WO2022223039A1 - Sos1降解剂及其制备方法和应用 - Google Patents
Sos1降解剂及其制备方法和应用 Download PDFInfo
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- WO2022223039A1 WO2022223039A1 PCT/CN2022/088590 CN2022088590W WO2022223039A1 WO 2022223039 A1 WO2022223039 A1 WO 2022223039A1 CN 2022088590 W CN2022088590 W CN 2022088590W WO 2022223039 A1 WO2022223039 A1 WO 2022223039A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Definitions
- the present invention belongs to the technical field of medicine, and specifically, the present invention relates to a SOS1 degrading agent, a preparation method thereof, and its application as a therapeutic agent for preventing and/or treating cancer.
- SOS1 (son of sevenless homolog 1) protein is a regulatory protein that is widely expressed in cells. As a key protein in signaling pathways, SOS1 plays an important regulatory role in many signal transduction pathways in cells, such as the regulation of Ras and Rac signaling pathway.
- SOS1 consists of 1333 amino acids and contains a proline-rich domain (PxxP) at its C-terminus, which can interact with growth factor receptor-bound protein 2 (growth factor receptor-bound protein 2) in the Ras pathway.
- Grb2 combined to form a complex of Grb2 and SOS1, thereby bringing SOS1 to the vicinity of Ras protein in the cell membrane.
- SOS1 catalyzes the combination of Ras and GTP, promotes the activation of Ras, and then activates multiple downstream signaling pathways, such as Ras-Raf-Mek -Erk, Ras-PI3K-AKT-mTOR.
- PxxP can also bind to the SH3 (Src homology 3) domain of proteins such as E3B1 in the Rac pathway to form EPS8-E3B1-SOS1 complexes, which connect actin filaments through EPS8, causing GTP switch, thereby activating Rac, which subsequently activates signaling pathways such as JNK and MAPK.
- Ras mutation gene is considered to be the main oncogene with high incidence of human cancer. Studies have shown that Ras mutation exists in 20-30% of tumor patients, among which KRas mutation accounts for 85%, NRas and HRas account for 12% respectively and 3%. However, directly acting on Ras to inhibit its activity is considered extremely challenging due to the picomolar affinity of GTP for its binding site and the smooth surface of Ras protein and lack of other suitable binding pockets.
- SOS1 The abnormal expression or mutation of SOS1 is also closely related to the occurrence of clinical diseases. Studies have shown that SOS1 mutations exist in NS patients and CFC patients. HGF1 is a rare autosomal dominant genetic disease, and its etiology is also related to the mutation of the PxxP domain of SOS1. In addition, abnormal expression or mutation of SOS1 is associated with The occurrence of cancer is also related.
- WO2018172250A1 discloses several types of SOS1 inhibitors, but so far, there is no relevant report on SOS1 degraders.
- Protein degradation targeting chimera is a technology different from traditional small molecule inhibitors, traditional small molecule inhibitors usually need to act on the active site of the target protein to inhibit its activity, while PROTAC is a A heterogeneous bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein, and the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase.
- This bifunctional molecule is in vivo It recognizes the target protein and E3 ubiquitin ligase, and draws the target protein and E3 ubiquitin ligase closer to form a ternary complex.
- the target protein After ubiquitinating the target protein, the target protein is degraded in vivo through the ubiquitin-proteasome pathway. Compared with traditional small molecule inhibitors, PROTAC only needs to bring the target protein closer to E3 ubiquitin ligase to degrade the substrate.
- the present invention provides compounds of formula I, or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof
- S is a small molecule compound that can inhibit the activity of SOS1 protein or bind to SOS1 protein;
- L is the linking chain, which connects S and E by covalent bonds
- E is E7a
- W is CH 2 , CR a R b , C(S), C(O) or SO 2 ;
- X is H 2 , CH 2 , O or S
- Z is H 2 , CH 2 , O or S
- G is selected from hydrogen, C1 - C6 alkyl, OH, -CH2 -heterocycloalkyl optionally substituted with R', -CH2 -phenyl optionally substituted with R';
- Q 1 , Q 2 , Q 3 and Q 4 are each independently carbon, nitrogen or nitrogen oxides
- A is hydrogen, C 1 -C 6 alkyl, cycloalkyl or halogen
- R is independently selected from hydrogen, hydroxy, halogen, -NH 2 , -N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkyl, -CONR'R", -OR', -NR'R", -SR', -SO2R ', -SO2NR'R ", -CR'R", -CR'NR'R", aryl, heteroaryl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -Cl, -F, -Br, -I, -CF 3 , -CN, -NR'SO 2 NR'R", -NR'C(O)NR'R",-C(O)NR'C(O)
- R' and R" are each independently selected from bond, hydrogen, C1 - C6 alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;
- n" is an integer from 1 to 4.
- E is E7a, the structure of E7a is as defined above.
- W is CH 2 or C(O).
- X is O or S.
- X is O
- Z is O.
- G is hydrogen
- Q 1 , Q 2 , Q 3 , and Q 4 are each independently carbon or nitrogen.
- Q 1 is carbon
- Q 2 is carbon
- Q 3 is carbon
- Q 4 is carbon
- Q 1 , Q 2 , Q 3 and Q 4 are carbon.
- A is hydrogen
- R is hydrogen
- the E is E7a';
- the E is E7a"
- Q 1 , Q 2 , Q 3 and Q 4 are each independently carbon or nitrogen;
- W is C(O) or CH 2 ;
- A is hydrogen, C1 - C6 alkyl or halogen (eg A is hydrogen);
- R is selected from hydrogen, hydroxy, halogen, -NH 2 , -N(C 1 -C 6 alkyl) 1-2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl;
- n" is 1, 2, 3 or 4;
- ----- is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer.
- W is CH2 or C(O);
- A is hydrogen, methyl, Cl or F (eg A is hydrogen);
- R is each independently selected from hydrogen, hydroxy, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
- n" is 1, 2, 3 or 4;
- ----- is a bond, which may be an R stereoisomer, an S stereoisomer, or a non-stereoisomer.
- the carbon atom to which the bond is attached when it has chirality, it is in the R configuration, the S configuration, or a mixture thereof (eg, 40%-60% R configuration and 60%- 40% mixture of S configurations).
- a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof , E is any of the following structures:
- the carbon atom marked with * is in R configuration, S configuration or a mixture thereof (eg a mixture of 40%-60% R configuration and 60%-40% S configuration).
- a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof , E is the following structure:
- the carbon atom marked with * is in R configuration, S configuration or a mixture thereof (eg a mixture of 40%-60% R configuration and 60%-40% S configuration).
- a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof , E is the following structure:
- the carbon atom marked with * is in R configuration, S configuration or a mixture thereof (eg a mixture of 40%-60% R configuration and 60%-40% S configuration).
- a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof , E is any of the following structures:
- Q 1 , Q 2 , Q 3 , and Q 4 are each independently carbon, N, or N substituted by R', or oxynitride.
- E A preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof , E is E9:
- R' is H.
- the S is S1:
- R 1 is selected from hydrogen, halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkylmercapto or -NR a R b , said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 heterocycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, Condensed heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C 1 -C 6 haloalkyl, -COOH, -COOR c ; the R c is -C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl or -C 4 -C 8
- R 1 is -NS(O)(R d )(R e ), and said R d and R e are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne base, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 6-10 membered aryl or 5-10 membered heteroaryl;
- R 1 is -NHC(O)-(C 1 -C 6 alkyl), -NHC(O)-NR a R b , said R a and R b are each independently hydrogen, -C 1 -C 6 alkane radical, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 1 is -NH-(CH 2 ) k -NH-C(O)-R aa , wherein R aa is C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl (eg, said R aa is C 1 -C 6 alkyl), and k is 1 or 2;
- R 1 is -NH-(CH 2 ) i -R f , wherein i is 0, 1 or 2 and R f is 4-7 membered heterocycloalkyl, heteroaryl, C 1 -C 6 alkylsulfonyl ;
- C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally selected from halogen, - OH, oxo, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4-7 membered hetero Cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH 2 )-heteroaryl, -NHC(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkoxy, phenoxy, heteroaryloxy or -NR
- R 1 is -O-(CH 2 ) z -phenyl, -O-(CH 2 ) z -(4-7 membered heterocycloalkyl), -O-(CH 2 ) z -heteroaryl, said z is 0, 1 or 2, the phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted with -OH, heterocycloalkyl or heterocycloalkenyl, and can be methyl or oxo replace;
- a 1 is C 4 -C 12 cycloalkyl, heterocycloalkyl, aryl (eg phenyl) or heteroaryl (eg thienyl);
- R 2 is hydrogen, -OH, oxo, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, - C 2 -C 6 alkynyl, -C 3 -C 8 cycloalkyl, -C 3 -C 8 cycloalkoxy, -C 3 -C 8 halocycloalkoxy, -C 4 -C 8 cycloalkenyl, 4-7 membered heterocycle Alkyl, -O-CH 2 -4-7-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl base, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 1 -C 6
- R 2 is -NR a R b , and said R a and R b are each independently hydrogen, C 1 -C 6 alkyl or -C(O)C 1 -C 3 alkyl;
- R 2 is -C(O)NR a R b , and said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 ring alkyl;
- R 2 is -C(O)OR g , said R g is hydrogen or C 1 -C 6 alkyl;
- R 2 is -OR h ; Described R h is C 1 -C 6 alkyl;
- R 2 is -(CH 2 )NR a R b , said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkane base;
- w is 1, 2, 3, or 4 (eg, the w is 1, 2, or 3);
- the A 2 (R 3 ) Y is hydrogen
- a 2 is C 4 -C 12 cycloalkyl, heterocycloalkyl, aryl (eg phenyl) or heteroaryl, and
- R 3 is hydrogen, halogen, -OH, oxo, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 ring Alkyl, C 4 -C 8 cycloalkenyl, C 7 -C 8 cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C 1 -C 6 haloalkyl;
- alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted by 1, 2 or 3 selected from halogen, -OH, oxo, -CN, -C1 - C6 alkyl, -C1 - C6 alkoxy, -C1 - C6 haloalkyl, phenyl, heteroaryl or - Substituent substitution of C(O)NR i R j , each of said R i and R j is independently hydrogen or C 1 -C 6 alkyl;
- alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted with -NRkRl
- the R k and R l are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkylsulfonyl, phenyl, heteroaryl, -CH 2 -C(O)-R m , -C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkyne alkenyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are each independently optionally selected from 1, 2 or 3 C1
- the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted with -NRsRt
- the -NR s R t is a 4-7-membered aza-heterocycloalkyl connected to other parts of the molecule through a nitrogen atom or a 6-10-membered aza-heterocycloalkyl connected to other parts of the molecule through a nitrogen atom, and further including up to two heteroatoms selected from N or O, optionally surrounded by 1, 2 or 3 selected from -OH, oxo, C1 - C6 alkyl, C1 - C6 hydroxyalkane group, -C(O)OR z substituent, the R z is C 1 -C 6 alkyl, halogen, -N(C 1 -C 6 al
- R 3 is C(O)R v , -C(O)NH 2 , -C(O)NHR v , -C(O)NR v R w , -C(O)OR v , said R v and R w is each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, phenyl or -(CH 2 ) 2 NR x R y , said R x and R y are each independently hydrogen , C 1 -C 4 alkyl or -(CH 2 ) 2 N(CH 3 ) 2 ;
- R 3 is -NH 2 , -NHR z , -NR z R za , -NHC(O)R z , -NHC(O)OR z , -NHS(O) 2 R z , 4-7 membered heterocycloalkane base, heteroaryl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, the R z and R za are each independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
- R 3 is C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -O(CH 2 ) s -C 3 -C 8 cycloalkyl, -O(CH 2 ) s -phenyl, -O(CH 2 ) s -heterocycloalkyl, -O(CH 2 ) s -heteroaryl, wherein s is 0, 1, 2 or 3;
- R 3 is -S(O) 2 R z , -S(O) 2 NH 2 , -S(O) 2 NHR z , -S(O) 2 NR z R za , each of said R z and R za independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
- Y is 0, 1, 2, 3, 4, or 5 (eg, Y is 0, 1, 2, or 3);
- R 4 and R 5 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkoxy, the alkyl, Alkoxy, cycloalkyl and cycloalkoxy are optionally cyano, hydroxy, C1 - C6alkoxy , C3 - C6cycloalkyl, C3 - C6cycloalkoxy or halogen replace.
