硫基、醯基、醯氧基、胺基甲酸酯基團、醯胺基團、脲基、環氧基團和酯基團等。 In some embodiments of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7 , R 8 or R 9 are optionally substituted by one or more substituents selected from the group consisting of -OH, -SH, halogen, -NH 2 , nitro, nitroso, -CN, an azido group, a sulfonyl group, a sulfonyl group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halogenated-alkyl group, a cycloalkyl group, a halogenated-cycloalkyl group, an alkenyl group, a halogenated-alkenyl group, a cycloalkenyl group, a halogenated-cycloalkenyl group, an alkynyl group, a halogenated-alkynyl group, a cycloalkynyl group, a halogenated-cycloalkynyl group, a heteroalkyl group, a halogenated-heteroalkyl group, an alkoxy group, an alkylthio group, an aryl group, an aromatic group, a The invention also includes a 3-D-type acrolein group, ...
在本發明的一些實施方案中,所述式(I)所示化合物、其異構物或其藥學上可接受的鹽,其中所述式(I)所示化合物選自式(I-1)所示化合物, 其中,X 1、X 2、X 3、X 4、X 5、X 6、R 2、R 3、R 4和R 6如式(I)所示化合物定義; R 3、R 4連接的碳原子可以為掌性碳原子,以(R)或(S)單一鏡像異構物形式或富含一種鏡像異構物形式存在。 In some embodiments of the present invention, the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (I) is selected from the compound represented by formula (I-1), Wherein, X1 , X2 , X3 , X4 , X5 , X6 , R2 , R3 , R4 and R6 are defined as the compound shown in formula (I); the carbon atom to which R3 and R4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer.
在本發明的一些實施方案中,所述式(I)所述化合物、其異構物或其藥學上可接受的鹽,其中所述式(I)所示化合物選自式(I-2)所示化合物 其中, X 4選自CH或N; X 1、X 2、R 2、L和R 6如式(I)所示化合物定義。 In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-2) Wherein, X 4 is selected from CH or N; X 1 , X 2 , R 2 , L and R 6 are as defined for the compound represented by formula (I).
在本發明的一些實施方案中,所述式(I)所述化合物、其異構物或其藥學上可接受的鹽,其中所述式(I)所示化合物選自式(I-3)所示化合物 其中, X 4選自CH或N; X 1、R 2、L和R 6如式(I)所示化合物定義。 In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-3) Wherein, X 4 is selected from CH or N; X 1 , R 2 , L and R 6 are as defined for the compound represented by formula (I).
在本發明的一些實施方案中,所述式(I)所述化合物、其異構物或其藥學上可接受的鹽,其中所述式(I)所示化合物選自式(I-4)所示化合物 其中, X 4選自CH或N; X 1、R 2、R 3、R 4和R 6如式(I)所示化合物定義; R 3、R 4連接的碳原子可以為掌性碳原子,以(R)或(S)單一鏡像異構物形式或富含一種鏡像異構物形式存在。 In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-4) Wherein, X4 is selected from CH or N; X1 , R2 , R3 , R4 and R6 are defined as the compound shown in formula (I); the carbon atom to which R3 and R4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or a form enriched in one mirror image isomer.
在本發明的一些實施方案中,所述式(I)所述化合物、其異構物或其藥學上可接受的鹽,其中所述式(I)所示化合物選自式(I-5)所示化合物 其中, X 4選自CH或N; Y 1、Y 2和Y 3分別獨立地選自CH或N; X 1、R 3、R 4、R 6和R 2a如式(I)所示化合物定義; R 3、R 4連接的碳原子可以為掌性碳原子,以(R)或(S)單一鏡像異構物形式或富含一種鏡像異構物形式存在。 In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-5) wherein X 4 is selected from CH or N; Y 1 , Y 2 and Y 3 are independently selected from CH or N; X 1 , R 3 , R 4 , R 6 and R 2a are as defined in the compound of formula (I); the carbon atom to which R 3 and R 4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer.
在本發明的一些實施方案中,Y 1選自N。 In some embodiments of the present invention, Y1 is selected from N.
在本發明的一些實施方案中,Y 1和Y 3均選自N。 In some embodiments of the present invention, Y1 and Y3 are both selected from N.
在本發明的一些實施方案中,Y 1、Y 2和Y 3均選自CH。 In some embodiments of the invention, Y 1 , Y 2 and Y 3 are all selected from CH.
在本發明的一些實施方案中,Y 1選自N,Y 2和Y 3均選自CH。 In some embodiments of the present invention, Y1 is selected from N, and Y2 and Y3 are both selected from CH.
在本發明的一些實施方案中,Y 1和Y 3均選自N,Y 2選自CH。 In some embodiments of the present invention, Y1 and Y3 are both selected from N, and Y2 is selected from CH.
在本發明的一些實施方案中,所述式(I)所述化合物、其異構物或其藥學上可接受的鹽,其中所述式(I)所示化合物選自式(I-6)所示化合物 其中, X 4選自CH或N; Y 1、Y 2和Y 3如式(I-5)所示化合物定義; X 1、R 3、R 4、R 2a和R 6a如式(I)所示化合物定義; R 3、R 4連接的碳原子可以為掌性碳原子,以(R)或(S)單一鏡像異構物形式或富含一種鏡像異構物形式存在。 In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-6) wherein X4 is selected from CH or N; Y1 , Y2 and Y3 are as defined in the compound shown in formula (I-5); X1 , R3 , R4 , R2a and R6a are as defined in the compound shown in formula (I); the carbon atom to which R3 and R4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer.
在本發明的一些實施方案中,所述式(I)所述化合物、其異構物或其藥學上可接受的鹽,其中所述式(I)所示化合物選自式(I-7)所示化合物 其中, X 4選自CH或N; Y 1、Y 2和Y 3如式(I-5)所示化合物定義; X 1、R 3、R 4、R 2a和R 6a如式(I)所示化合物定義; R 3、R 4連接的碳原子可以為掌性碳原子,以(R)或(S)單一鏡像異構物形式或富含一種鏡像異構物形式存在。 In some embodiments of the present invention, the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the compound of formula (I-7) wherein X4 is selected from CH or N; Y1 , Y2 and Y3 are as defined in the compound shown in formula (I-5); X1 , R3 , R4 , R2a and R6a are as defined in the compound shown in formula (I); the carbon atom to which R3 and R4 are connected may be a chiral carbon atom, existing in the form of a (R) or (S) single mirror image isomer or in a form enriched in one mirror image isomer.
本發明還有一些實施方案是由所述各變量任意組合而來。Some other embodiments of the present invention are obtained by any combination of the above variables.
另一方面,本發明還提供了下式化合物、其異構物或其藥學上可接受的鹽, 。 On the other hand, the present invention also provides a compound of the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, .
另一方面,本發明還提供了下式化合物、其異構物或其藥學上可接受的鹽, 。 On the other hand, the present invention also provides a compound of the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, .
另一方面,本發明還提供了藥物組成物,其含有治療或預防有效量的本發明所述化合物、其異構物或其藥學上可接受的鹽。在一些實施方案中,本發明的藥物組成物還包括藥學上可接受的佐劑。On the other hand, the present invention also provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of the present invention, its isomers or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition of the present invention also includes a pharmaceutically acceptable adjuvant.
另一方面,本發明還提供了本發明所述化合物、其異構物或其藥學上可接受的鹽或其藥物組成物在製備治療或預防與泛素特異性蛋白酶1 (USP1)的抑制相關的疾病的藥物中的應用。On the other hand, the present invention also provides the use of the compound, its isomer or pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a drug for treating or preventing diseases associated with the inhibition of ubiquitin-specific protease 1 (USP1).
另一方面,本發明還提供了治療或預防與泛素特異性蛋白酶1 (USP1)的抑制相關的疾病的方法,包括對需要該治療或預防的哺乳動物(優選人類)給予治療或預防有效量的本發明所述化合物、其異構物或其藥學上可接受的鹽或其藥物組成物。On the other hand, the present invention also provides a method for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1), comprising administering a therapeutically or preventively effective amount of the compound of the present invention, its isomers or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof to a mammal (preferably a human) in need of such treatment or prevention.
另一方面,本發明還提供了本發明所述化合物、其異構物或其藥學上可接受的鹽或其藥物組成物在治療或預防與泛素特異性蛋白酶1 (USP1)的抑制相關的疾病中的應用。On the other hand, the present invention also provides the use of the compound of the present invention, its isomer or pharmaceutically acceptable salt or its pharmaceutical composition in the treatment or prevention of diseases related to the inhibition of ubiquitin-specific protease 1 (USP1).
另一方面,本發明還提供了用於治療或預防與泛素特異性蛋白酶1 (USP1)的抑制相關的疾病的本發明所述化合物其異構物或其藥學上可接受的鹽或其藥物組成物。On the other hand, the present invention also provides the compound of the present invention, its isomers, or its pharmaceutically acceptable salt, or its pharmaceutical composition for treating or preventing diseases associated with the inhibition of ubiquitin-specific protease 1 (USP1).
另一方面,本發明的一些實施方案中,所述與泛素特異性蛋白酶1 (USP1)的抑制相關的疾病選自腫瘤或癌症(例如乳腺癌)。 技術效果 On the other hand, in some embodiments of the present invention, the disease associated with the inhibition of ubiquitin-specific protease 1 (USP1) is selected from tumors or cancers (such as breast cancer ).
本發明中的化合物作為全新結構的泛素特異性蛋白酶1 (USP1)的抑制劑,其對泛素特異性蛋白酶1 (USP1)的訊息傳遞有良好的抑制作用。本發明的化合物具有良好的體內外抑制作用,包括但不限於體外酶活性和細胞活性抑制作用良好,肝微粒體穩定性良好,藥代動力學性質良好,體內藥效良好等,可以發展成為新型USP1抑制劑類藥物。 相關定義 The compounds of the present invention are inhibitors of a completely new structure of ubiquitin-specific protease 1 (USP1), which have a good inhibitory effect on the signal transduction of ubiquitin-specific protease 1 (USP1). The compounds of the present invention have good inhibitory effects in vivo and in vitro, including but not limited to good inhibitory effects on in vitro enzyme activity and cell activity, good liver microsomal stability, good pharmacokinetic properties, good in vivo efficacy, etc., and can be developed into new USP1 inhibitor drugs. Related definitions
除非另有說明,本文所用的下列術語和短語旨在具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的,而應該按照普通的含義去理解。當本文中出現商品名時,意在指代其對應的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to the corresponding trade name or its active ingredient.
這裡所採用的術語“藥學上可接受的”,是針對那些化合物、材料、組成物和/或劑型而言,它們在可靠的醫學判斷的範圍之內,適用於與人類和動物的組織接觸使用,而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症,與合理的利益/風險比相稱。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.
術語“藥學上可接受的鹽”是指本發明化合物的鹽,由本發明發現的具有特定取代基的化合物與相對無毒的酸或鹼製備。當本發明的化合物中含有相對酸性的功能團時,可以透過在純的溶液或合適的惰性溶劑中用足夠量的鹼與這類化合物接觸的方式獲得鹼加成鹽。當本發明的化合物中含有相對鹼性的官能基時,可以透過在純的溶液或合適的惰性溶劑中用足夠量的酸與這類化合物接觸的方式獲得酸加成鹽。本發明的某些特定的化合物含有鹼性和酸性的官能基,從而可以被轉換成任一鹼或酸加成鹽。The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from the compounds having specific substituents discovered in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with sufficient amounts of base in pure solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with sufficient amounts of acid in pure solution or in a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.
本發明的藥學上可接受的鹽可由含有酸根或鹼基的母體化合物透過常規化學方法合成。一般情況下,這樣的鹽的製備方法是:在水或有機溶劑或兩者的混合物中,經由游離酸或鹼形式的這些化合物與化學計量的適當的鹼或酸反應來製備。The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or alkaline groups by conventional chemical methods. Generally, such salts are prepared by reacting free acid or alkaline forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.
本發明的化合物可以存在特定的幾何或立體異構物形式。本發明設想所有的這類化合物,包括順式和反式異構物、(-)- 和 (+)-鏡像異構物、( R)- 和 ( S)-鏡像異構物、非對映異構物、( D)-異構物、( L)-異構物,及其外消旋混合物和其他混合物,例如對映異構物或非鏡像異構物富集的混合物,所有這些混合物都屬於本發明的範圍之內。烷基等取代基中可存在另外的不對稱碳原子。所有這些異構物以及它們的混合物,均包括在本發明的範圍之內。 The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-mirror isomers, ( R )- and ( S )-mirror isomers, diastereoisomers, ( D )-isomers, ( L )-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereoisomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present invention.
除非另有規定,用楔形實線鍵( )和楔形虛線鍵( )表示一個立體中心的絕對構型,用直形實線鍵( )和直形虛線鍵( )表示立體中心的相對構型。 Unless otherwise specified, a solid wedge key ( ) and the Dashed Wedge Key ( ) represents the absolute configuration of a stereocenter, with a straight solid line key ( ) and the straight dash key ( ) represents the relative configuration of the stereocenter.
本發明的化合物和中間物還可以不同的互變異構物形式存在,並且所有這樣的形式包含於本發明的範圍內。術語“互變異構物”或“互變異構物形式”是指可經由低能量障壁互變的不同能量的結構異構物。例如,質子互變異構物(也稱為質子轉移互變異構物)包括經由質子遷移的互變,如酮-烯醇及亞胺-烯胺異構化。質子互變異構物的具體實例是咪唑部分,其中質子可在兩個環氮間遷移。價互變異構物包括透過一些成鍵電子的重組的互變。The compounds and intermediates of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called proton shift tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which the proton can migrate between two ring nitrogens. Valence tautomers include interconversions via reorganization of some bonding electrons.
本發明的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素標記化合物,比如氚( 3H),碘-125 ( 125I)或C-14 ( 14C)。又例如,可用重氫取代氫形成氘代藥物,氘與碳構成的鍵比普通氫與碳構成的鍵更堅固,相比於未氘化藥物,氘代藥物有降低毒副作用、增加藥物穩定性、增強療效、延長藥物生物半衰期等優勢。本發明的化合物的所有同位素組成的變換,無論放射性與否,都包括在本發明的範圍之內。 The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
術語“任選”或“任選地”指的是隨後描述的事件或狀況可能但不是必需出現的,並且該描述包括其中所述事件或狀況發生的情況以及所述事件或狀況不發生的情況。The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur.