- each of R 4 and R 5 in the S1 is independently a methyl group.
- the R a and R b at any one occurrence are each independently hydrogen or C 1 -C 6 alkyl.
- the Rd and Re at any one occurrence are each independently hydrogen or C1 - C6 alkyl.
- R 5 is a C 1 -C 6 alkyl group, such as methyl.
- R 4 is a C 1 -C 6 alkyl group, such as methyl.
- R 1 is hydrogen or C 1 -C 6 alkoxy.
- a 1 is an aryl group or a heteroaryl group.
- a 1 is an aryl group, such as a phenyl group.
- a 1 is a heteroaryl group, such as a thienyl group.
- R 2 is hydrogen, halogen, C 1 -C 6 alkyl or -C 1 -C 6 haloalkyl.
- L' is a bond
- a 2 (R 3 ) Y is hydrogen
- a 2 is an aryl group, such as a phenyl group.
- R 3 is hydrogen, halogen or C 1 -C 6 alkyl, and the alkyl is optionally substituted by -NR k R l ; the R k and R l are each independently hydrogen or C1 - C6 alkyl.
- R 3 is hydrogen, F, Cl, methyl or ethyl, and the methyl and ethyl are substituted by -NR k R 1 ; the R k is methyl or ethyl, R l is hydrogen, methyl or ethyl.
- R 3 is hydrogen, Cl, -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 .
- a 1 is an aryl group
- L' is a bond
- a 2 (R 3 ) Y is hydrogen
- a 1 is a heteroaryl group
- L' is a bond
- a 2 is an aryl group
- R 3 is hydrogen, halogen or C 1 -C 6 alkyl group, the alkyl group optionally substituted with -NRkRl ; said Rk and Rl are each independently hydrogen or C1 - C6 alkyl.
- the S is S1':
- the S is S1":
- R 1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and the C 1 -C 6 alkyl and C 1 -C6alkoxy is optionally substituted with C1 - C6alkoxy (eg methoxy).
- R 1 is hydrogen, methyl, methoxy or
- Fragment is
- the S is -X-S1', and the structure of S1' is as described above;
- X is O, NH or S, preferably O.
- the S is -X-S1", and the structure of S1" is as described above;
- X is O, NH or S, preferably O.
- the S is S1a
- x is 1 or 2;
- a 1 is selected from
- w 1, 2 or 3;
- Y is 1 or 2;
- w is 1 or 2.
- R 1 is hydrogen, -CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 CH(CH 3 ) 2 or -O( CH2 ) 3CH3 , eg -OCH3 .
- a 1 is
- a 1 is
- R 2 is hydrogen, halogen, -NH 2 , C 1 -C 6 alkyl or -C 1 -C 6 haloalkyl.
- L' is a bond
- a 2 (R 3 ) Y is hydrogen
- a 2 is
- R 3 is hydrogen, -F, -Cl, -Br, -CH 2 -NH-(CH 2 ) 3 CH 3 , -CH 2 -NH-CH 3 , -CH2 -N( CH3 ) 2 or -CH2 -NH - CH2CH3 .
- R 3 is hydrogen, Cl, -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 .
- a 1 is L' is a bond
- a 2 (R 3 ) Y is hydrogen
- a 1 is L' is the key
- a 2 is R 3 is hydrogen, -F, -Cl, -Br, -CH 2 -NH-(CH 2 ) 3 CH 3 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 ) 2 or -CH 2 -NH - CH2CH3 .
- the S is S1a':
- R 1 , R 2 , R 3 , L', A 1 , A 2 , w, x and Y are as described in S1 or S1a.
- the S is S1a":
- R 1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and the C 1 -C 6 alkyl and C 1 -C6alkoxy is optionally substituted with C1 - C6alkoxy (eg methoxy).
- R 1 is hydrogen, methyl, methoxy or
- the S is -X-S1a', and the structure of S1a' is as described above;
- X is O, NH or S, preferably O.
- the S is -X-S1a", and the structure of S1a" is as described above;
- X is O, NH or S, preferably O.
- the S1 is the specific compound of Example 1 (Example 1) to Example 458 (Example 458) in WO2018172250A1 (which is incorporated herein by reference in its entirety).
- the S is S2:
- R 1 is hydrogen, halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkyl mercapto or -NR a R b ; the R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 heterocycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, Condensed heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C 1 -C 6 haloalkyl, -COOH, -COOR c ; the R c is -C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl or -C 4 -C 8
- R 1 is -NS(O)(R d )(R e ), and said R d and R e are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne base, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl;
- R 1 is -NHC(O)-(C 1 -C 6 alkyl), -NHC(O)-NR a R b , the R a and R b are each independently hydrogen, C 1 -C 6 alkyl , C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 1 is -NH-(CH 2 ) k -NH-C(O)-(C 1 -C 6 alkyl), and the k is 1 or 2;
- R 1 is -NH-(CH 2 ) i -R f , wherein i is 0, 1 or 2 and R f is 4-7 membered heterocycloalkyl, heteroaryl, C 1 -C 6 alkylsulfonyl ;
- C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally selected from halogen, - OH, oxo, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4-7 membered hetero Cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH 2 )-heteroaryl, -NHC(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkoxy, phenoxy, heteroaryloxy or -NR
- R 1 is -O-(CH 2 ) z -phenyl, -O-(CH 2 ) z -(4-7 membered heterocycloalkyl), -O-(CH 2 ) z -heteroaryl, said z is 0, 1 or 2, the phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted with -OH, heterocycloalkyl or heterocycloalkenyl, and can be methyl or oxo replace;
- L 2 a is C(O)
- L 2 b is bond or C 1 -C 6 alkylene
- X 2 is
- said x is 1, 2, 3, or 4 (eg, said x is 1, 2, or 3);
- a 1 is C 4 -C 12 cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
- R 2 is hydrogen, -OH, oxo, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, - C 2 -C 6 alkynyl, -C 3 -C 8 cycloalkyl, -C 3 -C 8 cycloalkoxy, -C 3 -C 8 halocycloalkoxy, -C 4 -C 8 cycloalkenyl, 4-7 membered heterocycle Alkyl, -O-CH 2 -4-7-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl base, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 1 -C 6
- R 2 is -NR a R b , and said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 2 is -C(O)NR a R b, and said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 ring alkyl;
- R 2 is -C(O)OR g , said R g is hydrogen or C 1 -C 6 alkyl;
- R 2 is -OR h ; Described R h is C 1 -C 6 alkyl;
- R 2 is -(CH 2 )NR a R b , and said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl, or C 3 -C 8 ring alkyl;
- w is 1, 2, 3, or 4 (eg, the w is 1 or 2);
- the A 2 (R 3 ) Y is hydrogen
- a 2 is C 4 -C 12 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and
- R 3 is hydrogen, halogen, -OH, oxo, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 ring Alkyl, C 4 -C 8 cycloalkenyl, C 2 -C 8 cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C 1 -C 6 haloalkyl;
- alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted by 1, 2 or 3 selected from halogen, -OH, oxo, -CN, -C1 - C6 alkyl, -C1 - C6 alkoxy, -C1 - C6 haloalkyl, phenyl, heteroaryl or - Substituent substitution of C(O)NR i R j , each of said R i and R j is independently hydrogen or C 1 -C 6 alkyl;
- alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted with -NRkRl
- the R k and R l are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkylsulfonyl, phenyl, heteroaryl, -CH 2 -C(O)-R m , -C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkyne alkenyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are each independently optionally selected from 1, 2 or 3 C1
- the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted with -NRsRt
- the -NR s R t is a 4-7-membered aza-heterocycloalkyl connected to other parts of the molecule through a nitrogen atom or a 6-10-membered aza-heterocycloalkyl connected to other parts of the molecule through a nitrogen atom, and further including up to two heteroatoms selected from N or O, optionally surrounded by 1, 2 or 3 selected from -OH, oxo, C1 - C6 alkyl, C1 - C6 hydroxyalkane group, -C(O)OR z substituent, the R z is C 1 -C 6 alkyl, halogen, -N(C 1 -C 6 al
- R 3 is C(O)R v , -C(O)NH 2 , -C(O)NHR v , -C(O)NR v R w , -C(O)OR v , said R v and R w is each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, phenyl or -(CH 2 ) 2 NR x R y , said R x and R y are each independently hydrogen , C 1 -C 4 alkyl or -(CH 2 ) 2 NH(CH 3 ) 2 ;
- R 3 is -NH 2 , -NHR z , -NR z R za , -NHC(O)R z , -NHC(O)OR z , -NHS(O) 2 R z , 4-7 membered heterocycloalkane base, heteroaryl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, the R z and R za are each independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
- R 3 is C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -O(CH 2 ) s -C 3 -C 8 cycloalkyl, -O(CH 2 ) s -phenyl, -O(CH 2 ) s -heterocycloalkyl, -O(CH 2 ) s -heteroaryl, wherein s is 0, 1, 2 or 3;
- R 3 is -S(O) 2 R z , -S(O) 2 NH 2 , -S(O) 2 NHR z , -S(O) 2 NR z R za , each of said R z and R za independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
- Y is 0, 1, 2, 3, 4, or 5 (eg, the Y is 0, 1, 2, or 3);
- R 4 and R 5 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkoxy, the alkyl, Alkoxy, cycloalkyl and cycloalkoxy are optionally cyano, hydroxy, C1 - C6alkoxy , C3 - C6cycloalkyl, C3 - C6cycloalkoxy or halogen replace;
- Both T and V are N, or T is C and V is N, or T is N and V is C.
- each of R 4 and R 5 in the S2 is independently a methyl group.
- each of said Ra and Rb at any occurrence is independently hydrogen or C1 - C6 alkyl.
- both T and V are N.
- T is C
- V is N
- T is N
- V is C
- R 5 is a C 1 -C 6 alkyl group, such as methyl.
- R 4 is a C 1 -C 6 alkyl group, such as methyl.
- R 1 is hydrogen or C 1 -C 6 alkoxy.
- a 1 is an aryl group or a heteroaryl group.
- a 1 is an aryl group, such as a phenyl group.
- a 1 is a heteroaryl group, such as a thienyl group.
- R 2 is hydrogen, halogen, C 1 -C 6 alkyl or -C 1 -C 6 haloalkyl.
- L' is a bond
- a 2 (R 3 ) Y is hydrogen
- a 2 is an aryl group, such as a phenyl group.
- R 3 is hydrogen, halogen or C 1 -C 6 alkyl, and the alkyl is optionally substituted by -NR k R l ; the R k and R l are each independently hydrogen or C1 - C6 alkyl.
- R 3 is hydrogen, F, Cl, methyl or ethyl, and the methyl and ethyl are substituted by -NR k R 1 ; the R k is methyl or ethyl, R l is hydrogen, methyl or ethyl.
- R 3 is hydrogen, Cl, -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 .
- a 1 is an aryl group
- L' is a bond
- a 2 (R 3 ) Y is hydrogen
- a 1 is a heteroaryl group
- L' is a bond
- a 2 is an aryl group
- R 3 is hydrogen, halogen or C 1 -C 6 alkyl group, the alkyl group optionally substituted with -NRkRl ; said Rk and Rl are each independently hydrogen or C1 - C6 alkyl.
- the S is S2':
- the S is S2":
- R 1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and the C 1 -C 6 alkyl and C 1 -C 6 alkoxy optionally substituted with C 1 -C 6 alkoxy (eg, methoxy).
- R 1 is hydrogen, methyl, methoxy or
- Fragment is
- the S is -X-S2', and the structure of S2' is as described above;
- X is O, NH or S, preferably O.
- the S is -X-S2", and the structure of S2" is as described above;
- X is O, NH or S, preferably O.
- the S is S2a
- Both T and V are N, or T is C and V is N, or T is N and V is C;
- z is 1 or 2;
- x is 1 or 2;
- a 1 is selected from
- w 1, 2 or 3;
- Y is 1 or 2;
- the S2 is the specific compound of Example 1 (Example 1) to Example 100 (Example 100) in WO2019201848A1 (the entirety of which is incorporated herein by reference).
- w is 1 or 2.
- R 1 is hydrogen, methyl, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 CH(CH 3 ) 2 or -O(CH 2 ) 3 CH 3 , eg -OCH 3 .
- a 1 is
- a 1 is
- R 2 is hydrogen, halogen, -NH 2 , C 1 -C 6 alkyl or -C 1 -C 6 haloalkyl.
- L' is a bond
- a 2 (R 3 ) Y is hydrogen
- a 2 is
- R 3 is hydrogen, -F, -Cl, -Br, -CH 2 -NH-(CH 2 ) 3 CH 3 , -CH 2 -NH-CH 3 , -CH2 -N( CH3 ) 2 or -CH2 -NH - CH2CH3 .
- R 3 is hydrogen, Cl, -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 .
- a 1 is L' is a bond
- a 2 (R 3 ) Y is hydrogen
- a 1 is L' is the key
- a 2 is R 3 is hydrogen, -F, -Cl, -Br, -CH 2 -NH-(CH 2 ) 3 CH 3 , -CH 2 -NH-CH 3 , -CH 2 -N(CH 3 ) 2 or -CH 2 -NH - CH2CH3 .
- the S is S2a'
- the S is S2a
- T, V, R 2 , R 3 , L', A 1 , A 2 , w and Y are as described in S2 or S2a.
- R 1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, the C 1 -C 6 alkyl and C 1 -C6alkoxy is optionally substituted with C1 - C6alkoxy (eg methoxy).
- R 1 is hydrogen, methyl, methoxy or
- the S is -X-S2a', and the structure of S2a' is as described above;
- X is O, NH or S, preferably O.
- the S is -X-S2a", and the structure of S2a" is as described above;
- X is O, NH or S, preferably O.
- the S is S3:
- Q 1 and Q 2 are each independent CH or N;
- Q 3 , Q 4 and Q 7 are independently C or N, at least one of said Q 3 and Q 4 is C, and not all of said Q 3 , Q 4 and Q 7 are N;
- Q 5 is CH, N, NH, O or S
- Q 6 is CH, N, NH, N(C 1 -C 6 alkyl), N(C 1 -C 6 heteroalkyl), N(3-7 membered cycloalkyl), N(3-7 membered heteroalkyl) ring), O or S;
- At least one of the Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 is N, NH, O or S;
- R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, -NHR 1a , -OR 1a , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy or -CN; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkoxy are optionally selected from halogen, Substituent substitution of -NHR 1a or -OR 1a ; said R 1a is hydrogen, C 1 -C 6 alkyl, 3-6 membered heterocycle or C 1 -C 6 haloalkyl;
- R 2 is selected from hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkylmercapto, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -NR 2b R 2c , -OR 2a , 3-14-membered cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl and 5-
- the 10-membered heteroaryl groups are each independently optionally selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl,
- the R 2b is hydrogen or C 1 -C 6 alkyl
- the R 2c is hydrogen or C 1 -C 6 alkyl
- R 2 is -NHC(O)-(C 1 -C 6 alkyl), -NHC(O)-NR a R b , the R a and R b are each independently hydrogen, C 1 -C 6 alkyl , C 3 -C 8 heterocycloalkyl, or C 3 -C 8 cycloalkyl (eg, the R a and R b are each independently hydrogen or C 1 -C 6 alkyl);
- R 2 is -NH-(CH 2 ) k -NH-C(O)-(C 1 -C 6 alkyl), and the k is 1 or 2;
- R 2 is -NH-(CH 2 ) i -R f , wherein i is 0, 1 or 2 and R f is 4-7 membered heterocycloalkyl, heteroaryl, C 1 -C 6 alkylsulfonyl ;
- R 3 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkoxy; at least one of said R 3 and R 4 is not hydrogen, or the R 3 and R 4 and the atoms to which they are attached together form a 3-6 membered cycloalkyl; the alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally cyano, hydroxy, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy or halogen substituted;
- A is optionally substituted (eg optionally substituted with 1 or more R2, R2 is as defined in S1) 6 -membered aryl or optionally substituted (eg optionally substituted with 1 or more R2 Substituted, R2 is as defined in S1 ) 5-6 membered heteroaryl.