術語“被取代的”是指特定原子上的任意一個或多個氫原子被取代基取代,取代基可以包括重氫和氫的變異體,只要特定原子的價態是正常的並且取代後的化合物是穩定的。當取代基為氧(即=O)時,意味著兩個氫原子被取代。氧取代不會發生在芳香基上。術語“任選被取代的”是指可以被取代,也可以不被取代,除非另有規定,取代基的種類和數目在化學上可以實現的基礎上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on a chemically feasible basis.
本文所述的“取代基”包括本文上下文中所提及的所有取代基,例如包括下文提及的術語“C 1-12烷基”、“C 1-12烷氧基”、“C 1-12烷硫基”、“C 2-12烯基”、“C 2-12炔基”、“鹵素”、“C 3-12環烷基”、“C 3-12環烯基”、“3-6員雜環烷基”、“C 6-10芳基”、“5-10員雜芳基”、“3-12員雜環基”等相關基團所定義,及對應的非限制性或例示性基團,其中所述“取代基”一些非限制性實例包括羥基、巰基、鹵素、胺基、硝基、亞硝基、氰基、疊氮基團、亞碸基團、碸基團、磺醯胺基團、羧基、羧醛基團、亞胺基團、烷基、鹵代-烷基、環烷基、鹵代-環烷基、烯基、鹵代-烯基、環烯基、鹵代-環烯基、炔基、鹵代-炔基、環炔基、鹵代-環炔基、雜烷基、鹵代-雜烷基、烷氧基、烷硫基、芳基、芳基氧基、芳基硫基、芳烷基、芳基烷氧基、芳基烷硫基、雜芳基、雜芳基氧基、雜芳基硫基、雜芳烷基、雜芳基烷氧基、雜芳基烷硫基、雜環基、雜環基氧基、雜環基硫基、雜環基伸烷基、雜環基烷氧基、雜環基烷硫基、醯基、醯氧基、胺基甲酸酯基團、醯胺基團、脲基、環氧基團、酯基團、氧代和硫代等,所述基團任選地被一個或多個選自以下的取代基取代:氧代、羥基、胺基、硝基、鹵素、氰基、烷基、烯基、炔基、烷氧基、鹵代烷氧基、烷基胺基、二烷基胺基、鹵代烷基胺基、鹵代二烷基胺基、羧基、-C(O)O-烷基、- OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、環烷基、環烷基伸烷基、環烷基氧基、雜環基、雜環基伸烷基、雜環基氧基、雜環烷基、雜環烷基伸烷基、雜環烷基氧基、雜芳基、雜芳基伸烷基、雜芳基氧基、芳基、芳基伸烷基或芳基氧基。 The “substituent” described herein includes all substituents mentioned herein, for example, the terms “C 1-12 alkyl”, “C 1-12 alkoxy”, “C 1-12 alkylthio”, “C 2-12 alkenyl”, “C 2-12 alkynyl”, “halogen”, “C 3-12 cycloalkyl”, “C 3-12 cycloalkenyl”, “ 3-6 membered heterocycloalkyl”, “C 6-10 aryl”, “5-10 membered heteroaryl”, “3-12 membered heterocyclo” and the like, and the corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the “substituent” include hydroxyl, oxalyl, halogen, amine, nitro, nitroso, cyano, azido, sulfonamide, sulfonyl, sulfonyl, thiophene ... group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halogenated-alkyl group, cycloalkyl group, halogenated-cycloalkyl group, alkenyl group, halogenated-alkenyl group, cycloalkenyl group, halogenated-cycloalkenyl group, alkynyl group, halogenated-alkynyl group, cycloalkynyl group, halogenated-cycloalkynyl group, heteroalkyl group, halogenated-heteroalkyl group, alkoxy group, alkylthio group, aryl group, aryloxy group, arylthio group, aralkyl group, an arylalkoxy group, an arylalkylthio group, a heteroaryl group, a heteroaryloxy group, a heteroarylthio group, a heteroarylalkyl group, a heteroarylalkoxy group, a heteroarylalkylthio group, a heterocyclic group, a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic alkylene group, a heterocyclic alkoxy group, a heterocyclic alkylthio group, an acyl group, an acyloxy group, a carbamate group, an amide group, a urea group, an epoxide group, ester group, oxo and thio, etc., wherein the group is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amine, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, - OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O) -alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH - alkyl , -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclo, heterocycloalkylalkylene, heterocycloalkyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.
在本文的部分實施方案中,所述取代基選自羥基、巰基、鹵素、胺基、硝基、亞硝基、氰基、疊氮基團、亞碸基團、碸基團、磺醯胺基團、羧基、醛基、亞胺基團、C 1-12烷基、鹵代-C 1-12烷基、3-12員環烷基、鹵代-3-12員環烷基、C 2-12烯基、鹵代- C 2-12烯基、3-12員環烯基、鹵代-3-12員環烯基、C 2-12炔基、鹵代- C 2-12炔基、8-12員環炔基、鹵代-8-12員環炔基、C 1-12雜烷基、鹵代-C 1-12雜烷基、C 1-12烷氧基、C 1-12烷硫基、6-10員芳基、6-10員芳基氧基、6-10員芳基硫基、6-10員芳基C 1-12伸烷基、6-10員芳基C 1-12烷氧基、6-10員芳基C 1-12烷硫基、5-10員雜芳基、5-10員雜芳基氧基、5-10員雜芳基硫基、5-10員雜芳基伸烷基、5-10員雜芳基烷氧基、5-10員雜芳基烷硫基、3-12員雜環基、3-12員雜環基氧基、3-12員雜環基硫基、3-12員雜環基C 1-12伸烷基、3-12員雜環基C 1-12烷氧基、3-12員雜環基C 1-12烷硫基、C 1-12醯基、C 1-12醯氧基、胺基甲酸酯基團、C 1-12醯胺基、脲基、環氧基團、C 2-12酯基團、氧代和硫代等,所述取代基任選地被一個或多個選自以下的取代基取代:氧代、羥基、胺基、硝基、鹵素、氰基、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、鹵代C 1-12烷氧基、C 1-12烷基胺基、二C 1-12烷基胺基、鹵代C 1-12烷基胺基、鹵代二C 1-12烷基胺基、羧基、-C(O)O- C 1-12烷基、-OC(O)- C 1-12烷基、-C(O)NH 2、-C(O)NH-C 1-12烷基、-C(O)N(C 1-12烷基) 2、-NHC(O)- C 1-12烷基、-C(O)- C 1-12烷基、-S(O)-C 1-12烷基、-S(O) 2-C 1-12烷基、-S(O) 2NH 2、-S(O) 2NH-C 1-12烷基、-S(O) 2N(C 1-12烷基) 2、3-12員環烷基、3-12員環烷基C 1-12伸烷基、3-12員環烷基氧基、3-12員雜環基、3-12員雜環基C 1-12伸烷基、3-12員雜環基氧基、3-12員雜環烷基、3-12員雜環烷基C 1-12伸烷基、3-12員雜環烷基氧基、5-10員雜芳基、5-10員雜芳基C1-12伸烷基、5-10員雜芳基氧基、6-10員芳基、6-10員芳基C 1-12伸烷基或6-10員芳基氧基。 In some embodiments herein, the substituent is selected from hydroxyl, oxalyl, halogen, amine, nitro, nitroso, cyano, azido, sulfonyl, sulfonamide, carboxyl, aldehyde, imine, C1-12 alkyl, halogenated- C1-12 alkyl, 3-12 membered cycloalkyl, halogenated-3-12 membered cycloalkyl, C2-12 alkenyl, halogenated- C2-12 alkenyl, 3-12 membered cycloalkenyl, halogenated-3-12 membered cycloalkenyl, C2-12 alkynyl, halogenated- C2-12 alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C1-12 heteroalkyl, halogenated-C 1-12 membered heteroalkyl, C 1-12 membered alkoxy, C 1-12 membered alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 alkylene, 6-10 membered arylC 1-12 alkoxy, 6-10 membered arylC 1-12 alkylthio , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroaryl alkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclic group, 3-12 membered heterocyclic groupoxy, 3-12 membered heterocyclic groupthio, 3-12 membered heterocyclic groupC The substituents may be a C 1-12 alkylene group, a 3-12 membered heterocyclic C 1-12 alkoxy group, a 3-12 membered heterocyclic C 1-12 alkylthio group, a C 1-12 acyl group, a C 1-12 acyloxy group, a carbamate group, a C 1-12 amide group, a urea group, an epoxy group, a C 2-12 ester group, an oxo group, and a thioxo group, etc., wherein the substituents are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amine, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkylamino, halogenated di-C 1-12 1-12 alkylamino, carboxyl, -C(O)O- C 1-12 alkyl, -OC(O)- C 1-12 alkyl, -C(O)NH 2 , -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl) 2 , -NHC(O)- C 1-12 alkyl, -C(O)- C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O) 2 -C 1-12 alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-C 1-12 alkyl, -S(O) 2 N(C 1-12 alkyl) 2 , 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 The present invention may be a 1-12 membered alkylene group, a 3-12 membered cycloalkyloxy group, a 3-12 membered heterocycloyl group, a 3-12 membered heterocycloalkylC 1-12 alkylene group, a 3-12 membered heterocycloalkyloxy group, a 3-12 membered heterocycloalkyl group, a 3-12 membered heterocycloalkylC 1-12 alkylene group, a 3-12 membered heterocycloalkyloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroarylC 1-12 alkylene group, a 5-10 membered heteroaryloxy group, a 6-10 membered aryl group, a 6-10 membered arylC 1-12 alkylene group, or a 6-10 membered aryloxy group.
當任何變數(例如R)在化合物的組成或結構中出現一次以上時,其在每一種情況下的定義都是獨立的。因此,例如,如果一個基團被0-2個R所取代,則所述基團可以任選地至多被兩個R所取代,並且每種情況下的R都有獨立的選項。此外,取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and each occurrence of R is an independent choice. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
當其中一個變數選自單鍵時,表示其連接的兩個基團直接相連,比如A-L-Z中L代表單鍵時表示該結構實際上是A-Z。When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
當所列舉的連接基團沒有指明其連接方向,其連接方向是任意的,例如, 中連接基團L為-M-W-,此時-M-W-既可以按與從左往右的讀取順序相同的方向連接環A和環B構成 ,也可以按照與從左往右的讀取順序相反的方向連接環A和環B構成 。所述連接基團、取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。 When a linker group is listed without specifying its direction of attachment, the direction of attachment is arbitrary, e.g. The connecting group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right. , or by connecting Ring A and Ring B in the opposite direction of the reading order from left to right. Combinations of linking groups, substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
除非另有規定,當某一基團具有一個或多個可連接位點時,該基團的任意一個或多個位點可以透過化學鍵與其他基團相連。當該化學鍵的連接方式是不定位的,且可連接位點存在H原子時,則連接化學鍵時,該位點的H原子的個數會隨所連接化學鍵的個數而對應減少變成對應價數的基團。所述位點與其他基團連接的化學鍵可以用直形實線鍵( )、直形虛線鍵( )、或波浪線( )表示。例如-OCH 3中的直形實線鍵表示透過該基團中的氧原子與其他基團相連; 中的直形虛線鍵表示透過該基團中的氮原子的兩端與其他基團相連; 中的波浪線表示透過該苯基基團中的1和2位碳原子與其他基團相連; 或 表示該呱啶基上的任意可連接位點可以透過1個化學鍵與其他基團相連,至少包括 、 、 、 這4種連接方式,即使-N-上畫出了H原子,但是 仍包括 這種連接方式的基團,只是在連接1個化學鍵時,該位點的的H會對應減少1個變成對應的一價呱啶基。 Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected to become a group of corresponding valence. The chemical bonds connecting the site to other groups can be represented by straight solid bonds ( ), straight dashed line key( ), or a wavy line ( ) represents. For example, the straight solid bond in -OCH 3 represents the connection with other groups through the oxygen atom in the group; The straight dashed bonds in the figure indicate that the two ends of the nitrogen atom in the group are connected to other groups. The wavy line in the figure indicates that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group. or Indicates that any linkable site on the pyridinyl group can be linked to other groups via a chemical bond, including at least , , , These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that position will decrease by one and become the corresponding monovalent piperidinyl group.
除非另有規定,術語“C 1-12烷基”本身或作為另一取代基的一部分表示直鏈或支鏈的由1至12個碳原子組成的飽和碳氫基團。所述C 1-12烷基可以為C 1-6烷基或C 1-3烷基。除非另有規定,術語“C 1-6烷基”用於表示直鏈或支鏈的由1至6個碳原子組成的飽和碳氫基團。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等;其可以是一價(如甲基)、二價(如亞甲基)或者多價(如次甲基)。C 1-6烷基的實例包括但不限於甲基(Me)、乙基(Et)、丙基(包括 n-丙基和異丙基)、丁基(包括 n-丁基,異丁基, s-丁基和 t-丁基)、戊基(包括 n-戊基,異戊基和新戊基)、己基等。 Unless otherwise specified, the term "C 1-12 alkyl" by itself or as part of another substituent refers to a straight or branched saturated hydrocarbon group consisting of 1 to 12 carbon atoms. The C 1-12 alkyl may be a C 1-6 alkyl or a C 1-3 alkyl. Unless otherwise specified, the term "C 1-6 alkyl" is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), butyl (including n -butyl, isobutyl, s -butyl and t -butyl), pentyl (including n -pentyl, isopentyl and neopentyl), hexyl and the like.