- the S is S3a
- Q 1 and Q 2 are each independent CH or N;
- Q 3 and Q 4 are independently C or N, and at least one of the Q 3 and Q 4 is C;
- Q 6 is CH, N, NH, O or S
- Q 5 is CH, N, NH, O or S
- At least one of the Q 1 , Q 2 , Q 3 , Q 4 , Q 5 and Q 6 is N, NH, O or S;
- R 1 is selected from hydrogen, C 1 -C 6 alkyl, halogen, -OR 1a , cyclopropyl or -CN; said R 1a is hydrogen or C 1 -C 6 alkyl;
- L 2 is selected from bond, -C(O)-, -C(O)O-, -C(O)NH(CH 2 ) o -, -S(O) 2 -, -C(O)(CH 2 ) p -, -(CH 2 ) p - or 0; the o is 0, 1 or 2; the p is an integer from 1 to 6;
- R 2 is selected from hydrogen, -(CH 2 ) q CH 3 , 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered aryl membered heteroaryl; said q is an integer from 1 to 5; said 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl and 5 -10-membered heteroaryl groups are each independently optionally substituted with a substituent selected from C 1 -C 6 alkyl, -OH, halogen, -C(O)R 2a , -C(O)NR 2b R 2c ;
- the R 2a is C 1 -C 6 alkyl or -(CH 2 ) r OCH 3 , the r is 1, 2 or 3; the R 2b is hydrogen or
- R 3 and R 4 are each independently hydrogen or C 1 -C 6 alkyl, at least one of said R 3 and R 4 is not hydrogen, or said R 3 and R 4 together with the atoms to which they are attached form 3 -6-membered cycloalkyl;
- A is optionally substituted (eg optionally substituted with 1 or more R2, R2 is as defined in S1) phenyl or optionally substituted (eg optionally substituted with 1 or more R2, R2 2 is as defined in S1) 5-6 membered heteroaryl.
- the S3 is a specific compound of Example 1 (Example 1) to Example 103 (Example 103) in WO2020180768A1 (the entirety of which is incorporated herein by reference).
- the S is S4:
- Q 1 is CH or N
- Q 4 is CH, C or N
- Each Q 2 is independently CR 1 or N, and one of the Q 2 is N and the other Q 2 is CR 1 ;
- Each Q 3 and Q 5 molecule is independently C(R QC ) 2 , NR QN , C(O), O, S, or SO 2 , and each R QC is independently hydrogen, F, Cl, Br, or 6-10-membered aryl, each of the R QNs is independently hydrogen, C 1 -C 6 alkyl or 6-10-membered aryl;
- At least one of said Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is N, NR QN , O or SO 2 ;
- n 0, 1, 2 or 3;
- n 0, 1, 2 or 3;
- R 1 is selected from hydrogen, C 1 -C 6 alkyl, halogen, -C(O)NHR 1a , -NHR 1a , -OR 1a , cyclopropyl, azetidine or -CN; the C 1 - C6 alkyl and azetidine are optionally substituted with substituents selected from halogen, R 1a , -NHR 1a or -OR 1a ; said R 1a is hydrogen, C 1 -C 6 alkyl, cyclopropyl base, 3-6 membered heterocycle or C 1 -C 6 haloalkyl;
- the R 2b is hydrogen or C 1 -C 6 alkyl
- the R 2c is hydrogen or C 1 -C 6 alkyl
- R 3 and R 4 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen, -OH, at least one of said R 3 and R 4 is hydrogen, or said R 3 and R 4 and The atoms to which it is attached together form a 3-6 membered cycloalkyl;
- A is optionally substituted (eg optionally substituted with 1 or more R2, R2 is as defined in S1) 6 -membered aryl or optionally substituted (eg optionally substituted with 1 or more R2 substituted, R is as defined in S1 ) 5-6 membered heteroaryl;
- condition is when for , R 1 is not hydrogen.
- the S is S4a
- Q 1 is CH or N
- Q 4 is CH, C or N
- Each Q 2 is independently CR 1 or N;
- Each Q3 and Q5 molecule is independently C( RQC ) 2 , NRQN , C(O), O, S, or SO2, and each RQC is independently hydrogen , F, Cl, Br, or 6-10-membered aryl, each of the R QNs is independently hydrogen, C 1 -C 6 alkyl or 6-10-membered aryl;
- At least one of said Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is N, NR QN , O or SO 2 ;
- R 1 is selected from hydrogen, C 1 -C 6 alkyl, halogen, cyclopropyl, cyano or -OR 1a , said R 1a is hydrogen or C 1 -C 6 alkyl;
- L 2 is selected from bond, -C(O)-, -C(O)O-, -C(O)NH(CH 2 ) o -, -S(O) 2 -, -C(O)(CH 2 ) p -, -(CH 2 ) p - or 0; the o is 0, 1 or 2; the p is an integer from 1 to 6;
- R 2 is selected from hydrogen, -(CH 2 ) q CH 3 , 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered aryl membered heteroaryl; the q is a multiple of 1 to 5; the 3-14-membered cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl, 5-membered -10-membered heteroaryl groups are each independently optionally substituted with a group selected from C 1 -C 6 alkyl, hydroxy, halogen, -C(O)R 2a or -C(O)NR 2b R 2c ; the The R 2a is selected from C 1 -C 6 alkyl or -(CH 2 ) r OCH 3 ; the r is 1, 2 or 3; the
- R 3 and R 4 are each independently hydrogen or C 1 -C 6 alkyl, at least one of said R 3 and R 4 is hydrogen, or said R 3 and R 4 and the atoms to which they are attached together form a 3- 6-membered cycloalkyl;
- A is optionally substituted (eg optionally substituted with 1 or more R2, R2 is as defined in S1) 6 -membered aryl or optionally substituted (eg optionally substituted with 1 or more R2 Substituted, R2 is as defined in S1 ) 5-6 membered heteroaryl.
- R 3 and R 4 in the S4a are each independently hydrogen or methyl, and at least one of the R 3 and R 4 is hydrogen.
- the S4 is the specific compound of Example 1 (Example 1) to Example 540 (Example 540) in WO2020180770A1 (which is incorporated herein by reference in its entirety).
- the S is S5:
- the R 1 is hydrogen or R a1 ;
- R a1 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 10 Cycloalkenyl, 3-10-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6 -C 10 membered aryl and 5-10 membered heteroaryl is optionally substituted with one or more identical or different R b1 and/or R c1 ;
- Each R b1 is independently -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , - S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1 -C 4alkyl )C(O)R c1 , -NHC(O) OR c1 or -N(C 1 -C 4 alkyl)C(O)OR c1 ;
- Each R c1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl , C 4 -C 10 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6 -C
- the 10 -aryl and 5-10-membered heteroaryl groups are each independently optionally surrounded by 1 or more identical or different R d1 and/or R e1 ;
- Each R d1 is independently -OR e1 , -NR e1 R e1 , halogen, -CN, -C(O)R e1 , -C(O)OR e1 , -C(O)NR e1 R e1 , - S(O) 2 R e1 , -S(O) 2 NR e1 R e1 , -NHC(O)R e1 , -N(C 1 -C 4 alkyl)C(O)R e1 , -NHC(O) OR e1 or -N(C 1 -C 4 alkyl)C(O)OR e1 ;
- Each R e1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl , C 4 -C 10 cycloalkenyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;
- R 2 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl or halogen;
- Ring A is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or 9-10 membered biheterocycloalkyl;
- p 1, 2 or 3;
- Each R 4 is independently hydrogen, hydroxy, oxo, halogen, cyano, C 1 -C 4 alkyl, -NH 2 , C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 hydroxyalkyl, hydroxy-C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, 3-6 membered heterocycle Alkyl, C 3 -C 6 hydroxycycloalkyl, C 1 -C 4 haloalkyl substituted by 3-6 membered heterocycloalkyl, substituted by hydroxy, halogen, -NH 2 , -S(O) 2 -(C 1 -C 4 alkyl) or oxo-substituted 3-6 membered heterocycloalkyl, and the oxo group is only substituted on a
- R 4 is -NR a R b , and said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 4 is -C(O)NR a R b, and said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 ring alkyl;
- R 4 is -C(O)OR g , and said R g is hydrogen or C 1 -C 6 alkyl;
- R 4 is -OR h ; Described R h is C 1 -C 6 alkyl;
- R 4 is -(CH 2 )NR a R b , said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 ring alkyl;
- R 3 and R 5 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkoxy, the alkane radical, alkoxy, cycloalkyl and cycloalkoxy optionally by cyano, hydroxy, C1 - C6alkoxy , C3 - C6cycloalkyl, C3 - C6cycloalkoxy or halogen substituted.
- R 5 in the S5 is methyl.
- the Ra and Rb at any one occurrence are each independently hydrogen or C1 - C6 alkyl.
- the S is S5':
- the S is -X-S5', and the structure of S5' is as described above;
- X is O, NH or S, preferably O.
- the S is S5a:
- R 1 , R 2 , R 3 , R 4 , ring A and p are as defined and described in S5.
- the S is S5a':
- the S is -X-S5a', and the structure of S5a' is as described above;
- X is O, NH or S, preferably O.
- the S5 is a specific compound of I-1 to I-179 in WO2019122129A1 (which is incorporated herein by reference in its entirety).