除非另有規定,術語“C 1-12伸烷基”本身或作為另一取代基的一部分表示直鏈或支鏈的由1至12個碳原子組成的二價烴基,包括具有1至12個、1至8個、1至6個、1至4個、1至3個或1至2個碳原子的情形。例如,術語“C 1-6伸烷基”指含有1至6個碳原子的伸烷基。伸烷基的非限制性實例包括但不限於伸甲基(-CH 2-)、伸乙基(-CH 2CH 2-)、伸丙基(-CH 2CH 2CH 2-或-CH 2CH(CH 3)-)、伸丁基(-CH 2CH 2CH 2CH 2-、-CH 2CH(CH 3)CH 2-或-CH 2CH 2CH(CH 3)-)等。所述伸烷基任選地被一個或多個選自以下的取代基取代:氧代、羥基、胺基、硝基、鹵素、氰基、烯基、炔基、烷氧基、鹵代烷氧基、烷基胺基、二烷基胺基、鹵代烷基胺基、鹵代二烷基胺基、環烷基、環烷基氧基、雜環基、雜環基氧基、雜環烷基、雜環烷基氧基、雜芳基、雜芳基氧基、芳基或芳基氧基。 Unless otherwise specified, the term "C 1-12 alkylene" by itself or as part of another substituent means a linear or branched divalent hydrocarbon radical consisting of 1 to 12 carbon atoms, including those having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 alkylene" refers to an alkylene radical containing 1 to 6 carbon atoms. Non-limiting examples of alkylene radicals include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 - or -CH 2 CH(CH 3 )-), butylene (-CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - or -CH 2 CH 2 CH(CH 3 )-), and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amine, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, cycloalkyl, cycloalkyloxy, heterocyclo, heterocyclooxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
除非另有規定,術語“C 1-12烷氧基”表示透過一個氧原子連接到分子的其餘部分的那些包含1至12個碳原子的烷基基團。所述C 1-12烷氧基可以為C 1-6烷氧基或C 1-3烷氧基。除非另有規定,術語“C 1-6烷氧基”表示透過一個氧原子連接到分子的其餘部分的那些包含1至6個碳原子的烷基基團。所述C 1-6烷氧基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷氧基等。C 1-6烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基(包括正丙氧基和異丙氧基)、丁氧基(包括正丁氧基,異丁氧基,仲丁氧基和叔丁氧基)、戊氧基(包括正戊氧基,異戊氧基和新戊氧基)、己氧基等。 Unless otherwise specified, the term "C 1-12 alkoxy" refers to an alkyl group containing 1 to 12 carbon atoms that is attached to the rest of the molecule via an oxygen atom. The C 1-12 alkoxy group may be a C 1-6 alkoxy group or a C 1-3 alkoxy group. Unless otherwise specified, the term "C 1-6 alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms that is attached to the rest of the molecule via an oxygen atom. The C 1-6 alkoxy group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkoxy groups, etc. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy and the like.
除非另有規定,術語“C 1-12烷硫基”表示透過一個硫原子連接到分子的其餘部分的那些包含1至12個碳原子的烷基基團。所述C 1-12烷硫基可以為C 1-6烷硫基或C 1-3烷硫基。除非另有規定,術語“C 1-6烷硫基”表示透過一個硫原子連接到分子的其餘部分的那些包含1至6個碳原子的烷基基團。所述C 1-6烷硫基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷硫基等。C 1-6烷硫基的實例包括但不限於甲硫基、乙硫基、丙硫基(包括正丙硫基和異丙硫基)、丁硫基(包括正丁硫基,異丁硫基,仲丁硫基和叔丁硫基)、戊硫基(包括正戊硫基,異戊硫基和新戊硫基)、己硫基等。 Unless otherwise specified, the term "C 1-12 alkylthio" means an alkyl group containing 1 to 12 carbon atoms that is attached to the rest of the molecule via a sulfur atom. The C 1-12 alkylthio group may be a C 1-6 alkylthio group or a C 1-3 alkylthio group. Unless otherwise specified, the term "C 1-6 alkylthio" means an alkyl group containing 1 to 6 carbon atoms that is attached to the rest of the molecule via a sulfur atom. The C 1-6 alkylthio group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkylthio groups, etc. Examples of C1-6 alkylthio include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio and neopentylthio), hexylthio and the like.
除非另有規定,“C 2-12烯基”用於表示直鏈或支鏈的包含至少一個碳-碳雙鍵的由2至12個碳原子組成的碳氫基團,碳-碳雙鍵可以位於該基團的任何位置上。所述C 2-12烯基可以為C 2-6烯基、C 2-3烯基或C 2-3烯基。所述C 2-4烯基包括C 2-3、C 4、C 3和C 2烯基等;所述C 2-4烯基可以是一價、二價或者多價。C 2-4烯基的實例包括但不限於乙烯基、丙烯基、丁烯基、丁間二烯基等。除非另有規定,“C 2-3烯基”用於表示直鏈或支鏈的包含至少一個碳-碳雙鍵的由2至3個碳原子組成的碳氫基團,碳-碳雙鍵可以位於該基團的任何位置上。所述C 2-3烯基包括C 3和C 2烯基;所述C 2-3烯基可以是一價、二價或者多價。C 2-3烯基的實例包括但不限於乙烯基、丙烯基等。 Unless otherwise specified, "C 2-12 alkenyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 12 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group. The C 2-12 alkenyl group can be a C 2-6 alkenyl group, a C 2-3 alkenyl group or a C 2-3 alkenyl group. The C 2-4 alkenyl group includes C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; the C 2-4 alkenyl group can be monovalent, divalent or polyvalent. Examples of C 2-4 alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, butadienyl, etc. Unless otherwise specified, "C 2-3 alkenyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group may be monovalent, divalent or polyvalent. Examples of C 2-3 alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.
除非另有規定,“C 2-12炔基”用於表示直鏈或支鏈的包含至少一個碳-碳三鍵的由2至12個碳原子組成的碳氫基團,碳-碳三鍵可以位於該基團的任何位置上。所述C 2-12炔基包括C 2-6、C 2-3、C 4、C 3和C 2炔基等。其可以是一價、二價或者多價。C 2-3炔基的實例包括但不限於乙炔基、丙炔基等。 Unless otherwise specified, "C 2-12 alkynyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 12 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. The C 2-12 alkynyl group includes C 2-6 , C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It may be monovalent, divalent or polyvalent. Examples of C 2-3 alkynyl groups include, but are not limited to, ethynyl, propynyl, etc.
除非另有規定,術語 “鹵素”本身或作為另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise stated, the term "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom.
除非另有規定,C n-n+m或C n-C n+m包括n至n+m個碳的任何一種具體情況,例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12,也包括n至n+m中的任何一個範圍,例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等;同理,n員至n+m員表示環上原子數為n至n+m個,例如3-12員環包括3員環、4員環、5員環、6員環、7員環、8員環、9員環、10員環、11員環、和12員環,也包括n至n+m中的任何一個範圍,例如3-12員環包括3-6員環、3-9員環、5-6員環、5-7員環、6-7員環、6-8員環、和6-10員環等。 Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9, C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 . Similarly , n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.
除非另有規定,“C 3-12環烷基”表示由3至12個碳原子組成的飽和環狀碳氫基團,其為單環和雙環體系,所述C 3-12環烷基包括C 3-8、C 3-6和C 5-6環烷基等;其可以是一價、二價或者多價。C 3-12環烷基的實例包括,但不限於環丙基、環丁基、環戊基、環己基、降冰片基(雙環[2.2.1]庚基)、雙環[2.2.2]辛基、金剛烷基等。 Unless otherwise specified, "C 3-12 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-12 cycloalkyl includes C 3-8 , C 3-6 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-12 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.
除非另有規定,術語“C 3-12環烯基”本身或者與其他術語聯合分別表示包含至少一個碳-碳雙鍵的由3至12個環原子組成的部分不飽和的環狀碳氫基團,其可以是一價、二價或者多價。所述C 3-12環烯基包括C 3-6環烯基、C 5-6環烯基等。C 3-6環烯基的實例包括但不限於 、 或 。 Unless otherwise specified, the term "C 3-12 cycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic hydrocarbon group consisting of 3 to 12 ring atoms containing at least one carbon-carbon double bond, which may be monovalent, divalent or polyvalent. The C 3-12 cycloalkenyl includes C 3-6 cycloalkenyl, C 5-6 cycloalkenyl, etc. Examples of C 3-6 cycloalkenyl include but are not limited to , or .
除非另有規定,術語“5-7員雜環烯基”本身或者與其他術語聯合分別表示包含至少一個碳-碳雙鍵的由5至7個環原子組成的部分不飽和的環狀基團,其1、2、3或4個環原子為獨立選自O、S、N或Se的雜原子,其餘為碳原子,其中氮原子任選地被季銨化,氮和硫雜原子可任選被氧化(即NO和S(O) p,p是1或2)。其包括單環和雙環體系,其中雙環體系包括螺環、并環和橋環,此體系的任意環都是非芳香性的。其可以是一價、二價或者多價。此外,就該“5-7員雜環烯基”而言,雜原子可以佔據雜環烯基與分子其餘部分的連接位置。所述5-7員雜環烯基包括5-6員雜環烯基。5-6員雜環烯基的實例包括但不限於 、 、 、 或 。 Unless otherwise specified, the term "5-7 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 7 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, N or Se, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings, and any ring of this system is non-aromatic. It can be monovalent, divalent or polyvalent. In addition, for the "5-7 membered heterocycloalkenyl", a hetero atom may occupy the position where the heterocycloalkenyl is connected to the rest of the molecule. The 5-7 membered heterocycloalkenyl includes 5-6 membered heterocycloalkenyl. Examples of 5-6 membered heterocycloalkenyl include but are not limited to , , , or .
除非另有規定,術語“3-6員雜環烷基”本身或者與其他術語聯合分別表示由3至6個環原子組成的飽和環狀基團,其1、2、3或4個環原子為獨立選自O、S和N的雜原子,其餘為碳原子,其中氮原子任選地被季銨化,氮和硫雜原子可任選被氧化(即NO和S(O) p,p是1或2)。其為單環體系。此外,就該“3-6員雜環烷基”而言,雜原子可以佔據雜環烷基與分子其餘部分的連接位置。所述3-6員雜環烷基包括3員、4員、5員和6員雜環烷基等。3-6員雜環烷基的實例包括但不限於氧雜環丙基、硫雜環丙基、氮雜環丙基、氮雜環丁基、氧雜環丁基、硫雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基(包括四氫噻吩-2-基和四氫噻吩-3-基等)、四氫噻吩1,1,-二氧化物-3-基、四氫噻吩1,1,-二氧化物-2-基、四氫呋喃基(包括四氫呋喃-2-基等)、四氫吡喃基、呱啶基(包括1-呱啶基、2-呱啶基和3-呱啶基等)、呱嗪基(包括1-呱嗪基和2-呱嗪基等)、嗎啉基(包括3-嗎啉基和4-嗎啉基等)、二噁烷基、二噻烷基、異噁唑烷基、異噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氫噠嗪基、高呱嗪基或高呱啶基等。 Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It is a monocyclic system. In addition, with respect to the "3-6 membered heterocycloalkyl", the heteroatom may occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 3-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, cyclopropyl oxadiazole, cyclopropyl thiodiazole, cyclopropyl aziride, cyclobutyl aziride, cyclobutyl oxadiazole, cyclobutyl thiodiazole, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl), tetrahydrothienyl 1,1,-dioxide-3-yl, tetrahydrothienyl 1,1,-dioxide-2-yl, tetrahydrofuran ...2-yl, tetrahydrofuranyl ( The invention also includes but is not limited to tetrahydrofuran-2-yl, tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydroxazinyl, homopiperazinyl or homopiperidinyl, etc.
除非另有規定,術語“C 6-10芳基”表示由6至10個碳原子組成的具有共軛π電子體系的環狀碳氫基團,它可以是單環、稠合雙環或稠合三環體系,其中各個環均為芳香性的。其可以是一價、二價或者多價。C 6-10芳基包括C 9、C 10和C 6芳基。C 6-10芳基的實例包括但不限於苯基、萘基(包括1-萘基和2-萘基等)。 Unless otherwise specified, the term "C 6-10 aryl" means a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It can be monovalent, divalent or polyvalent. C 6-10 aryl includes C 9 , C 10 and C 6 aryl. Examples of C 6-10 aryl include but are not limited to phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).
除非另有規定,術語“5-10員雜芳基”是表示由5至10個環原子組成的具有共軛π電子體系的環狀基團,其1、2、3或4個環原子為獨立選自O、S、N或Se的雜原子,其餘為碳原子。其可以是單環、稠合雙環或稠合三環體系,其中各個環均為芳香性的。其中氮原子任選地被季銨化,氮和硫雜原子可任選被氧化(即NO和S(O) p,p是1或2)。其可以是一價、二價或者多價。5-10員雜芳基可透過雜原子或碳原子連接到分子的其餘部分。所述5-10員雜芳基包括5-8員、5-7員、5-6員、5員和6員雜芳基等。所述5-10員雜芳基的實例包括但不限於吡咯基(包括 N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括 N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1 H-1,2,3-三唑基、2 H-1,2,3-三唑基、1 H-1,2,4-三唑基和4 H-1,2,4-三唑基等)、四唑基、異噁唑基(3-異噁唑基、4-異噁唑基和5-異噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、異喹啉基(包括1-異喹啉基和5-異喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。 Unless otherwise specified, the term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N or Se, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It can be monovalent, divalent or polyvalent. The 5-10 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N -imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl ( 1H -1,2,3-triazolyl, 2H -1,2,3-triazolyl, 1H -1,2,4-triazolyl and 4H -1, -1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidine The invention may be substituted or alternatively selected from the group consisting of 2-pyrimidinyl, 4-pyrimidinyl, benzothiazolyl, 5-benzothiazolyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, isoquinolyl, 1-isoquinolyl, 5-isoquinolyl, quinoxalinyl, 2-quinoxalinyl, 5-quinoxalinyl, quinolyl, 3-quinolyl, 6-quinolyl, etc.
術語“3-12員雜環基”是指完全飽和的或部分不飽和的(但不是完全不飽和的雜芳族)並且可以以單環、橋環或螺環存在的非芳族環。除非另有指示,該雜環通常為含有1至3個獨立地選自硫、氧和/或氮的雜原子(優選1或2個雜原子)的3至12員環。雜環基的非限制性實例包括但不限於環氧乙烷基、四氫呋喃基、二氫呋喃基、吡咯烷基、N-甲基吡咯烷基、二氫吡咯基、呱啶基、呱嗪基、吡唑烷基、4H-吡喃基、嗎啉基、硫代嗎啉基、四氫噻吩基等。所述雜環基任選地被一個或多個以下基團取代:氧代、羥基、胺基、硝基、鹵素、氰基、烷基、烯基、炔基、烷氧基、鹵代烷氧基、烷基胺基、二烷基胺基、鹵代烷基胺基、鹵代二烷基胺基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、環烷基、環烷基氧基、雜環基、雜環基氧基、雜環烷基、雜環烷基氧基、雜芳基、雜芳基氧基、芳基或芳基氧基。所述3-12員雜環烷基包括3-8員、3-6員、4-5員、4-6員、5-6員、4員、5員和6員雜環烷基等。“3-12員雜環烷基”和“3-6員雜環烷基”的實例包括但不限於氮雜環丁基、氧雜環丁基、硫雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基(包括四氫噻吩-2-基和四氫噻吩-3-基等)、四氫呋喃基(包括四氫呋喃-2-基等)、四氫吡喃基、呱啶基(包括1-呱啶基、2-呱啶基和3-呱啶基等)、呱嗪基(包括1-呱嗪基和2-呱嗪基等)、嗎啉基(包括3-嗎啉基和4-嗎啉基等)、二噁烷基、二噻烷基、異噁唑烷基、異噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氫噠嗪基、高呱嗪基、高呱啶基或二氧雜環庚烷基等。 The term "3-12 member heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 12 member ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Non-limiting examples of heterocyclic groups include, but are not limited to, oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc. The heterocyclic group is optionally substituted with one or more of the following groups: oxo, hydroxyl, amine, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2NH2 , -S(O) 2NH - alkyl, -S(O) 2N (alkyl) 2 The 3-12 membered heterocycloalkyl group includes 3-8 membered, 3-6 membered, 4-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups, etc. Examples of “3-12 membered heterocycloalkyl” and “3-6 membered heterocycloalkyl” include, but are not limited to, azacyclobutyl, oxacyclobutyl, thiacyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including The invention also includes but is not limited to 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydroxazinyl, homopiperazinyl, homopiperidinyl or dioxacycloheptanyl, etc.
術語“治療”意為將本發明所述化合物或製劑進行給藥以改善或消除疾病或與所述疾病相關的一個或多個症狀,且包括: (i) 抑制疾病或疾病狀態,即遏制其發展; (ii) 緩解疾病或疾病狀態,即使該疾病或疾病狀態消退。 The term "treatment" means administering the compounds or formulations of the present invention to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting a disease or disease state, i.e., curbing its development; (ii) relieving a disease or disease state, i.e., causing the disease or disease state to regress.
術語“預防”意為將本發明所述化合物或製劑進行給藥以預防疾病或與所述疾病相關的一個或多個症狀,且包括:預防疾病或疾病狀態在哺乳動物中出現,特別是當這類哺乳動物易患有該疾病狀態,但尚未被診斷為已患有該疾病狀態時。The term "prevention" means that the compounds or formulations of the present invention are administered to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
術語“治療或預防有效量”意指(i)治療特定疾病、病況或障礙,或(ii)減輕、改善或消除特定疾病、病況或障礙的一種或多種症狀,或(iii)預防或延遲本文中所述的特定疾病、病況或障礙的本發明化合物的用量。構成“治療或預防有效量”的本發明化合物的量取決於該化合物、疾病狀態及其嚴重性、給藥方式以及待被治療的哺乳動物的年齡而改變,但可例行性地由本領域技術人員根據其自身的知識及本發明內容而確定。The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present invention that (i) treats a specific disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays a specific disease, condition or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically or prophylactically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art based on his or her own knowledge and the content of the present invention.
本發明化合物的治療或預防劑量可根據例如以下而定:治療或預防的具體用途、給予化合物的方式、患者的健康和狀態,以及簽處方醫師的判斷。本發明化合物在藥用組成物中的比例或濃度可不固定,取決於多種因素,它們包括劑量、化學特性(例如疏水性)和給藥途徑。在某些實施方案中,劑量範圍為約0.001 mg/kg~約1000 mg/kg體重/日。劑量很可能取決於此類變數,如疾病或病症的種類和發展程度、具體患者的一般健康狀態、所選擇的化合物的相對生物學效力、賦形劑製劑及其給藥途徑。可透過由體外或動物模型試驗系統匯出的劑量-反應曲線外推,得到有效劑量。The therapeutic or preventive dose of the compounds of the present invention may be based on, for example, the specific use for treatment or prevention, the mode of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present invention in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. In certain embodiments, the dosage range is about 0.001 mg/kg to about 1000 mg/kg of body weight/day. The dosage is likely to depend on such variables as the type and degree of development of the disease or condition, the general health of the specific patient, the relative biological efficacy of the selected compound, the formulation and its route of administration. The effective dose can be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.
詞語"包括(comprise)"或"包含(comprise)"及其英文變體例如comprises或comprising 應理解為開放的、非排他性的意義,即“包括但不限於”。The word "comprise" or "comprises" and its English variants such as comprises or comprising should be construed in an open, non-exclusive sense, ie, "including but not limited to".
“藥物組成物”表示含有一種或多種本發明所述化合物、其異構物或其藥學上可接受的鹽,以及其他組分例如生理學/可藥用的載劑和賦形劑。藥物組成物的目的是促進對生物體的給藥,利於活性成分的吸收進而發揮生物活性。"Drug composition" means a composition containing one or more compounds of the present invention, their isomers or pharmaceutically acceptable salts thereof, and other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a drug composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thereby exert biological activity.
本發明的藥物組成物可透過將本發明的化合物與適宜的藥學上可接受的佐劑組合而製備,例如可配製成固態、半固態、液態或氣態製劑。The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable adjuvant, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation.
本發明的藥物組成物可以採用本領域眾所周知的方法製造。The pharmaceutical composition of the present invention can be produced by methods well known in the art.
本發明的化合物可以透過本領域技術人員所熟知的多種合成方法來製備,包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式,優選的實施方式包括但不限於本發明的實施例。The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.
本發明具體實施方式的化學反應是在合適的溶劑中完成的,所述的溶劑須適合於本發明的化學變化及其所需的試劑和物料。為了獲得本發明的化合物,有時需要本領域技術人員在已有實施方式的基礎上對合成步驟或者反應流程進行修改或選擇。The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.
本發明實施方式中所用原料或中間物可以透過市售獲得或透過現有技術的方法製備得到。The raw materials or intermediates used in the embodiments of the present invention can be obtained from the market or prepared by methods of the prior art.
本領域合成途徑規劃中的一個重要考量因素是為反應性官能基(如本發明中的胺基)選擇合適的保護基,例如,可參考Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc。An important consideration in planning synthetic routes in this field is the selection of an appropriate protecting group for a reactive functional group (such as an amine group in the present invention), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.
在一些實施方案中,本發明的部分化合物可以由有機合成領域技術人員參考以下途徑來製備: 其中, X 1、X 2、X 3、X 4、X 5、X 6、L、R 2、R 6、R 7和R 8如上式(I)化合物所述; Y選自鹵素、-OH、甲基磺醯基氧基、苯磺醯基氧基或對甲苯磺醯基氧基。 In some embodiments, some compounds of the present invention can be prepared by organic synthesis technicians by referring to the following methods: wherein X1 , X2 , X3 , X4 , X5 , X6 , L, R2 , R6 , R7 and R8 are as described above for the compound of formula (I); and Y is selected from halogen, -OH, methylsulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy.
在本申請的一些實施方案中,Y選自-Cl、-Br、-I、-OH、甲基磺醯基氧基或對甲苯磺醯基氧基。In some embodiments of the present application, Y is selected from -Cl, -Br, -I, -OH, methylsulfonyloxy or p-toluenesulfonyloxy.
在本申請的一些實施方案中,Y選自-Cl。In some embodiments of the present application, Y is selected from -Cl.
為清楚起見,進一步用實施例來闡述本發明,但是實施例並非限制本發明的範圍。本發明所使用的所有試劑是市售的,無需進一步純化即可使用。For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present invention. All reagents used in the present invention are commercially available and can be used without further purification.
具體實施方式Specific implementation methods
下面透過實施例對本發明進行詳細描述,但並不意味著對本發明任何不利限制。本文已經詳細地描述了本發明,其中也揭示了其具體實施例方式,對本領域的技術人員而言,在不脫離本發明精神和範圍的情況下針對本發明具體實施方式進行各種變化和改進將是顯而易見的。 製備例 1 The present invention is described in detail below through examples, but it does not mean any adverse limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Preparation Example 1
將化合物 A-1(3.2 g)溶於四氫呋喃(100 mL),氮氣保護下,-20℃下加入二異丙胺(4.01 g),再加入正丁基鋰(2.4 M於正己烷中,31.2 mL),攪拌半小時。升溫至0℃,攪拌30分鐘後逐滴加入1,2-二溴乙烷(10.64 g),轉移至室溫攪拌反應過夜。加入飽和氯化銨水溶液,矽藻土抽氣過濾,濾液以乙酸乙酯萃取,有機層依次用水洗、飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,管柱層析分離純化,得到740 mg化合物1-1。 Compound A-1 (3.2 g) was dissolved in tetrahydrofuran (100 mL). Under nitrogen protection, diisopropylamine (4.01 g) was added at -20°C, and then n-butyl lithium (2.4 M in n-hexane, 31.2 mL) was added, and stirred for half an hour. The temperature was raised to 0°C, and after stirring for 30 minutes, 1,2-dibromoethane (10.64 g) was added dropwise, and the mixture was transferred to room temperature and stirred overnight. A saturated aqueous ammonium chloride solution was added, and the solution was vacuum filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Vacuum filtered, concentrated, and purified by column chromatography to obtain 740 mg of compound 1-1.
MS (ESI,[M+H] +) m/z: 196.07。 MS (ESI, [M+H] + ) m/z: 196.07.
1H NMR (500 MHz, DMSO- d 6) δ 11.94 (s, 1H), 8.13 (d, J= 1.5 Hz, 1H), 1.83 (q, J= 4.0 Hz, 2H), 1.62 (q, J= 4.0 Hz, 2H)。 製備例 2 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.94 (s, 1H), 8.13 (d, J = 1.5 Hz, 1H), 1.83 (q, J = 4.0 Hz, 2H), 1.62 (q, J = 4.0 Hz, 2H). Preparation Example 2
將化合物 A-2(500 mg)溶於四氫呋喃(15 mL),氮氣保護下,-20℃下加入二異丙胺(0.63 g),再加入正丁基鋰(2.4 M於正己烷中,4.9 mL),攪拌半小時。升溫至0℃,攪拌30分鐘後逐滴加入1,2-二溴乙烷(1.67 g),轉移至室溫攪拌反應過夜。加入飽和氯化銨水溶液,以乙酸乙酯萃取,有機層依次用水洗、飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,所得粗產物加入石油醚製漿(30 mL)。抽氣過濾,得到0.4 g化合物2-1。 Compound A-2 (500 mg) was dissolved in tetrahydrofuran (15 mL). Under nitrogen protection, diisopropylamine (0.63 g) was added at -20°C, and then n-butyl lithium (2.4 M in n-hexane, 4.9 mL) was added, and stirred for half an hour. The temperature was raised to 0°C, and after stirring for 30 minutes, 1,2-dibromoethane (1.67 g) was added dropwise, and the mixture was transferred to room temperature and stirred for reaction overnight. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Vacuum filtration was performed, and the crude product was added to petroleum ether for slurry (30 mL). Vacuum filtration was performed to obtain 0.4 g of compound 2-1.
MS (ESI,[M+H] +) m/z: 195.07。 MS (ESI, [M+H] + ) m/z: 195.07.
1H NMR (500 MHz, DMSO- d 6) δ 11.19 (s, 1H), 7.92 (s, 1H), 6.95 (s, 1H), 1.75 (q, J= 3.9 Hz, 2H), 1.55 (q, J= 3.9 Hz, 2H)。 實施例 1 步驟一:中間物 1-2 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.19 (s, 1H), 7.92 (s, 1H), 6.95 (s, 1H), 1.75 (q, J = 3.9 Hz, 2H), 1.55 (q, J = 3.9 Hz, 2H). Example 1 Step 1: Preparation of intermediate 1-2
將中間物 1-1(680 mg)、 B-1(1.5 g)、碳酸鉀(1.4 g)和 N, N-二甲基二醯胺(10 mL)混合,80℃攪拌反應1小時。以乙酸乙酯萃取,有機相依次以水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,矽膠管柱層析純化,得到1.5 g中間物 1-2。 Intermediate 1-1 (680 mg), B-1 (1.5 g), potassium carbonate (1.4 g) and N , N -dimethyldiamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in sequence and dried over anhydrous sodium sulfate. The mixture was vacuum filtered, concentrated, and purified by silica gel column chromatography to obtain 1.5 g of intermediate 1-2 .
MS (ESI,[M+H]+) m/z: 550.15。MS (ESI, [M+H]+) m/z: 550.15.
1H NMR (500 MHz, DMSO- d 6) δ 8.24 (s, 1H), 8.16 (d, J= 1.4 Hz, 1H), 7.85 – 7.72 (m, 2H), 7.46 (d, J= 8.2 Hz, 2H), 5.40 (s, 2H), 5.01 (s, 2H), 3.63 – 3.50 (m, 2H), 1.96 - 1.94 (m, 2H), 1.76 - 1.73 (m, 2H), 0.82 (dd, J= 8.6, 7.4 Hz, 2H), -0.09 (s, 9H)。 步驟二:中間物 1-3 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.24 (s, 1H), 8.16 (d, J = 1.4 Hz, 1H), 7.85 – 7.72 (m, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.40 (s, 2H), 5.01 (s, 2H), 3.63 – 3.50 (m, 2H), 1.96 - 1.94 (m, 2H), 1.76 - 1.73 (m, 2H), 0.82 (dd, J = 8.6, 7.4 Hz, 2H), -0.09 (s, 9H). Step 2: Preparation of intermediate 1-3
將中間物 1-2(700 mg)、 C-1(494 mg)、碳酸銫(1.24 g)、四三苯基膦鈀(147 mg)、二氧六環(10 mL)和水(0.5 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。以乙酸乙酯萃取,有機相依次以水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,矽膠管柱層析純化,得到0.49 g中間物 1-3。 Intermediate 1-2 (700 mg), C-1 (494 mg), cesium carbonate (1.24 g), tetrakistriphenylphosphine palladium (147 mg), dioxane (10 mL) and water (0.5 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in turn and dried over anhydrous sodium sulfate. The mixture was vacuum filtered, concentrated, and purified by silica gel column chromatography to obtain 0.49 g of intermediate 1-3 .
MS (ESI,[M+H] +) m/z: 664.40。 MS (ESI, [M+H] + ) m/z: 664.40.