- the S is S6:
- R 2 is selected from hydrogen, halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkylmercapto or -NR a R b , said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 2 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 heterocycloalkoxy (eg ), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 4-7 membered heterocycloalkyl (eg ), 5-10 membered heterocyclic alkenyl, spiro heterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C 1 -C 6 haloalkyl, -COOH, -COOR c ; Described R c is -C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl or
- R 2 is -NS(O)(R d )(R e ), and said R d and R e are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne base, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 6-10 membered aryl or 5-10 membered heteroaryl;
- R 2 is -NHC(O)-(C 1 -C 6 alkyl), -NHC(O)-NR a R b , and said R a and R b are each independently hydrogen, -C 1 -C 6 alkane radical, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 2 is -NH-(CH 2 ) k -NH-C(O)-R aa which is C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl, and k is 1 or 2;
- R 2 is -NH-(CH 2 ) i -R f , wherein i is 0, 1 or 2 and R f is 4-7 membered heterocycloalkyl, heteroaryl, C 1 -C 6 alkylsulfonyl ;
- C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally selected from halogen, - OH, oxo, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4-7 membered hetero Cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH 2 )-heteroaryl, -NHC(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkoxy, phenoxy, heteroaryloxy or -NR
- R 2 is -O-(CH 2 ) z -phenyl, -O-(CH 2 ) z -(4-7 membered heterocycloalkyl), -O-(CH 2 ) z -heteroaryl, said z is 0, 1 or 2, the phenyl, heterocycloalkyl and heteroaryl are optionally substituted with -OH, heterocycloalkyl or heterocycloalkenyl, and can be methyl or oxo replace;
- R 1 is hydrogen or -OR A ;
- R A is hydrogen, C 3 -C 10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3 -C 10 cycloalkyl and 3-10 membered heterocycloalkyl are optionally composed of one or more same or different R a1 and/or R c1 substitutions;
- Each R a1 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3 -10-membered heterocycloalkyl or 5-10-membered heteroaryl; said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl , C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are each independently optionally substituted by one or more identical or different R b1 and/or R c1 ;
- Each R b1 is independently -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , - S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1 -C 4 alkyl)C(O)R c1 , oxo substituted , and the oxo group is only substituted on a non-aromatic ring;
- Each R c1 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl , 3-10 membered heterocycloalkyl or 5-10 heteroaryl;
- R 1 is selected from C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally surrounded by one or more R a2 and/or R b2 substitutions;
- Each R a2 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkane base, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl optionally substituted by 1 or more R c2 and/or R b2 ;
- Each R c2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by one or more R d2 and/or R e2 ;
- Each R d2 is independently -OR e2 , -NR e2 Re2 , halogen, -CN, -C(O)R e2 , -C(O)OR e2 , -C(O)NR e2 Re2 , - S(O) 2 R e2 , -S(O) 2 NR e2 R e2 , -NHC(O)R e2 , -N(C 1 -C 4 alkyl)C(O)R e2 , oxo, all The oxo group is only substituted on a non-aromatic ring;
- Each R e2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by one or more R f2 and/or R g2 ;
- Each R f2 is independently selected from -OR g2 , -NR g2 R g2 , halogen, -CN, -C(O)R g2 , -C(O)OR g2 , -C(O)NR g2 R g2 , -S(O) 2 R g2 , -S(O) 2 NR g2 R g2 , -NHC(O)R g2 , -N(C 1 -C 4 alkyl)C(O)R g2 , oxo,
- the oxo group is only substituted on a non-aromatic ring;
- Each R g2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
- R 1 is selected from C 2 -C 4 alkyl, C 2 -C 4 alkenyl; the C 2 -C 4 alkyl and C 2 -C 4 alkenyl are optionally substituted by R b3 ;
- R b3 is selected from -C(O)R c3 , -C(O)OR c3 , -C(O)NR c3 R c3 , -C(O)NHOR c3 or -C(O)N(C 1 -C 4 alkyl) OR c3 ;
- Each R c3 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by 1 or more R d3 and/or R e3 ;
- Each R d3 is independently selected from -OR e3 , -NR e3 R e3 , halogen, -CN, -C(O)R e3 , -C(O)OR e3 , -C(O)NR e3 R e3 , -S(O) 2 R e3 , -S(O) 2 NR e3 R e3 , -NHC(O)R e3 , -N(C 1 -C 4 alkyl)C(O)R e3 , oxo,
- the oxo group is only substituted on a non-aromatic ring;
- Each R e3 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
- R 3 is selected from hydrogen, C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 or halogen;
- R 5 is selected from hydrogen, hydroxyl or -NHR';
- R' is selected from hydrogen, C 1 -C 3 alkyl and -C(O)C 1 -C 3 alkyl;
- R 4 is selected from C 1 -C 4 alkyl, hydroxy, oxo, cyano, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, hydroxy-C 1 -C 4 haloalkyl, C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, C 3 -C 6 cycloalkoxy, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl , 3-6 membered hydroxy heterocycloalkyl, halogen or -SO 2 -C 1 -C 4 alkyl;
- R 6 is selected from hydrogen, C 1 -C 4 alkyl or halogen
- R 7 and R 8 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkoxy, the alkyl, Alkoxy, cycloalkyl and cycloalkoxy are optionally cyano, hydroxy, C1 - C6alkoxy , C3 - C6cycloalkyl, C3 - C6cycloalkoxy or halogen replace.
- the Fragment is E.g
- R 1 is hydrogen or -OR A
- RA is hydrogen
- R 1 is hydrogen
- R 2 is hydrogen, C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -NH 2 , -NH(C 1 -C 4 alkyl) ), -N(C 1 -C 4 alkyl) 2 or halogen, said C 1 -C 4 alkyl and -O(C 1 -C 4 alkyl) are each independently optionally -O(C 1 - C 4 alkyl) substituted.
- R 2 is hydrogen, C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -NH 2 , -NH(C 1 -C 4 alkyl) ), -N(C 1 -C 4 alkyl) 2 or halogen.
- R 2 is hydrogen, C 1 -C 4 alkyl or -O(C 1 -C 4 alkyl), and -O(C 1 -C 4 alkyl) is any Optionally substituted with -O(C 1 -C 4 alkyl).
- R 2 is
- R3 is hydrogen
- R 5 is hydrogen or -NHR'.
- R 4 is C 1 -C 4 haloalkyl
- R 6 is hydrogen or halogen
- R 4 , R 6 and the carbon atom to which they are attached together form a ring such that the Fragment is
- R 7 is C 1 -C 6 alkyl.
- R 8 is C 1 -C 6 alkyl.
- R 1 is hydrogen or -OR A ;
- R A is hydrogen
- R 2 is hydrogen, C 1 -C 4 alkyl, or -O(C 1 -C 4 alkyl) (eg, methoxy), optionally -O(C 1 -C 4 alkyl) (C 1 -C 4 alkyl) (eg methoxy) substituted;
- R 3 is hydrogen
- R 5 is hydrogen or -NHR'
- R' is selected from hydrogen, C 1 -C 3 alkyl and -C(O)C 1 -C 3 alkyl;
- R 4 is C 1 -C 4 haloalkyl
- R 6 is hydrogen or halogen
- R 4 , R 6 and the carbon atoms to which they are attached together form a ring so that the Fragment is
- R 7 is C 1 -C 6 alkyl
- R 8 is C 1 -C 6 alkyl.
- the C 1 -C 4 alkyl may be methyl.
- the -O(C 1 -C 4 alkyl) may be -OCH 3 .
- R 2 is hydrogen, methyl, -OCH 3 or
- R 2 is hydrogen, methyl or -OCH 3 .
- R3 is hydrogen
- the C 1 -C 3 alkyl group may be ethyl or isopropyl.
- the -C(O)C 1 -C 3 alkyl can be -C(O ) CH 3 .
- R 5 is hydrogen or -NHR', wherein R' is hydrogen, ethyl, isopropyl or -C(O)CH 3 .
- R 5 is -NHR', wherein R' is hydrogen.
- R 4 is C 1 -C 4 haloalkyl
- R 6 is hydrogen or halogen
- R 4 , R 6 and the carbon atoms to which they are attached together form a ring so that the Fragment is
- the C 1 -C 4 haloalkyl may be C 1 -C 4 fluoroalkyl, such as trifluoromethyl base.
- R 7 is C 1 -C 6 alkyl.
- the C 1 -C 6 alkyl group may be a methyl group.
- R 8 is C 1 -C 6 alkyl.
- the C 1 -C 6 alkyl group may be a methyl group.
- the S6 Fragments can be any type of S6 Fragments.
- the S6 Fragments can be any type of S6 Fragments.
- the S6 Fragments are preferably
- the S6 Fragments are preferably
- the S6 Fragments can be preferably
- the S6 Fragment is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
- the S6 Fragment is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
- R 8 in the S6 is methyl.
- the S is S6':
- Fragment is
- the S is -X-S6', and the structure of S6' is as described above;
- X is O, NH or S, preferably O.
- the S is S6a:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined and described in S6.
- R 1 is hydrogen;
- R 2 is selected from -O(C 1 -C 4 alkyl);
- R 3 is hydrogen;
- R 4 is C 1 - C 4 haloalkyl;
- R 5 is selected from -NH 2 ;
- R 7 is selected from C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
- the S is S6b:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined and described in S6.
- the S is S6c:
- R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined and described in S6.
- the S is -X-S6c, and the structure and definition of S6c are as described above; wherein, X is O, NH or S, preferably O.
- the S is S6d:
- X is O, NH or S, preferably O;
- R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined and described in S6.
- the S6 is a specific compound of I-1 to I-383 in WO2018115380A1 (the entirety of which is incorporated herein by reference).
- the S is S6e:
- R 2 , R 3 and R 7 are as defined and described in any one of the schemes of S6.
- the S is -X-S6e, and the structure and definition of S6e are as described above; wherein, X is O, NH or S, preferably O.
- R 2 is -O(C 1 -C 4 alkyl); R 3 is hydrogen; R 7 is C 1 -C 6 alkyl.
- R 2 is -OCH 3 ;
- R 3 is hydrogen;
- R 7 is methyl.
- the S6, S6', S6a or S6c is any of the following structures:
- the S6, S6', S6a, S6c or S6e are identical to each other.
- the S is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- S6 is S6 ":
- R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined and described in S6.
- Fragment is
- the S is -X-S6"', and the structure of S6"' is as described above; wherein X is O, NH or S, preferably O.
- the S6" is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the S is S6a":
- R 1 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined and described in S6.
- the S is S6b":
- R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined and described in S6.
- the S is S6c":
- R 3 , R 4 , R 5 , R 6 and R 7 are as defined and described in S6.