1H NMR (500 MHz, DMSO- d 6) δ 8.67 (s, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 7.76 (d, J= 7.9 Hz, 2H), 7.50 (d, J= 7.9 Hz, 2H), 5.38 (s, 2H), 5.04 (s, 2H), 3.85 (s, 3H), 3.56 (t, J= 8.1 Hz, 2H), 1.98 (q, J= 4.2 Hz, 2H), 1.82 – 1.69 (m, 3H), 1.03 (t, J= 3.6 Hz, 2H), 0.86 - 0.81 (m, 4H), -0.09 (s, 9H)。 步驟三:中間物 1-4 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.67 (s, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 5.38 (s, 2H), 5.04 (s, 2H), 3.85 (s, 3H), 3.56 (t, J = 8.1 Hz, 2H), 1.98 (q, J = 4.2 Hz, 2H), 1.82 – 1.69 (m, 3H), 1.03 (t, J = 3.6 Hz, 2H), 0.86 - 0.81 (m, 4H), -0.09 (s, 9H). Step 3: Preparation of intermediates 1-4
將中間物 1-3(400 mg)和四氫呋喃(5 mL)混合,依次加入三乙基矽烷(0.96 mL)、三氟乙酸(7.43 mL),室溫攪拌反應16小時。加入飽和碳酸氫鈉調節pH至中性,乙酸乙酯萃取,無水硫酸鈉乾燥。抽氣過濾,濃縮,矽膠管柱層析純化,得到0.13 g中間物 1-4。 Mix the intermediate 1-3 (400 mg) and tetrahydrofuran (5 mL), add triethylsilane (0.96 mL) and trifluoroacetic acid (7.43 mL) in sequence, and stir at room temperature for 16 hours. Add saturated sodium bicarbonate to adjust the pH to neutral, extract with ethyl acetate, and dry with anhydrous sodium sulfate. Filter under vacuum, concentrate, and purify by silica gel column chromatography to obtain 0.13 g of intermediate 1-4 .
MS (ESI,[M+H] +) m/z: 534.31。 MS (ESI, [M+H] + ) m/z: 534.31.
1H NMR (500 MHz, DMSO- d 6) δ 13.18 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 7.92 – 7.89 (m, 3H), 7.45 (d, J= 8.2 Hz, 2H), 5.00 (s, 2H), 3.85 (s, 3H), 1.99 - 1.97 (m, 2H), 1.76 - 1.74 (m, 2H), 1.73 – 1.70 (m, 1H), 1.04 - 1.02 (m, 2H), 0.86 - 0.83 (m, 2H)。 步驟四:化合物 1 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 13.18 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 7.92 – 7.89 (m, 3H), 7.45 (d, J = 8.2 Hz, 2H), 5.00 (s, 2H), 3.85 (s, 3H), 1.99 - 1.97 (m, 2H), 1.76 - 1.74 (m, 2H), 1.73 – 1.70 (m, 1H), 1.04 - 1.02 (m, 2H), 0.86 - 0.83 (m, 2H). Step 4: Preparation of compound 1
將中間物 1-4(110 mg)、碳酸銫(336 mg)、 N, N-二甲基甲醯胺(5 mL)混合,加入異丙基碘(140 mg),80℃攪拌反應16小時。以乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到0.031 g化合物 1。 Intermediate 1-4 (110 mg), cesium carbonate (336 mg), N , N -dimethylformamide (5 mL) were mixed, isopropyl iodide (140 mg) was added, and the mixture was stirred at 80°C for 16 hours. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was vacuum filtered and concentrated, and the crude product was purified by column chromatography to obtain 0.031 g of compound 1 .
MS (ESI,[M+H] +) m/z: 576.37。 MS (ESI, [M+H] + ) m/z: 576.37.
1H NMR (500 MHz, CDCl 3) δ 8.66 (s, 1H), 8.15 (s, 1H), 7.62 (d, J= 8.0 Hz, 2H), 7.48 (d, J= 8.1 Hz, 2H), 7.40 (d, J= 1.3 Hz, 1H), 5.11 (s, 2H), 4.53 (h, J= 6.7 Hz, 1H), 3.95 (s, 3H), 1.93 (q, J= 4.3 Hz, 2H), 1.78 - 1.72 (m, 3H), 1.44 (d, J= 6.7 Hz, 6H), 1.25 – 1.22 (m, 2H), 0.90 - 0.87 (m, 2H)。 實施例 2 步驟一:中間物 2-1 的製備 1 H NMR (500 MHz, CDCl 3 ) δ 8.66 (s, 1H), 8.15 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 1.3 Hz, 1H), 5.11 (s, 2H), 4.53 (h, J = 6.7 Hz, 1H), 3.95 (s, 3H), 1.93 (q, J = 4.3 Hz, 2H), 1.78 - 1.72 (m, 3H), 1.44 (d, J = 6.7 Hz, 6H), 1.25 – 1.22 (m, 2H), 0.90 - 0.87 (m, 2H). Embodiment 2 Step 1: Preparation of intermediate 2-1
將中間物 1-1(200 mg)、 B-2(309 mg)、碳酸鉀(424 mg)和N,N-二甲基甲醯胺(10 mL)混合,80℃攪拌反應1小時。乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到0.36 g中間物 2-1。 Intermediate 1-1 (200 mg), B-2 (309 mg), potassium carbonate (424 mg) and N,N-dimethylformamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.36 g of intermediate 2-1 .
MS (ESI,[M+H] +) m/z: 434.25。 MS (ESI, [M+H] + ) m/z: 434.25.
1H NMR (500 MHz, DMSO- d 6) δ 8.25 (s, 1H), 7.56 (d, J= 8.5 Hz, 2H), 7.50 (d, J= 8.5 Hz, 2H), 6.75 (s, 1H), 5.03 (s, 2H), 2.41 – 2.31 (m, 3H), 1.96 (q, J= 4.1 Hz, 2H), 1.75 (q, J= 4.0 Hz, 2H)。 步驟二:化合物 2 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.25 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 5.03 (s, 2H), 2.41 – 2.31 (m, 3H), 1.96 (q, J = 4.1 Hz, 2H), 1.75 (q, J = 4.0 Hz, 2H). Step 2: Preparation of compound 2
將中間物 2-1(200 mg)、化合物C- 1(179 mg)、二氯二叔丁基-(4-二甲基胺基苯基)磷鈀(32.6 mg)、磷酸三鉀(294 mg)、二氧六環(10 mL)和水(0.1 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。抽氣過濾,濃縮,矽膠管柱層析純化,得到0.064 g化合物 2。 Intermediate 2-1 (200 mg), compound C- 1 (179 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine (32.6 mg), tripotassium phosphate (294 mg), dioxane (10 mL) and water (0.1 mL) were mixed, heated to 90°C under nitrogen atmosphere, stirred and reacted for 2 hours. Vacuum filtration, concentration, and silica gel column chromatography were performed to obtain 0.064 g of compound 2 .
MS (ESI,[M+H] +) m/z: 548.23。 MS (ESI, [M+H] + ) m/z: 548.23.
1H NMR (500 MHz, DMSO- d 6) δ 8.66 (s, 1H), 8.47 (s, 1H), 7.60 – 7.47 (m, 4H), 6.75 (s, 1H), 5.06 (s, 2H), 3.84 (s, 3H), 2.32 (s, 3H), 1.99 (q, J= 4.0 Hz, 2H), 1.76 (q, J= 3.9 Hz, 2H), 1.72 - 1.69 (m, 1H), 1.04 - 1.01 (m, 2H), 0.85 – 0.83 (m, 2H)。 實施例 3 步驟一:中間物 3-1 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.66 (s, 1H), 8.47 (s, 1H), 7.60 – 7.47 (m, 4H), 6.75 (s, 1H), 5.06 (s, 2H), 3.84 (s, 3H), 2.32 (s, 3H), 1.99 (q, J = 4.0 Hz, 2H), 1.76 (q, J = 3.9 Hz, 2H), 1.72 - 1.69 (m, 1H), 1.04 - 1.01 (m, 2H), 0.85 – 0.83 (m, 2H). Example 3 Step 1: Preparation of intermediate 3-1
將中間物 1-1(100 mg)、 B-3(154 mg)、碳酸鉀(212 mg)和 N, N-二甲基甲醯胺(5 mL)混合,80℃攪拌反應1小時。乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到0.15 g化合物 3-1。 Intermediate 1-1 (100 mg), B-3 (154 mg), potassium carbonate (212 mg) and N , N -dimethylformamide (5 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.15 g of compound 3-1 .
MS (ESI,[M+H] +) m/z: 434.25。 MS (ESI, [M+H] + ) m/z: 434.25.
1H NMR (500 MHz, DMSO- d 6) δ8.25 (s, 1H), 7.93 (s, 1H), 7.71 (d, J= 8.3 Hz, 2H), 7.46 (d, J= 8.3 Hz, 2H), 5.02 (s, 2H), 3.77 (s, 3H), 1.96 (dd, J= 8.2, 4.1 Hz, 2H), 1.75 (dd, J= 8.1, 3.9 Hz, 2H)。 步驟二:化合物 3 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.25 (s, 1H), 7.93 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 5.02 (s, 2H), 3.77 (s, 3H), 1.96 (dd, J = 8.2, 4.1 Hz, 2H), 1.75 (dd, J = 8.1, 3.9 Hz, 2H). Step 2: Preparation of compound 3
將中間物 3-1(150 mg)、C-2 (150 mg)、三(二亞苄基丙酮)二鈀(33 mg)、2-二環己基膦-2',4',6'-三異丙基聯苯(31 mg)、磷酸三鉀(220 mg)、二氧六環(7 mL)和水(2 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。抽氣過濾,濃縮,矽膠管柱層析純化,得到0.06 g化合物 3。 Intermediate 3-1 (150 mg), C-2 (150 mg), tris(dibenzylideneacetone)dipalladium (33 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31 mg), tripotassium phosphate (220 mg), dioxane (7 mL) and water (2 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was vacuum filtered, concentrated and purified by silica gel column chromatography to obtain 0.06 g of compound 3 .
MS (ESI,[M+H] +) m/z: 519.21。 MS (ESI, [M+H] + ) m/z: 519.21.
1H NMR (500 MHz, DMSO- d 6) δ 8.62 (d, J= 3.4 Hz, 1H), 8.48 (s, 1H), 7.98 (d, J= 7.6 Hz, 1H), 7.92 (s, 1H), 7.70 (d, J= 8.0 Hz, 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.38 – 7.27 (m, 1H), 5.08 (s, 2H), 3.76 (s, 3H), 3.63 (dt, J= 13.2, 6.6 Hz, 1H), 1.99 (d, J= 3.8 Hz, 2H), 1.77 (d, J= 3.8 Hz, 2H), 1.13 (d, J= 6.7 Hz, 6H)。 實施例 4 步驟一:化合物 4 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.62 (d, J = 3.4 Hz, 1H), 8.48 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.38 – 7.27 (m, 1H), 5.08 (s, 2H), 3.76 (s, 3H), 3.63 (dt, J = 13.2, 6.6 Hz, 1H), 1.99 (d, J = 3.8 Hz, 2H), 1.77 (d, J = 3.8 Hz, 2H), 1.13 (d, J = 6.7 Hz, 6H). Example 4 Step 1: Preparation of compound 4
將中間物 2-1(130 mg)、 C-2(99 mg)、三(二亞苄基丙酮)二鈀(27.4 mg)、2-二環己基膦-2',4',6'-三異丙基聯苯(28.5 mg)、磷酸三鉀(191 mg)、二氧六環(7 mL)和水(0.5 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。抽氣過濾,濃縮,矽膠管柱層析純化,得到0.02 g化合物 4。 Intermediate 2-1 (130 mg), C-2 (99 mg), tris(dibenzylideneacetone)dipalladium (27.4 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (28.5 mg), tripotassium phosphate (191 mg), dioxane (7 mL) and water (0.5 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was vacuum filtered, concentrated and purified by silica gel column chromatography to obtain 0.02 g of compound 4 .
MS (ESI,[M+H] +) m/z: 519.30。 MS (ESI, [M+H] + ) m/z: 519.30.
1H NMR (500 MHz, DMSO- d 6) δ 8.62 (dd, J= 4.7, 1.8 Hz, 1H), 8.48 (s, 1H), 7.98 (dd, J= 7.8, 1.9 Hz, 1H), 7.56 (d, J= 8.3 Hz, 2H), 7.51 (d, J= 8.3 Hz, 2H), 7.32 (dd, J= 7.8, 4.7 Hz, 1H), 6.74 (s, 1H), 5.10 (s, 2H), 3.62 (p, J= 6.7 Hz, 1H), 2.32 (s, 3H), 1.99 (q, J= 4.1 Hz, 2H), 1.78 (q, J= 4.0 Hz, 2H), 1.12 (d, J= 6.6 Hz, 6H)。 實施例 5 步驟一:中間物 5-1 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.62 (dd, J = 4.7, 1.8 Hz, 1H), 8.48 (s, 1H), 7.98 (dd, J = 7.8, 1.9 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.32 (dd, J = 7.8, 4.7 Hz, 1H), 6.74 (s, 1H), 5.10 (s, 2H), 3.62 (p, J = 6.7 Hz, 1H), 2.32 (s, 3H), 1.99 (q, J = 4.1 Hz, 2H), 1.78 (q, J = 4.0 Hz, 2H), 1.12 (d, J = 6.6 Hz, 6H). Example 5 Step 1: Preparation of intermediate 5-1
將中間物 1-1(100 mg)、 B-4(155 mg)、碳酸鉀(141 mg)和 N, N-二甲基甲醯胺(2 mL)混合,室溫反應過夜。加入水和乙酸乙酯,分取水相,以乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到185 mg中間物 5-1。 Intermediate 1-1 (100 mg), B-4 (155 mg), potassium carbonate (141 mg) and N , N -dimethylformamide (2 mL) were mixed and reacted at room temperature overnight. Water and ethyl acetate were added, the aqueous phase was separated, extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. Vacuum filtration was performed, and the crude product was concentrated and purified by column chromatography to obtain 185 mg of intermediate 5-1 .
MS (ESI,[M+H] +) m/z: 435.27。 MS (ESI, [M+H] + ) m/z: 435.27.
1HNMR (500 MHz, DMSO-d 6): δ8.66 (d, J=1.5Hz, 1H), 8.24 (s, 1H), 8.06 (d, J=8.0Hz, 1H), 7.99 (s, 1H), 7.88 (dd, J 1 =8.3Hz, J 2 =2.3Hz, 1H), 5.04 (s, 2H), 4.07 (s, 3H), 1.96-1.94 (m, 2H), 1.76-1.74 (m, 2H)。 步驟二:化合物 5 的製備 1 HNMR (500 MHz, DMSO-d 6 ): δ 8.66 (d, J =1.5Hz, 1H), 8.24 (s, 1H), 8.06 (d, J =8.0Hz, 1H), 7.99 (s, 1H), 7.88 (dd, J 1 =8.3Hz, J 2 =2.3Hz, 1H), 5.04 (s, 2H), 4.07 (s, 3H), 1.96-1.94 (m, 2H), 1.76-1.74 (m, 2H). Step 2: Preparation of Compound 5
將中間物 5-1(150 mg)、C-3 (113 mg)、三(二亞苄基丙酮)二鈀(32 mg)、2-二環己基膦-2',4',6'-三異丙基聯苯(33 mg)、磷酸三鉀(220 mg)、二氧六環(5 mL)和水(1 mL)混合,氮氣氛圍下加熱至90℃攪拌反應1小時。抽氣過濾,濃縮,矽膠管柱層析純化,得到38 mg化合物 5。 Intermediate 5-1 (150 mg), C-3 (113 mg), tris(dibenzylideneacetone)dipalladium (32 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (33 mg), tripotassium phosphate (220 mg), dioxane (5 mL) and water (1 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 1 hour. The mixture was vacuum filtered, concentrated and purified by silica gel column chromatography to obtain 38 mg of compound 5 .
MS (ESI,[M+H] +) m/z: 519.33。 MS (ESI, [M+H] + ) m/z: 519.33.
1H NMR (500 MHz, DMSO-d 6): δ 8.66 (s, 1H), 8.45 (s, 1H), 8.06 (d, J=8.5Hz, 1H), 7.98 (s, 1H), 7.87 (d, J=7.5Hz, 1H), 7.53 (d, J=7.5Hz, 1H), 7.43-7.40 (m, 2H), 7.27 (t, J=6.5Hz, 1H), 5.10 (s, 2H), 4.06 (s, 3H), 3.46-3.41 (m, 1H), 1.97 (d, J=3.5Hz, 2H), 1.76 (d, J=3.5Hz, 2H), 1.08 (d, J=7.0Hz, 6H)。 實施例 6 步驟一:中間物 6-1 的製備 1 H NMR (500 MHz, DMSO-d 6 ): δ 8.66 (s, 1H), 8.45 (s, 1H), 8.06 (d, J =8.5 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J =7.5 Hz, 1H), 7.53 (d, J =7.5 Hz, 1H), 7.43-7.40 (m, 2H), 7.27 (t, J =6.5 Hz, 1H), 5.10 (s, 2H), 4.06 (s, 3H), 3.46-3.41 (m, 1H), 1.97 (d, J =3.5 Hz, 2H), 1.76 (d, J =3.5 Hz, 2H), 1.08 (d, J =7.0 Hz, 6H). Embodiment 6 Step 1: Preparation of intermediate 6-1
將中間物 2-1(350 mg)、中間物 B-5(599 mg)、碳酸鉀(746 mg)和 N, N-二甲基甲醯胺(10 mL)混合,80℃攪拌反應1小時。乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到0.46 g中間物 6-1。 Intermediate 2-1 (350 mg), intermediate B-5 (599 mg), potassium carbonate (746 mg) and N , N -dimethylformamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.46 g of intermediate 6-1 .
MS (ESI,[M+H] +) m/z: 461.26。 MS (ESI, [M+H] + ) m/z: 461.26.
1H NMR (500 MHz, DMSO- d 6) δ 8.16 (d, J= 1.4 Hz, 1H), 8.02 (s, 1H), 7.56 (d, J= 8.3 Hz, 2H), 7.47 (dd, J= 8.3, 1.9 Hz, 2H), 7.35 (s, 1H), 5.09 (s, 2H), 4.49 – 4.43 (m, 1H), 1.89 (q, J= 4.0 Hz, 2H), 1.70 (q, J= 3.9 Hz, 2H), 1.39 (d, J= 6.7 Hz, 6H)。 步驟二:化合物 6 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.16 (d, J = 1.4 Hz, 1H), 8.02 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.47 (dd, J = 8.3, 1.9 Hz, 2H), 7.35 (s, 1H), 5.09 (s, 2H), 4.49 – 4.43 (m, 1H), 1.89 (q, J = 4.0 Hz, 2H), 1.70 (q, J = 3.9 Hz, 2H), 1.39 (d, J = 6.7 Hz, 6H). Step 2: Preparation of compound 6
將中間物 6-1(150 mg)、C-1 (126 mg)、三(二亞苄基丙酮)二鈀(29.8 mg)、2-二環己基膦-2',4',6'-三異丙基聯苯(31.0 mg)、磷酸三鉀(138 mg)、二氧六環(7 mL)和水(0.7 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。以乙酸乙酯萃取,有機層依次用水洗、飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,所得粗產物以管柱層析純化得到65 mg化合物 6。 Intermediate 6-1 (150 mg), C-1 (126 mg), tris(dibenzylideneacetone)dipalladium (29.8 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31.0 mg), tripotassium phosphate (138 mg), dioxane (7 mL) and water (0.7 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution in turn and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under vacuum, and the crude product was purified by column chromatography to obtain 65 mg of compound 6 .
MS (ESI,[M+H] +) m/z: 575.29。 MS (ESI, [M+H] + ) m/z: 575.29.
1H NMR (500 MHz, DMSO- d 6) δ 8.62 (s, 1H), 8.29 (s, 1H), 8.23 – 8.12 (m, 1H), 7.59 – 7.54 (m, 2H), 7.49 (d, J= 7.9 Hz, 2H), 7.33 (s, 1H), 5.09 (s, 2H), 4.43 (p, J= 6.7 Hz, 1H), 3.77 (s, 3H), 1.92 (q, J= 4.0 Hz, 2H), 1.72 (q, J= 3.8 Hz, 3H), 1.39 (d, J= 6.5 Hz, 6H), 0.99 (t, J= 3.6 Hz, 2H), 0.85 – 0.75 (m, 2H)。 實施例 7 步驟一:中間物 7-1 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.62 (s, 1H), 8.29 (s, 1H), 8.23 – 8.12 (m, 1H), 7.59 – 7.54 (m, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.33 (s, 1H), 5.09 (s, 2H), 4.43 (p, J = 6.7 Hz, 1H), 3.77 (s, 3H), 1.92 (q, J = 4.0 Hz, 2H), 1.72 (q, J = 3.8 Hz, 3H), 1.39 (d, J = 6.5 Hz, 6H), 0.99 (t, J = 3.6 Hz, 2H), 0.85 – 0.75 (m, 2H). Example 7 Step 1: Preparation of intermediate 7-1
將中間物 1-1(200 mg)、 B-6(480 mg)、碳酸鉀(424 mg)和 N, N-二甲基甲醯胺(5 mL)混合,80℃攪拌反應1小時。乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到0.42 g中間物7-1。 Intermediate 1-1 (200 mg), B-6 (480 mg), potassium carbonate (424 mg) and N , N -dimethylformamide (5 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered under vacuum, concentrated, and the crude product was purified by column chromatography to obtain 0.42 g of intermediate 7-1.
MS (ESI,[M+H]+) m/z: 476.26。MS (ESI, [M+H]+) m/z: 476.26.
1HNMR (500 MHz, DMSO- d 6) δ。 1 HNMR (500 MHz, DMSO- d 6 ) δ .
1HNMR (500 MHz,DMSO-d 6) δ 8.23 (s, 1H), 8.17 (d, J= 0.9 Hz, 1H), 7.56 – 7.51 (m, 4H), 5.75 (q, J= 7.2 Hz, 1H), 4.47 (dt, J= 13.3, 6.7 Hz, 1H), 1.94-1.93 (m, 5H), 1.74 – 1.70 (m, 2H), 1.40 (d, J= 6.6 Hz, 6H)。 步驟二:化合物 7 的製備 1HNMR (500 MHz,DMSO-d 6 ) δ 8.23 (s, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.56 – 7.51 (m, 4H), 5.75 (q, J = 7.2 Hz, 1H), 4.47 (dt, J = 13.3, 6.7 Hz, 1H), 1.94-1.93 (m, 5H), 1.74 – 1.70 (m, 2H), 1.40 (d, J = 6.6 Hz, 6H). Step 2: Preparation of compound 7
將中間物 7-1(370 mg)、 C-1(800 mg) 、二氯二叔丁基-(4-二甲基胺基苯基)膦鈀(II)(100 mg)、磷酸鉀(400 mg)、二氧六環(15 mL)和水(3 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。抽氣過濾,濃縮,矽膠管柱層析純化,得到0.28g化合物 7。 Intermediate 7-1 (370 mg), C-1 (800 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (100 mg), potassium phosphate (400 mg), dioxane (15 mL) and water (3 mL) were mixed, heated to 90°C under nitrogen atmosphere and stirred for 2 hours. Vacuum filtration, concentration, and silica gel column chromatography were performed to obtain 0.28 g of compound 7 .
MS (ESI,[M+H] +) m/z: 590.15。 MS (ESI, [M+H] + ) m/z: 590.15.
1H NMR (500 MHz, DMSO- d 6) δ8.66 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.54 (q, J= 8.5 Hz, 4H), 5.80 (t, J= 7.2 Hz, 1H), 4.44 (dt, J= 13.3, 6.6 Hz, 1H), 3.84 (s, 3H), 1.96 (dd, J= 14.2, 5.7 Hz, 5H), 1.81 – 1.64 (m, 3H), 1.39 (d, J= 6.6 Hz, 6H), 1.25 (t, J= 5.8 Hz, 2H), 1.02 (d, J= 4.3 Hz, 2H)。 實施例 8 步驟一:中間物 8-1 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.66 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.54 (q, J = 8.5 Hz, 4H), 5.80 (t, J = 7.2 Hz, 1H), 4.44 (dt, J = 13.3, 6.6 Hz, 1H), 3.84 (s, 3H), 1.96 (dd, J = 14.2, 5.7 Hz, 5H), 1.81 – 1.64 (m, 3H), 1.39 (d, J = 6.6 Hz, 6H), 1.25 (t, J = 5.8 Hz, 2H), 1.02 (d, J = 4.3 Hz, 2H). Embodiment 8 Step 1: Preparation of intermediate 8-1
將中間物 1-1(100 mg)、 B-7(171 mg)、碳酸鉀(141 mg)和 N, N-二甲基甲醯胺(2 mL)混合,室溫反應2小時。加入水和乙酸乙酯,分取水相,以乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到155 mg中間物 8-1。 Intermediate 1-1 (100 mg), B-7 (171 mg), potassium carbonate (141 mg) and N , N -dimethylformamide (2 mL) were mixed and reacted at room temperature for 2 hours. Water and ethyl acetate were added, the aqueous phase was separated, extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. Vacuum filtration was performed, and the crude product was concentrated and purified by column chromatography to obtain 155 mg of intermediate 8-1 .
MS (ESI,[M+H] +) m/z: 463.25。 MS (ESI, [M+H] + ) m/z: 463.25.
1HNMR (500 MHz, DMSO-d 6) δ8.85 (d, J=2.0Hz, 1H), 8.24-8.23 (m, 2H), 8.03 (d, J=8.5Hz, 1H), 7.90 (dd, J1=8.3Hz, J2=2.3Hz, 1H), 5.75-5.69 (m, 1H), 5.05 (s, 2H), 1.96-1.94 (m, 2H), 1.76-1.74 (m, 2H), 1.44 (d, J=6.5Hz, 6H)。 步驟二:化合物 8 的製備 1 HNMR (500 MHz, DMSO-d 6 ) δ 8.85 (d, J=2.0Hz, 1H), 8.24-8.23 (m, 2H), 8.03 (d, J =8.5Hz, 1H), 7.90 (dd, J1 =8.3Hz, J2 =2.3Hz, 1H), 5.75-5.69 (m, 1H), 5.05 (s, 2H), 1.96-1.94 (m, 2H), 1.76-1.74 (m, 2H), 1.44 (d, J =6.5Hz, 6H). Step 2: Preparation of Compound 8
將中間物 8-1(150 mg)、(2-異丙基吡啶-3-基)硼酸(107 mg)、三(二亞苄基丙酮)二鈀(30 mg)、2-二環己基膦-2',4',6'-三異丙基聯苯(31 mg)、磷酸三鉀(206 mg)、二氧六環(5 mL)和水(1 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。抽氣過濾,濃縮,矽膠管柱層析純化,得到73 mg化合物 8。 Intermediate 8-1 (150 mg), (2-isopropylpyridin-3-yl)boronic acid (107 mg), tris(dibenzylideneacetone)dipalladium (30 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31 mg), tripotassium phosphate (206 mg), dioxane (5 mL) and water (1 mL) were mixed and heated to 90°C under nitrogen atmosphere and stirred for 2 hours. The mixture was vacuum filtered, concentrated and purified by silica gel column chromatography to obtain 73 mg of compound 8 .
MS (ESI,[M+H] +) m/z: 548.25。 MS (ESI, [M+H] + ) m/z: 548.25.
1H NMR (500 MHz, DMSO-d 6): δ 8.67 (d, J=1.5Hz, 1H), 8.62 (dd, J 1 =4.8Hz, J 2 =1.8Hz, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.04 (d, J=8.5Hz, 1H), 7.98 (dd, J 1 =8.3Hz, J 2 =1.8Hz, 1H), 7.90 (dd, J 1 =8.3Hz, J 2 =2.3Hz, 1H), 7.33 (dd, J 1 =7.5Hz, J 2 =2.3Hz, 1H), 5.75-5.70 (m, 1H), 5.12 (s, 2H), 3.63-3.57 (m, 1H), 2.00-1.98 (m, 2H), 1.80-1.77 (m, 2H), 1.44 (d, J=6.5Hz, 6H), 1.10 (d, J=7.0Hz, 6H)。 實施例 9 步驟一:中間物 9-1 的製備 1 H NMR (500 MHz, DMSO-d 6 ): δ 8.67 (d, J =1.5 Hz, 1H), 8.62 (dd, J 1 =4.8 Hz, J 2 =1.8 Hz, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.04 (d, J =8.5 Hz, 1H), 7.98 (dd, J 1 =8.3 Hz, J 2 =1.8 Hz, 1H), 7.90 (dd, J 1 =8.3 Hz, J 2 =2.3 Hz, 1H), 7.33 (dd, J 1 =7.5 Hz, J 2 =2.3 Hz, 1H), 5.75-5.70 (m, 1H), 5.12 (s, 2H), 3.63-3.57 (m, 1H), 2.00-1.98 (m, 2H), 1.80-1.77 (m, 2H), 1.44 (d, J =6.5Hz, 6H), 1.10 (d, J =7.0Hz, 6H). Example 9 Step 1: Preparation of intermediate 9-1
將中間物 1-1(120 mg)、B-8 (225 mg)、碳酸鉀(265 mg)和 N, N-二甲基甲醯胺(3 mL)混合,室溫攪拌反應1小時。乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到0.22 g中間物 9-1。 Intermediate 1-1 (120 mg), B-8 (225 mg), potassium carbonate (265 mg) and N , N -dimethylformamide (3 mL) were mixed and stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.22 g of intermediate 9-1 .