- the S is -X-S6c", and the structure and definition of S6c" are as described above; wherein, X is O, NH or S, preferably O.
- the S is S6d":
- X is O, NH or S, preferably O;
- R 3 , R 4 , R 5 , R 6 and R 7 are as defined and described in S6.
- the S is S6e":
- the S is -X-S6e", and the structure and definition of S6e" are as described above; wherein, X is O, NH or S, preferably O.
- R 3 is hydrogen; R 7 is C 1 -C 6 alkyl.
- R 3 is hydrogen; R 7 is methyl.
- the S6", S6c" or S6e" is N-(2-aminoe)
- the S is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the S is
- the S is
- the S is S7:
- R 2 is selected from hydrogen, halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkylmercapto or -NR a R b , said R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 2 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 heterocycloalkoxy (eg ), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 4-7 membered heterocycloalkyl (eg ), 5-10 membered heterocyclic alkenyl, spiro heterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C 1 -C 6 haloalkyl, -COOH, -COOR c ; Described R c is -C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl or
- R 2 is -NS(O)(R d )(R e ), and said R d and R e are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne base, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 6-10 membered aryl or 5-10 membered heteroaryl;
- R 2 is -NHC(O)-(C 1 -C 6 alkyl), -NHC(O)-NR a R b , and said R a and R b are each independently hydrogen, -C 1 -C 6 alkane radical, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl;
- R 2 is -NH-(CH 2 ) k -NH-C(O)-R aa which is C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 cycloalkyl, and k is 1 or 2;
- R 2 is -NH-(CH 2 ) i -R f , wherein i is 0, 1 or 2 and R f is 4-7 membered heterocycloalkyl, heteroaryl, C 1 -C 6 alkylsulfonyl ;
- C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally selected from halogen, - OH, oxo, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4-7 membered hetero Cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH 2 )-heteroaryl, -NHC(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkoxy, phenoxy, heteroaryloxy or -NR
- R 2 is -O-(CH 2 ) z -phenyl, -O-(CH 2 ) z -(4-7 membered heterocycloalkyl), -O-(CH 2 ) z -heteroaryl, said z is 0, 1 or 2, the phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted with -OH, heterocycloalkyl or heterocycloalkenyl, and can be methyl or oxo replace;
- R 1 is hydrogen or -OR A ;
- R A is hydrogen, C 3 -C 10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3 -C 10 cycloalkyl and 3-10 membered heterocycloalkyl are optionally composed of one or more same or different R a1 and/or R c1 substitutions;
- Each R a1 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3 -10-membered heterocycloalkyl or 5-10-membered heteroaryl; said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl , C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are each independently optionally substituted by one or more identical or different R b1 and/or R c1 ;
- Each R b1 is independently -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , - S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1 -C 4 alkyl)C(O)R c1 , oxo substituted , and the oxo group is only substituted on a non-aromatic ring;
- Each R c1 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl , 3-10 membered heterocycloalkyl or 5-10 heteroaryl;
- R 1 is selected from C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally surrounded by one or more R a2 and/or R b2 substitutions;
- Each R a2 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkane base, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl optionally substituted by 1 or more R c2 and/or R b2 ;
- Each R c2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by one or more R d2 and/or R e2 ;
- Each R d2 is independently -OR e2 , -NR e2 Re2 , halogen, -CN, -C(O)R e2 , -C(O)OR e2 , -C(O)NR e2 Re2 , - S(O) 2 R e2 , -S(O) 2 NR e2 R e2 , -NHC(O)R e2 , -N(C 1 -C 4 alkyl)C(O)R e2 , oxo, all The oxo group is only substituted on a non-aromatic ring;
- Each R e2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by one or more R f2 and/or R g2 ;
- Each R f2 is independently selected from -OR g2 , -NR g2 R g2 , halogen, -CN, -C(O)R g2 , -C(O)OR g2 , -C(O)NR g2 R g2 , -S(O) 2 R g2 , -S(O) 2 NR g2 R g2 , -NHC(O)R g2 , -N(C 1 -C 4 alkyl)C(O)R g2 , oxo,
- the oxo group is only substituted on a non-aromatic ring;
- Each R g2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
- R 1 is selected from C 2 -C 4 alkyl, C 2 -C 4 alkenyl; the C 2 -C 4 alkyl and C 2 -C 4 alkenyl are optionally substituted by R b3 ;
- R b3 is selected from -C(O)R c3 , -C(O)OR c3 , -C(O)NR c3 R c3 , -C(O)NHOR c3 or -C(O)N(C 1 -C 4 alkyl) OR c3 ;
- Each R c3 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by one or more R d3 and/or R e3 ;
- Each R d3 is independently selected from -OR e3 , -NR e3 R e3 , halogen, -CN, -C(O)R e3 , -C(O)OR e3 , -C(O)NR e3 R e3 , -S(O) 2 R e3 , -S(O) 2 NR e3 R e3 , -NHC(O)R e3 , -N(C 1 -C 4 alkyl)C(O)R e3 , oxo,
- the oxo group is only substituted on a non-aromatic ring;
- Each R e3 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
- R 4 is selected from hydrogen, C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 or halogen;
- the A 2 (R 3 ) Y is hydrogen
- a 2 is C 4 -C 12 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and
- R 3 is hydrogen, halogen, -OH, oxo, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 ring Alkyl, C 4 -C 8 cycloalkenyl, C 7 -C 8 cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C 1 -C 6 haloalkyl;
- alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted by 1, 2 or 3 selected from halogen, -OH, oxo, -CN, -C1 - C6 alkyl, -C1 - C6 alkoxy, -C1 - C6 haloalkyl, phenyl, heteroaryl or - Substituent substitution of C(O)NR i R j , each of said R i and R j is independently hydrogen or C 1 -C 6 alkyl;
- alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted with -NRkRl
- the R k and R l are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkylsulfonyl, phenyl, heteroaryl, -CH 2 -C(O)-R m , -C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkyne alkenyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are each independently optionally selected from 1, 2 or 3 C1
- the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted with -NRsRt
- the -NR s R t is a 4-7-membered aza-heterocycloalkyl connected to other parts of the molecule through a nitrogen atom or a 6-10-membered aza-heterocycloalkyl connected to other parts of the molecule through a nitrogen atom, and further including up to two heteroatoms selected from N or O, optionally surrounded by 1, 2 or 3 selected from -OH, oxo, C1 - C6 alkyl, C1 - C6 hydroxyalkane group, -C(O)OR z substituent, the R z is C 1 -C 6 alkyl, halogen, -N(C 1 -C 6 al
- R 3 is C(O)R v , -C(O)NH 2 , -C(O)NHR v , -C(O)NR v R w , -C(O)OR v , said R v and R w is each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, phenyl or -(CH 2 ) 2 NR x R y , said R x and R y are each independently hydrogen , C 1 -C 4 alkyl or -(CH 2 ) 2 N(CH 3 ) 2 ;
- R 3 is -NH 2 , -NHR z , -NR z R za , -NHC(O)R z , -NHC(O)OR z , -NHS(O) 2 R z , 4-7 membered heterocycloalkane base, heteroaryl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, the R z and R za are each independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
- R 3 is C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -O(CH 2 ) s -C 3 -C 8 cycloalkyl, -O(CH 2 ) s -phenyl, -O(CH 2 ) s -heterocycloalkyl, -O(CH 2 ) s -heteroaryl, wherein s is 0, 1, 2 or 3;
- R 3 is -S(O) 2 R z , -S(O) 2 NH 2 , -S(O) 2 NHR z , -S(O) 2 NR z R za , each of said R z and R za independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
- Y is 0, 1, 2, 3, 4 or 5;
- R 7 and R 8 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkoxy, the alkyl, Alkoxy, cycloalkyl and cycloalkoxy are optionally cyano, hydroxy, C1 - C6alkoxy , C3 - C6cycloalkyl, C3 - C6cycloalkoxy or halogen replace.