MS (ESI,[M+H] +) m/z: 480.26。 MS (ESI, [M+H] + ) m/z: 480.26.
1H NMR (500 MHz, DMSO- d 6) δ8.25 (s, 1H), 8.24 (s, 1H), 7.54 (t, J= 7.7 Hz, 1H), 7.38 (d, J= 10.7 Hz, 1H), 7.29 (d, J= 9.4 Hz, 1H), 5.05 (s, 2H), 4.15 (dt, J= 13.2, 6.5 Hz, 1H), 1.96 (dd, J= 8.2, 4.1 Hz, 2H), 1.76 (dd, J= 8.1, 3.9 Hz, 2H), 1.35 (d, J= 6.6 Hz, 6H)。 步驟二:化合物 9 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.25 (s, 1H), 8.24 (s, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 10.7 Hz, 1H), 7.29 (d, J = 9.4 Hz, 1H), 5.05 (s, 2H), 4.15 (dt, J = 13.2, 6.5 Hz, 1H), 1.96 (dd, J = 8.2, 4.1 Hz, 2H), 1.76 (dd, J = 8.1, 3.9 Hz, 2H), 1.35 (d, J = 6.6 Hz, 6H). Step 2: Preparation of compound 9
將中間物 9-1(180 mg)、C-1 (500 mg)、4-三苯基膦鈀(50 mg)、碳酸銫(320 mg)、二氧六環(7 mL)和水(2 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。抽氣過濾,濃縮,矽膠管柱層析純化,得到0.11g化合物 9。 Intermediate 9-1 (180 mg), C-1 (500 mg), 4-triphenylphosphine palladium (50 mg), cesium carbonate (320 mg), dioxane (7 mL) and water (2 mL) were mixed, heated to 90°C under nitrogen atmosphere, stirred and reacted for 2 hours. Vacuum filtration, concentration, and silica gel column chromatography were performed to purify the product to obtain 0.11 g of compound 9 .
MS (ESI,[M+H] +) m/z: 594.22。 MS (ESI, [M+H] + ) m/z: 594.22.
1H NMR (500 MHz, DMSO- d 6) δ8.66 (s, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 7.52 (t, J= 7.7 Hz, 1H), 7.39 (d, J= 10.3 Hz, 1H), 7.30 (d, J= 7.9 Hz, 1H), 5.07 (s, 2H), 4.11 (dt, J= 13.2, 6.5 Hz, 1H), 3.83 (s, 3H), 1.99 (dd, J= 8.0, 4.0 Hz, 2H), 1.77 (dd, J= 7.9, 3.8 Hz, 2H), 1.72 (td, J= 8.0, 4.1 Hz, 1H), 1.34 (d, J= 6.6 Hz, 6H), 1.10 – 0.96 (m, 2H), 0.86 – 0.80 (m, 2H)。 實施例 10 步驟一:中間物 10-1 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.66 (s, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 10.3 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 5.07 (s, 2H), 4.11 (dt, J = 13.2, 6.5 Hz, 1H), 3.83 (s, 3H), 1.99 (dd, J = 8.0, 4.0 Hz, 2H), 1.77 (dd, J = 7.9, 3.8 Hz, 2H), 1.72 (td, J = 8.0, 4.1 Hz, 1H), 1.34 (d, J = 6.6 Hz, 6H), 1.10 – 0.96 (m, 2H), 0.86 – 0.80 (m, 2H). Example 10 Step 1: Preparation of intermediate 10-1
將中間物 1-1(200 mg)、B-5 (371 mg)、碳酸鉀(47.7 mg)、二氧六環(424 mg)和 N,N-二甲基乙醯胺(10 mL)混合,氮氣氛圍下加熱至80℃攪拌反應1小時。以乙酸乙酯萃取,有機相依次以水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,矽膠管柱層析純化,得到371 mg中間物10-1。 Intermediate 1-1 (200 mg), B-5 (371 mg), potassium carbonate (47.7 mg), dioxane (424 mg) and N,N -dimethylacetamide (10 mL) were mixed and heated to 80°C under nitrogen atmosphere and stirred for 1 hour. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in sequence and dried over anhydrous sodium sulfate. The mixture was vacuum filtered, concentrated, and purified by silica gel column chromatography to obtain 371 mg of intermediate 10-1.
MS (ESI,[M+H]+) m/z: 462.27。MS (ESI, [M+H]+) m/z: 462.27.
1H NMR (500 MHz, DMSO- d 6 ) δ 8.24 (s, 1H), 8.16 (d, J= 0.8 Hz, 1H), 7.55 (d, J= 8.2 Hz, 2H), 7.46 (d, J= 8.2 Hz, 2H), 5.02 (s, 2H), 4.46 (hept, J= 6.5 Hz, 1H), 1.96 (dd, J= 8.2, 4.1 Hz, 2H), 1.75 (dd, J= 8.1, 3.9 Hz, 2H), 1.39 (d, J= 6.6 Hz, 6H)。 步驟二:化合物 10 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.24 (s, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.02 (s, 2H), 4.46 (hept, J = 6.5 Hz, 1H), 1.96 (dd, J = 8.2, 4.1 Hz, 2H), 1.75 (dd, J = 8.1, 3.9 Hz, 2H), 1.39 (d, J = 6.6 Hz, 6H). Step 2: Preparation of compound 10
將中間物 10-1(100 mg)、C-4 (108 mg)、磷酸鉀(69 mg)、二氯二叔丁基-(4-二甲基胺基苯基)膦鈀(II)(15 mg)和二氧六環(10 mL)、水(0.5 mL)混合,氮氣氛圍下加熱至100℃攪拌反應4 h。以乙酸乙酯萃取,有機相依次以水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,矽膠管柱層析純化,得到25 mg化合物 10。 Intermediate 10-1 (100 mg), C-4 (108 mg), potassium phosphate (69 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (15 mg), dioxane (10 mL), and water (0.5 mL) were mixed, heated to 100°C under nitrogen atmosphere, stirred and reacted for 4 h. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was vacuum filtered, concentrated, and purified by silica gel column chromatography to obtain 25 mg of compound 10 .
MS (ESI,[M+H] +) m/z: 550.23。 MS (ESI, [M+H] + ) m/z: 550.23.
1H NMR (500 MHz, DMSO- d 6 ) δ 8.46 (s, 1H), 8.15 (s, 1H), 7.55 (d, J= 8.2 Hz, 2H), 7.46 (d, J= 8.2 Hz, 2H), 7.36 (s, 1H), 5.34 – 5.24 (m, 1H), 5.09 (s, 2H), 4.47 – 4.38 (m, 1H), 2.12 (s, 3H), 1.98 (dd, J= 8.0, 4.0 Hz, 2H), 1.78 (dd, J= 7.9, 3.8 Hz, 2H), 1.38 (d, J = 6.6 Hz, 6H), 1.29 (d, J= 6.6 Hz, 6H)。 實施例 11 步驟一:中間物 11-1 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.46 (s, 1H), 8.15 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.36 (s, 1H), 5.34 – 5.24 (m, 1H), 5.09 (s, 2H), 4.47 – 4.38 (m, 1H), 2.12 (s, 3H), 1.98 (dd, J = 8.0, 4.0 Hz, 2H), 1.78 (dd, J = 7.9, 3.8 Hz, 2H), 1.38 (d, J = 6.6 Hz, 6H), 1.29 (d, J = 6.6 Hz, 6H). Example 11 Step 1: Preparation of intermediate 11-1
將中間物 3-1(250 mg)、 B-5(400 mg)、碳酸鉀(600 mg)和 N, N-二甲基甲醯胺(6 mL)混合,室溫攪拌反應2小時。乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到0.44 g中間物 11-1。 Intermediate 3-1 (250 mg), B-5 (400 mg), potassium carbonate (600 mg) and N , N -dimethylformamide (6 mL) were mixed and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 0.44 g of intermediate 11-1 .
MS (ESI,[M+H] +) m/z: 464.18。 MS (ESI, [M+H] + ) m/z: 464.18.
1H NMR (500 MHz, DMSO- d 6) δ8.53 (s, 1H), 8.17 (s, 1H), 7.56 (d, J= 8.2 Hz, 2H), 7.43 (d, J= 8.3 Hz, 2H), 4.95 (s, 2H), 4.47 (dt, J= 13.3, 6.6 Hz, 1H), 1.43 (s, 6H), 1.40 (d, J= 6.6 Hz, 6H)。 步驟二:化合物 11 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.53 (s, 1H), 8.17 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 4.95 (s, 2H), 4.47 (dt, J = 13.3, 6.6 Hz, 1H), 1.43 (s, 6H), 1.40 (d, J = 6.6 Hz, 6H). Step 2: Preparation of compound 11
將中間物 11-1(220 mg)、 C-1(200 mg)、四(三苯基膦)鈀(50 mg)、碳酸銫(420 mg)、二氧六環(5 mL)和水(1 mL)混合,氮氣氛圍下加熱至90℃攪拌反應2小時。抽氣過濾,濃縮,矽膠管柱層析純化,得到0.06g化合物 11。 Intermediate 11-1 (220 mg), C-1 (200 mg), tetrakis(triphenylphosphine)palladium (50 mg), cesium carbonate (420 mg), dioxane (5 mL) and water (1 mL) were mixed, heated to 90°C under nitrogen atmosphere, stirred and reacted for 2 hours. Vacuum filtration, concentration and silica gel column chromatography were performed to obtain 0.06 g of compound 11 .
MS (ESI,[M+H] +) m/z: 578.31。 MS (ESI, [M+H] + ) m/z: 578.31.
1H NMR (500 MHz, DMSO- d 6) δ8.75 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 7.53 (d, J= 8.2 Hz, 2H), 7.43 (d, J= 8.2 Hz, 2H), 4.98 (s, 2H), 4.44 (dt, J= 13.3, 6.6 Hz, 1H), 3.84 (s, 3H), 1.77 – 1.68 (m, 1H), 1.48 (s, 6H), 1.39 (d, J= 6.6 Hz, 6H), 1.04 – 0.98 (m, 2H), 0.81 (dt, J= 11.5, 3.3 Hz, 2H)。 實施例 12 步驟一:中間物 12-2 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.75 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 4.98 (s, 2H), 4.44 (dt, J = 13.3, 6.6 Hz, 1H), 3.84 (s, 3H), 1.77 – 1.68 (m, 1H), 1.48 (s, 6H), 1.39 (d, J = 6.6 Hz, 6H), 1.04 – 0.98 (m, 2H), 0.81 (dt, J = 11.5, 3.3 Hz, 2H). Embodiment 12 Step 1: Preparation of intermediate 12-2
將化合物 12-1(50 g)、( E)-1-乙氧乙烯基-2-硼酸頻那醇酯(36.4 g)、氫氧化鋰一水合物(23.10 g)、1,1-二(二苯膦基)二茂鐵二氯化鈀(13.4 g)和 N, N-二甲基甲醯胺(500 mL)混合,氮氣保護下,將混合物加熱至80 oC反應2小時。矽藻土抽氣過濾,濾液加入水和乙酸乙酯稀釋,以乙酸乙酯萃取,依次以水、飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,矽膠管柱層析純化得到32 g中間物 12-2。 Compound 12-1 (50 g), ( E )-1-ethoxyvinyl-2-boronic acid pinacol ester (36.4 g), lithium hydroxide monohydrate (23.10 g), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (13.4 g) and N , N -dimethylformamide (500 mL) were mixed and heated to 80 ° C for 2 hours under nitrogen protection. The filtrate was filtered by vacuum filtration through diatomaceous earth, diluted with water and ethyl acetate, extracted with ethyl acetate, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Vacuum filtration, concentration, and purification by silica gel column chromatography gave 32 g of intermediate 12-2 .
MS: (ESI,[M+H]+) m/z: 217.27。MS: (ESI, [M+H]+) m/z: 217.27.
1H NMR (500 MHz, DMSO- d 6) δ 7.78 (s, 1H), 7.04 (d, J= 12.7 Hz, 1H), 6.36 (s, 2H), 5.78 (d, J= 12.7 Hz, 1H), 3.93 (q, J= 7.0 Hz, 2H), 1.26 (t, J= 7.0 Hz, 3H)。 步驟二:中間物 12-3 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.78 (s, 1H), 7.04 (d, J = 12.7 Hz, 1H), 6.36 (s, 2H), 5.78 (d, J = 12.7 Hz, 1H), 3.93 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H). Step 2: Preparation of intermediate 12-3
將中間物 12-2(2.5g)溶於甲醇(50 mL),逐滴加入鹽酸(9.27 mL),70℃攪拌反應2小時。冷卻至室溫,冰浴下逐滴加入飽和碳酸氫鈉水溶液調節pH至中性,以乙酸乙酯萃取,依次以水、飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,得到1.7 g中間物 12-3。 Dissolve the intermediate 12-2 (2.5 g) in methanol (50 mL), add hydrochloric acid (9.27 mL) dropwise, and stir at 70°C for 2 hours. Cool to room temperature, add saturated sodium bicarbonate solution dropwise under ice bath to adjust pH to neutral, extract with ethyl acetate, wash with water and saturated sodium chloride solution in sequence, and dry over anhydrous sodium sulfate. Filter under vacuum and concentrate to obtain 1.7 g of intermediate 12-3 .
MS: (ESI,[M+H] +) m/z: 171.04。 MS: (ESI, [M+H] + ) m/z: 171.04.