- the S is S7:
- R 1 is hydrogen or -OR A ;
- R A is hydrogen, C 3 -C 10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3 -C 10 cycloalkyl and 3-10 membered heterocycloalkyl are optionally composed of one or more same or different R a1 and/or R c1 substitutions;
- Each R a1 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3 -10-membered heterocycloalkyl or 5-10-membered heteroaryl; said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl , C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are each independently optionally substituted by one or more identical or different R b1 and/or R c1 ;
- Each R b1 is independently -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , - S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1 -C 4 alkyl)C(O)R c1 , oxo substituted , and the oxo group is only substituted on a non-aromatic ring;
- Each R c1 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl , 3-10 membered heterocycloalkyl or 5-10 heteroaryl;
- R 1 is selected from C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 6 -C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally surrounded by one or more R a2 and/or R b2 substitutions;
- Each R a2 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkane base, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl optionally substituted by 1 or more R c2 and/or R b2 ;
- Each R c2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by one or more R d2 and/or R e2 ;
- Each R d2 is independently -OR e2 , -NR e2 Re2 , halogen, -CN, -C(O)R e2 , -C(O)OR e2 , -C(O)NR e2 Re2 , - S(O) 2 R e2 , -S(O) 2 NR e2 R e2 , -NHC(O)R e2 , -N(C 1 -C 4 alkyl)C(O)R e2 , oxo, all The oxo group is only substituted on a non-aromatic ring;
- Each R e2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by one or more R f2 and/or R g2 ;
- Each R f2 is independently selected from -OR g2 , -NR g2 R g2 , halogen, -CN, -C(O)R g2 , -C(O)OR g2 , -C(O)NR g2 R g2 , -S(O) 2 R g2 , -S(O) 2 NR g2 R g2 , -NHC(O)R g2 , -N(C 1 -C 4 alkyl)C(O)R g2 , oxo,
- the oxo group is only substituted on a non-aromatic ring;
- Each R g2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
- R 1 is selected from C 2 -C 4 alkyl, C 2 -C 4 alkenyl; the C 2 -C 4 alkyl and C 2 -C 4 alkenyl are optionally substituted by R b3 ;
- R b3 is selected from -C(O)R c3 , -C(O)OR c3 , -C(O)NR c3 R c3 , -C(O)NHOR c3 or -C(O)N(C 1 -C 4 alkyl) OR c3 ;
- Each R c3 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 aryl, 3-10-membered heterocycloalkyl or 5-10-membered heteroaryl are optionally substituted by one or more R d3 and/or R e3 ;
- Each R d3 is independently selected from -OR e3 , -NR e3 R e3 , halogen, -CN, -C(O)R e3 , -C(O)OR e3 , -C(O)NR e3 R e3 , -S(O) 2 R e3 , -S(O) 2 NR e3 R e3 , -NHC(O)R e3 , -N(C 1 -C 4 alkyl)C(O)R e3 , oxo,
- the oxo group is only substituted on a non-aromatic ring;
- Each R e3 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl base, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;
- R 2 is selected from hydrogen, C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 or halogen;
- R 4 is selected from hydrogen, C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 or halogen;
- the A 2 (R 3 ) Y is hydrogen
- a 2 is C 4 -C 12 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and
- R 3 is hydrogen, halogen, -OH, oxo, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 ring Alkyl, C 4 -C 8 cycloalkenyl, C 7 -C 8 cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C 1 -C 6 haloalkyl;
- alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted by 1, 2 or 3 selected from halogen, -OH, oxo, -CN, -C1 - C6 alkyl, -C1 - C6 alkoxy, -C1 - C6 haloalkyl, phenyl, heteroaryl or - Substituent substitution of C(O)NR i R j , each of said R i and R j is independently hydrogen or C 1 -C 6 alkyl;
- alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted with -NRkRl
- the R k and R l are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkylsulfonyl, phenyl, heteroaryl, -CH 2 -C(O)-R m , -C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkyne alkenyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are each independently optionally selected from 1, 2 or 3 C1
- the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted with -NRsRt
- the -NR s R t is a 4-7-membered aza-heterocycloalkyl connected to other parts of the molecule through a nitrogen atom or a 6-10-membered aza-heterocycloalkyl connected to other parts of the molecule through a nitrogen atom, and further including up to two heteroatoms selected from N or O, optionally surrounded by 1, 2 or 3 selected from -OH, oxo, C1 - C6 alkyl, C1 - C6 hydroxyalkane group, -C(O)OR z substituent, the R z is C 1 -C 6 alkyl, halogen, -N(C 1 -C 6 al
- R 3 is C(O)R v , -C(O)NH 2 , -C(O)NHR v , -C(O)NR v R w , -C(O)OR v , said R v and R w is each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, phenyl or -(CH 2 ) 2 NR x R y , said R x and R y are each independently hydrogen , C 1 -C 4 alkyl or -(CH 2 ) 2 N(CH 3 ) 2 ;
- R 3 is -NH 2 , -NHR z , -NR z R za , -NHC(O)R z , -NHC(O)OR z , -NHS(O) 2 R z , 4-7 membered heterocycloalkane base, heteroaryl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, the R z and R za are each independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
- R 3 is C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -O(CH 2 ) s -C 3 -C 8 cycloalkyl, -O(CH 2 ) s -phenyl, -O(CH 2 ) s -heterocycloalkyl, -O(CH 2 ) s -heteroaryl, wherein s is 0, 1, 2 or 3;
- R 3 is -S(O) 2 R z , -S(O) 2 NH 2 , -S(O) 2 NHR z , -S(O) 2 NR z R za , each of said R z and R za independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl;
- Y is 0, 1, 2, 3, 4 or 5;
- R 7 and R 8 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkoxy, the alkyl, Alkoxy, cycloalkyl and cycloalkoxy are optionally cyano, hydroxy, C1 - C6alkoxy , C3 - C6cycloalkyl, C3 - C6cycloalkoxy or halogen replace.
- R 1 is hydrogen
- R 2 is hydrogen, C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 or halogen, said C 1 -C 4 alkyl and -O(C 1 -C 4 alkyl) are each independently optionally replaced by -O(C 1 -C 4 alkyl) substituted.
- R 2 is hydrogen, C 1 -C 4 alkyl, -O(C 1 -C 4 alkyl), -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 or halogen.
- R 2 is hydrogen, C 1 -C 4 alkyl or -O(C 1 -C 4 alkyl), the -O(C 1 -C 4 alkyl) ) is optionally substituted with -O(C 1 -C 4 alkyl).
- R 2 is
- R 2 is -O(C 1 -C 4 alkyl).
- R 4 is hydrogen
- R 3 is hydrogen, halogen or C 1 -C 6 alkyl, and the alkyl is optionally substituted by -NR k R l ; the R k and R l are each independently hydrogen or C1 - C6 alkyl.
- a 2 is an aryl group.
- Y is 0, 1, 2 or 3.
- L' is a bond
- R 7 is a C 1 -C 6 alkyl group.
- R 8 is a C 1 -C 6 alkyl group.
- R 1 is hydrogen
- R 2 is hydrogen, C 1 -C 4 alkyl, or -O(C 1 -C 4 alkyl) (eg, methoxy), optionally -O(C 1 -C 4 alkyl) (C 1 -C 4 alkyl) (eg methoxy) substituted;
- R 4 is hydrogen
- R 3 is hydrogen, halogen or C 1 -C 6 alkyl, and said alkyl is optionally substituted by -NR k R l ; said R k and R l are each independently hydrogen or C 1 -C 6 alkyl;
- a 2 is aryl
- Y is 0, 1, 2 or 3;
- R 7 is C 1 -C 6 alkyl
- R 8 is C 1 -C 6 alkyl.
- R 2 is hydrogen, methyl, -OCH 3 or
- R 2 is -O(C 1 -C 4 alkyl), such as -OCH 3 .
- R 3 is hydrogen, F, Cl, methyl or ethyl, and the methyl and ethyl are substituted by -NR k R 1 ; the R k is methyl or ethyl, R l is hydrogen, methyl or ethyl.
- R 3 is hydrogen, Cl, -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 .
- a 2 is a phenyl group.
- R 7 is methyl
- R 8 is methyl
- the S is S7':
- R 2 , R 3 , R 4 , R 7 , R 8 , Y, A 2 and L' are as defined and described in S7.
- Fragment is
- the S is -O-S7', wherein the structure and definition of S7' are as described above.
- the S is S7":
- R 2 , R 3 , R 4 , R 7 , Y, A 2 and L' are as defined and described in S7.
- the S is -O-S7", wherein the structure and definition of S7" are as described above.
- the S is S7a:
- R 1 , R 2 , R 3 , R 4 , R 7 , R 8 and Y are as defined and described in S7.
- the S is S7a':
- R 2 , R 3 , R 4 , R 7 , R 8 and Y are as defined and described in S7.
- Fragment is
- the S is -O-S7a', wherein the structure and definition of S7a' are as described above.
- the S is S7a":
- R 2 , R 3 , R 4 , R 7 and Y are as defined and described in S7.
- the S is -O-S7a", wherein the structure and definition of S7a" are as described above.
- R 3a and R 3b are independently as described for R 3 .
- R 3b is a C 1 -C 6 alkyl group, and the alkyl group is substituted by -NR k R l ; the R k and R l are each independently hydrogen or C 1 -C 6 alkane base.
- R 3b is methyl or ethyl, and said methyl and ethyl are substituted by -NHR 1 or -NR k R 1 ; said R k and R 1 are each independently methyl or ethyl.
- R 3b is -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 .
- R3a is hydrogen or halogen, such as H or Cl.
- the S, S7, S7', S7", S7a, S7a' and S7a" are any of the following structures:
- the S, S7, S7', S7", S7a, S7a' and S7a" are provided.
- the S, S7, S7', S7", S7a, S7a' and S7a" have the following structures:
- the S, S7, S7', S7", S7a, S7a' and S7a" have the following structures:
- the S is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L is a bond
- L is -(CH 2 ) j -, and one or more methylene groups in the -(CH 2 ) j - are optionally selected from -NR 3' -, - O-, -S-, -S(O)-, -S(O)NR 3' -, -NR 3' S(O)-, -S(O) 2 -, -S(O) 2 NR 3 ' -, -NR 3' S(O) 2 -, -NR 4' S(O) 2 NR 3' -, -CR 1' R 2' -, -C(O)-, -C(O)O -, -OC(O)-, -NR 3' C(O)O-, -OC(O)NR 3' -, -C(O)NR 3' -, -NR 3' C(O)NR 3' -, -NR 3' C(O)NR 3' -, -NR 3' C(
- L is -(CH 2 ) j -, and one or more methylene groups in the -(CH 2 ) j - are optionally selected from -NR 3' -, -O-, -CR 1' R 2' -, -C(O)-, -S(O)-, -S(O) 2 -, -C(O)O-, -OC(O) -, -C(O)NR 3' -, -NR 3' C(O)-, -S(O) 2 NR 3' -, -NR 3' S(O) 2 -, vinylidene, acetylene base, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered Saturated or partially unsaturated fused
- L is -(CH 2 ) j -, and one or more methylene groups in the -(CH 2 ) j - are optionally selected from -NR 3' -, -O-, -CR 1' R 2' -, -C(O)-, -S(O)-, -S(O) 2 -, -C(O)O-, -OC(O) -, -C(O)NR 3' -, -NR 3' C(O)-, -S(O) 2 NR 3' -, -NR 3' S(O) 2 -, vinylidene, acetylene base, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated monocyclic cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5- 11-membered saturated or partially unsaturated fuse
- L is -(CH 2 ) j -, and 1, 2, 3, 4 or 5 methylene groups in the -(CH 2 ) j - are any selected from the group consisting of -NH-, -NCH3-, -O-, -C( CH3 ) 2- , -CHF-, -CHCF3- , -C(O)-, -C(O)O- , -OC(O)-, -C(O)NH-, -C(O)NCH 3 -, -NHC(O)-, -NCH 3 C(O)-, vinylidene, ethynylene, Cyclopropyl, cyclobutylene, cyclopentylene, cyclohexylene, oxiranylene, oxetylene, oxolane, oxane, aziridine base, azetidine, azetidine, piperid
- L is -(CH 2 ) j -, and 1, 2, 3, 4 or 5 methylene groups in the -(CH 2 ) j - are any selected from the group consisting of -NH-, -NCH3-, -O-, -C( CH3 ) 2- , -CHF-, -CHCF3- , -C(O)-, -C(O)O- , -OC(O)-, -C(O)NH-, -C(O)NCH 3 -, -NHC(O)-, -NCH 3 C(O)-, cyclopropylene, cyclobutylene , cyclopentylene, cyclohexylene, oxane, oxetylene, oxolane, oxane, aziridine, aziridine , nitrosyl, piperidinide, piperazinide, morpholinide,
- L is -(CH 2 ) j -, and 1, 2, 3, 4 or 5 methylene groups in the -(CH 2 ) j - are any selected from -O-, -NH-, -NCH3-, -C(O)-, -C(O)NH-, -NHC(O) - , -NCH3C (O)-, - C(O)NCH 3 -, cyclohexylene, azidopropyl, azidobutyl, azidopentyl, piperidinylene, piperazinylene, group substitution, j is 4, 5, 6, 7, 8, 9 or 10.