1H NMR (500 MHz, DMSO- d 6) δ 12.38 (s, 1H), 8.51 (d, J= 1.5 Hz, 1H), 7.60 (d, J= 3.2 Hz, 1H), 6.73 (t, J= 3.3 Hz, 1H)。 步驟三:中間物 12-4 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 12.38 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 3.2 Hz, 1H), 6.73 (t, J = 3.3 Hz, 1H). Step 3: Preparation of intermediate 12-4
將中間物 12-3(1.0 g)溶於叔丁醇(50 mL),分批加入三溴化吡啶(4.69 g),40℃油浴攪拌反應過夜。減壓濃縮蒸除溶劑,加入水和乙酸乙酯稀釋,以乙酸乙酯萃取,依次以水、飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,得到1.6 g中間物 12-4。 Dissolve the intermediate 12-3 (1.0 g) in tert-butyl alcohol (50 mL), add pyridinium tribromide (4.69 g) in batches, and stir in an oil bath at 40°C overnight. Concentrate under reduced pressure to remove the solvent, add water and ethyl acetate to dilute, extract with ethyl acetate, wash with water and saturated sodium chloride solution in sequence, and dry over anhydrous sodium sulfate. Filter under vacuum and concentrate to obtain 1.6 g of intermediate 12-4 .
MS: (ESI,[M-H] -) m/z: 340.75。 MS: (ESI, [MH] - ) m/z: 340.75.
1H NMR (500 MHz, DMSO- d 6) δ 12.68 (s, 1H), 8.49 (s, 1H)。 步驟四:中間物 12-5 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 12.68 (s, 1H), 8.49 (s, 1H). Step 4: Preparation of intermediate 12-5
將中間物 12-4(1.5 g)溶於四氫呋喃(10 mL),加入鋅粉(1.4 g),冰浴下逐滴加入冰醋酸(5 mL),攪拌反應30分鐘後矽藻土抽氣過濾。濾液加入水和乙酸乙酯稀釋,以乙酸乙酯萃取,無水硫酸鈉乾燥。抽氣過濾,濃縮,矽膠管柱層析純化得到540mg中間物 12-5。 Dissolve the intermediate 12-4 (1.5 g) in tetrahydrofuran (10 mL), add zinc powder (1.4 g), add glacial acetic acid (5 mL) dropwise in an ice bath, stir and react for 30 minutes, then filter through diatomaceous earth. Dilute the filtrate with water and ethyl acetate, extract with ethyl acetate, and dry over anhydrous sodium sulfate. Filter through vacuum, concentrate, and purify by silica gel column chromatography to obtain 540 mg of intermediate 12-5 .
MS: (ESI,[M+H] +) m/z: 187.1。 MS: (ESI, [M+H] + ) m/z: 187.1.
1H NMR (500 MHz, DMSO- d 6) δ 11.62 (s, 1H), 7.96 (d, J= 1.0 Hz, 1H), 3.67 (d, J= 1.1 Hz, 2H)。 步驟五: 中間物 12-6 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.62 (s, 1H), 7.96 (d, J = 1.0 Hz, 1H), 3.67 (d, J = 1.1 Hz, 2H). Step 5 : Preparation of intermediate 12-6
將中間物 12-5(0.5 g)溶於四氫呋喃(5 mL),氮氣保護下,-20℃下逐滴加入二異丙基胺基鋰(2 M於四氫呋喃中, 8 mL),攪拌反應1小時後,逐滴加入硫酸乙烯酯(1.0 g)的四氫呋喃溶液(5 mL),轉移至室溫攪拌反應過夜。加入飽和氯化銨水溶液淬滅反應,以乙酸乙酯萃取,無水硫酸鈉乾燥。抽氣過濾,濃縮,矽膠管柱層析純化得到35 mg中間物 12-6。 The intermediate 12-5 (0.5 g) was dissolved in tetrahydrofuran (5 mL). Under nitrogen protection, lithium diisopropylamine (2 M in tetrahydrofuran, 8 mL) was added dropwise at -20°C. After stirring for 1 hour, a solution of vinyl sulfate (1.0 g) in tetrahydrofuran (5 mL) was added dropwise. The mixture was transferred to room temperature and stirred overnight. A saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After vacuum filtration, concentration, and purification by silica gel column chromatography, 35 mg of the intermediate 12-6 was obtained.
MS: (ESI,[M+H] +) m/z: 213.13。 MS: (ESI, [M+H] + ) m/z: 213.13.
1H NMR (500 MHz, DMSO- d 6) δ 11.83 (s, 1H), 7.84 (s, 1H), 1.82 (q, J= 3.9 Hz, 2H), 1.61 (q, J= 3.9 Hz, 2H)。 步驟六:中間物 12-7 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.83 (s, 1H), 7.84 (s, 1H), 1.82 (q, J = 3.9 Hz, 2H), 1.61 (q, J = 3.9 Hz, 2H). Step 6: Preparation of intermediate 12-7
將中間物 12-6(40 mg)、 B-5(85 mg)、碳酸鉀(78 mg)和 N, N-二甲基甲醯胺(6 mL)混合,室溫攪拌反應過夜。乙酸乙酯萃取,依次用水和飽和氯化鈉水溶液洗,無水硫酸鈉乾燥。抽氣過濾,濃縮,粗產物以管柱層析純化得到64 mg中間物 12-7。 Intermediate 12-6 (40 mg), B-5 (85 mg), potassium carbonate (78 mg) and N , N -dimethylformamide (6 mL) were mixed and stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated by vacuum filtration. The crude product was purified by column chromatography to obtain 64 mg of intermediate 12-7 .
MS (ESI,[M+H] +) m/z: 479.24。 MS (ESI, [M+H] + ) m/z: 479.24.
1H NMR (500 MHz, DMSO- d 6) δ8.17 (d, J= 1.3 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J= 8.3 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 5.16 (s, 2H), 4.46 (p, J= 6.7 Hz, 1H), 1.98 (q, J= 4.0 Hz, 2H), 1.78 (q, J= 4.0 Hz, 2H), 1.40 (d, J= 6.6 Hz, 6H)。 步驟七:化合物 12 的製備 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.17 (d, J = 1.3 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.16 (s, 2H), 4.46 (p, J = 6.7 Hz, 1H), 1.98 (q, J = 4.0 Hz, 2H), 1.78 (q, J = 4.0 Hz, 2H), 1.40 (d, J = 6.6 Hz, 6H). Step 7: Preparation of compound 12
將中間物 12-7(55 mg)、 C-1(67 mg)、三(二亞苄基丙酮)二鈀(15 mg)、2-二環己基膦-2',4',6'-三異丙基聯苯(15 mg)、碳酸銫(112 mg)、二氧六環(5 mL)和水(1 mL)混合,氮氣氛圍下加熱至90℃攪拌反應過夜。抽氣過濾,濃縮,矽膠管柱層析純化,得到20 mg化合物 12。 Intermediate 12-7 (55 mg), C-1 (67 mg), tris(dibenzylideneacetone)dipalladium (15 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (15 mg), cesium carbonate (112 mg), dioxane (5 mL) and water (1 mL) were mixed, heated to 90°C under nitrogen atmosphere, stirred and reacted overnight. Vacuum filtration, concentration and silica gel column chromatography were performed to obtain 20 mg of compound 12 .
MS (ESI,[M+H] +) m/z: 593.29。 MS (ESI, [M+H] + ) m/z: 593.29.
1H NMR (500 MHz, CDCl 3) δ8.64 (s, 1H), 7.98 (d, J= 1.1 Hz, 1H), 7.52 - 7.48 (m, 4H), 7.40 (d, J= 1.3 Hz, 1H), 5.28 - 5.14 (m, 2H), 4.53 (hept, J= 6.7 Hz, 1H), 3.90 (s, 3H), 1.98 - 1.96 (m, 2H), 1.83 - 1.79 (m, 2H), 1.70 - 1.65 (m, 1H), 1.44 (dd, J= 6.7, 1.5 Hz, 6H), 1.28 - 1.23 (m, 1H), 1.18 - 1.13 (m, 1H), 0.96 - 0.91 (m, 1H), 0.86 - 0.80 (m, 1H)。 試驗例 1 :體外細胞增殖抑制活性1.1 MDA-MB-436細胞增殖抑制活性測定 1 H NMR (500 MHz, CDCl 3 ) δ 8.64 (s, 1H), 7.98 (d, J = 1.1 Hz, 1H), 7.52 - 7.48 (m, 4H), 7.40 (d, J = 1.3 Hz, 1H), 5.28 - 5.14 (m, 2H), 4.53 (hept, J = 6.7 Hz, 1H), 3.90 (s, 3H), 1.98 - 1.96 (m, 2H), 1.83 - 1.79 (m, 2H), 1.70 - 1.65 (m, 1H), 1.44 (dd, J = 6.7, 1.5 Hz, 6H), 1.28 - 1.23 (m, 1H), 1.18 - 1.13 (m, 1H), 0.96 - 0.91 (m, 1H), 0.86 - 0.80 (m, 1H). Experimental Example 1 : In vitro cell proliferation inhibitory activity 1.1 Determination of MDA-MB-436 cell proliferation inhibitory activity
取處於生長狀態良好的MDA-MB-436細胞,收集至離心管,調整細胞密度至10 4個/mL,接種於96孔培養盤上(100μL/孔),細胞培養箱中培養過夜,使用奈升樣品加載儀進行化合物加入樣品,使化合物終濃度為1000 nM-0.457 nM,2個重複孔,同時設置對照。細胞培養箱中繼續培養7天後,加入檢測試劑CCK-8 (廠商:同仁化學,10 μL/孔),細胞培養箱中培育2小時後,Envision ELISA讀取儀450 nm處檢測其吸光值,四參數分析,擬合量效曲線,計算IC 50。 Take MDA-MB-436 cells in good growth state, collect them into centrifuge tubes, adjust the cell density to 10 4 cells/mL, inoculate them into 96-well culture plates (100 μL/well), culture them in a cell culture incubator overnight, use a nanoliter sample loader to add compounds to the samples, so that the final concentration of the compound is 1000 nM-0.457 nM, 2 replicate wells, and set up controls at the same time. After 7 days of continuous culture in the cell culture incubator, the test reagent CCK-8 (supplier: Tongren Chemical, 10 μL/well) was added. After 2 hours of culture in the cell culture incubator, the absorbance was measured at 450 nm using the Envision ELISA reader. The four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .
實驗結果如表1所示,其中A代表:0 nM<IC
50≤50 nM;B代表:50 nM<IC
50≤100 nM;C代表:100 nM<IC
50≤1000 nM;D代表:1000 nM<IC
50。
表1 MDA-MB-436細胞增殖抑制活性
USP1/UAF1蛋白溶液(濃度10 nM),按每孔10 μl加入至檢測孔中,用奈升樣品加載儀將DMSO溶解的不同化合物加入到檢測孔中,使化合物終濃度為1000 nM-0.24 nM,2個重複孔,同時設對照。上述體系室溫培育30分鐘後,將Ub-Rhodamine (濃度300 nM),按每孔10 μL加入檢測孔中;室溫反應90分鐘後,PerkinElmer Envision多功能ELISA讀取儀進行培養盤讀取檢測(Ex. 490 nm/ Em. 520 nm),採用四參數擬合,計算IC 50。 USP1/UAF1 protein solution (concentration 10 nM) was added to the test wells at 10 μl per well. Different compounds dissolved in DMSO were added to the test wells using a nanoliter sample loader to make the final concentration of the compound 1000 nM-0.24 nM. Two replicate wells were set up at the same time. After the above system was incubated at room temperature for 30 minutes, Ub-Rhodamine (concentration 300 nM) was added to the test wells at 10 μL per well. After 90 minutes of reaction at room temperature, the culture plate was read and detected using a PerkinElmer Envision multi-function ELISA reader (Ex. 490 nm/ Em. 520 nm), and IC 50 was calculated using a four-parameter fit.
實驗結果如表2所示,其中A代表:0 nM<IC
50≤50 nM;B代表:50 nM<IC
50≤100 nM;C代表:100 nM<IC
50≤1000 nM;D代表:1000 nM<IC
50。
表2 USP1/UAF1酵素抑制活性
本發明化合物具有良好的USP1/UAF1酵素抑制活性。 試驗例 3 :體外肝微粒體代謝穩定性 The compounds of the present invention have good USP1/UAF1 enzyme inhibitory activity. Experimental Example 3 : In vitro liver microsome metabolic stability
肝微粒體溫孵樣本製備為混合PBS緩衝液(pH7.4),肝微粒體溶液(0.5 mg/ml),受試化合物及NADPH +MgCl 2溶液於37℃及300 rpm培育1小時。0小時樣本製備為混合PBS緩衝液(pH7.4),肝微粒體溶液(0.5 mg/ml),受試化合物。樣本加入含內部標準的乙腈溶液經蛋白沉澱製備上清液,稀釋後用於LC/MS/MS測定。 The liver microsome incubation sample was prepared by mixing PBS buffer (pH7.4), liver microsome solution (0.5 mg/ml), test compound and NADPH + MgCl 2 solution at 37°C and 300 rpm for 1 hour. The 0 hour sample was prepared by mixing PBS buffer (pH7.4), liver microsome solution (0.5 mg/ml), test compound. The sample was added with acetonitrile solution containing internal standard and protein precipitation was performed to prepare supernatant, which was diluted and used for LC/MS/MS determination.
實驗結果如表3所示。
表3 體外肝微粒體代謝穩定性
本發明化合物具有良好的體外肝微粒體穩定性。 試驗例 4 :體內藥代動力學性質測定 The compounds of the present invention have good in vitro liver microsome stability. Test Example 4 : Determination of in vivo pharmacokinetic properties
ICR小鼠,體重18~22 g,適應3~5天後,隨機分組,每組9隻,按10 mg/kg劑量灌胃受試化合物溶液。ICR mice, weighing 18-22 g, were randomly divided into groups after 3-5 days of adaptation, with 9 mice in each group, and were intragastrically administered with the test compound solution at a dose of 10 mg/kg.
採血時間點15 min、0.5 h、1 h、2 h、4 h、6 h、8 h、10 h、24 h,於眼眶取血製備待測血漿樣品。Blood was collected from the eye sockets at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h to prepare plasma samples for testing.
吸取30 µL待測血漿樣品和標曲樣品,加入含內部標準的乙腈溶液經蛋白沉澱得到上清液,稀釋後用於LC/MS/MS測定。30 µL of plasma sample and standard sample were taken, and acetonitrile solution containing internal standard was added to obtain supernatant after protein precipitation. After dilution, it was used for LC/MS/MS determination.
採用非房室模型擬合藥代參數。The non-compartmental model was used to fit the pharmacokinetic parameters.
本發明化合物具有良好的體內藥代動力學性質。The compounds of the present invention have good in vivo pharmacokinetic properties.
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