- L is selected from -(CH 2 ) j-1 -C(O)-, the methylene group in the -(CH 2 ) j-1 -C(O)- as defined in L above, optionally substituted by one or more groups, and said j is as defined in L above.
- L is selected from
- the L is any of the following structures:
- the L is LA
- Ring A is a bond, C 3 -C 12 cycloalkylene (eg wherein the a-terminus is attached to S and the b-terminus is attached to X"') or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g.
- the cycloalkylene and heterocycloalkylene are optionally selected from halogen, oxo, cyano, amino, hydroxy, C 1 -C 6 Substituent substitution of alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
- Ring B is a bond, C 3 -C 12 cycloalkylene (eg, wherein the c-terminus is attached to X"' and the d-terminus is attached to L3) or a 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S (eg wherein the c-terminus is attached to X"' and the d - terminus is attached to L3), the cycloalkylene and heterocycloalkylene are optionally selected from halogen, oxo, cyano, amino, hydroxyl, C1 -C Substituent substitution of 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
- Ring C is C 3 -C 12 cycloalkylene (eg wherein the e-terminus is attached to L and the f-terminus is attached to X”) or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g.
- the cycloalkylene and heterocycloalkylene are optionally selected from halogen, oxo, cyano, amino, hydroxyl, C1 - C6 Substituent substitution of alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl or -O-(C 1 -C 6 alkyl);
- L 3 is -(CH 2 ) k , and one or two methylene groups in said L 3 are optionally selected from -O-, -NH-, -C ⁇ C-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -C(O)-, -N(C 1 -C 6 hydroxyalkyl)- or -N(C 3 -C 8 cycloalkane base)-substitution, k is 0, 1, 2, 3, 4, 5, 6 or 7;
- Ring A is C 3 -C 12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, said cycloalkylene and heterocycloalkylene is optionally selected from halogen, oxo, cyano, amino, hydroxy, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl or -O-( C1 -C 6 alkyl) substituent substitution;
- Ring B is C 3 -C 12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, said cycloalkylene and heterocycloalkylene is optionally selected from halogen, oxo, cyano, amino, hydroxy, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl or -O-( C1 -C 6 alkyl) substituent substitution;
- Ring C is C 3 -C 12 cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, said cycloalkylene and heterocycloalkylene is optionally selected from halogen, oxo, cyano, amino, hydroxy, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl or -O-( C1 -C 6 alkyl) substituent substitution;
- L 3 is -(CH 2 ) k , and one or two methylene groups in said L 3 are optionally selected from -O-, -NH-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -N(C 1 -C 6 hydroxyalkyl)- or -N(C 3 -C 8 cycloalkyl)- substitution, k is 0, 1, 2, 3 or 4;
- L 3 is -(CH 2 ) k , and one or two methylene groups in the L 3 are optionally selected from -O-, -NH-, -C ⁇ C-, -N(C 1 -C 6 alkyl)-, -N(C 1 -C 6 haloalkyl)-, -N(C 1 -C 6 hydroxyalkyl)- or -N(C 3 - C8cycloalkyl )-substitution, k is 0, 1, 2, 3, 4, 5, 6 or 7.
- ring A is a bond.
- ring A is a 3-7 membered saturated or partially unsaturated cycloalkylene, a 4-11 membered saturated or partially unsaturated spirocycloalkylene , 4-11-membered saturated or partially unsaturated fused cycloalkylene, 8-10-membered bicyclic saturated or partially unsaturated cycloalkylene, with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur 4-7 membered saturated or partially unsaturated heterocycloalkylene, 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene with 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur , 4-11-membered saturated or partially unsaturated fused heterocycloalkylene groups with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur 8- to 10-membered bicyclic saturated or partially unsaturated heterocycloalkylene of atoms
- ring A is a 3-6 membered saturated cycloalkylene group or a 4-7 membered saturated cycloalkylene group with 1 or 2 heteroatoms independently selected from nitrogen of monocyclic heterocycloalkylene.
- ring A is a cyclohexylene group (such as cyclohexylene-1,4-diyl, such as trans-cyclohexylene-1,4-diyl), a piperidinyl (eg piperidine-1,4-diyl) or piperazinylene (eg piperazine-1,4-diyl).
- cyclohexylene group such as cyclohexylene-1,4-diyl, such as trans-cyclohexylene-1,4-diyl
- piperidinyl eg piperidine-1,4-diyl
- piperazinylene eg piperazine-1,4-diyl
- ring A is The a-end is connected to S, and the b-end is connected to X"'.
- ring A is The a-end is connected to S, and the b-end is connected to X"'.
- ring A is The a-end is connected to S, and the b-end is connected to X"'.
- ring B is a bond.
- ring B is a 3-7 membered saturated or partially unsaturated cycloalkylene, a 4-11 membered saturated or partially unsaturated spirocycloalkylene , 4-11-membered saturated or partially unsaturated fused cycloalkylene, 8-10-membered bicyclic saturated or partially unsaturated cycloalkylene, with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur 4-7 membered saturated or partially unsaturated heterocycloalkylene, 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene with 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur , 4-11-membered saturated or partially unsaturated fused heterocycloalkylene groups with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur 8- to 10-membered bicyclic saturated or partially unsaturated heterocycloalkylene of atoms
- ring B is a 4-7-membered saturated monocyclic heterocycloalkylene containing one or two nitrogen heteroatoms, containing one or two nitrogen heteroatoms. 7-11 membered spiroheterocycloalkylene or fused heterocycloalkylene with nitrogen heteroatom.
- ring B is a piperidinide group (such as piperidine-1,4-diyl) or a piperazinide group (such as piperazine-1,4-diyl) base).
- ring B is Wherein the c-terminal is connected with X''', and the d - terminal is connected with L3.
- ring B is Wherein the c-terminal is connected with X''', and the d - terminal is connected with L3.
- ring C is a 3-7 membered saturated or partially unsaturated cycloalkylene, a 4-11 membered saturated or partially unsaturated spirocycloalkylene , 4-11-membered saturated or partially unsaturated fused cycloalkylene, 8-10-membered bicyclic saturated or partially unsaturated cycloalkylene, with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur 4-7 membered saturated or partially unsaturated heterocycloalkylene, 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene with 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur , 4-11-membered saturated or partially unsaturated fused heterocycloalkylene groups with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur 8- to 10-membered bicyclic saturated or partially unsaturated heterocycloalkylene of atoms
- ring C is a 4-7 membered saturated monocyclic heterocycloalkylene containing one or two nitrogen heteroatoms, containing one or two nitrogen heteroatoms. 7-11 membered spiroheterocycloalkylene or fused heterocycloalkylene with nitrogen heteroatom.
- ring C is a piperidinide group (such as piperidine-1,4-diyl), a piperazinide group (such as piperazine-1,4-diyl) base), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g )or (E.g ).
- a piperidinide group such as piperidine-1,4-diyl
- a piperazinide group such as piperazine-1,4-diyl
- ring C is The e end is connected to L 3 and the f end is connected to X".
- ring C is The e end is connected to L 3 and the f end is connected to X".
- X" is a bond or -C(O)-.
- X is a bond.
- X" is -C(O)-.
- X"' is a bond or -C(O)-.
- X"' is a bond.
- X"' is -C(O)-.
- k is 1, 2, 3, 4 or 5.
- L 3 is -(CH 2 ) k
- k is 1, 2, 3, 4 or 5.
- L 3 is -(CH 2 ) k , and one or two methylene groups in the L 3 are optionally -O-, -NH- , -C ⁇ C- or -N(C 1 -C 6 alkyl)- (eg -N(CH 3 )-) substitution, and k is 1, 2, 3, 4 or 5.
- k is 1, 2, 3 or 4.
- L 3 is -(CH 2 ) k -, wherein one or two CH 2 contained in the L 3 are each independently optionally -O -, -NH- or -N(C 1 -C 6 alkyl)- (eg -N(CH 3 )-) is replaced, or one -CH 2 CH 2 - contained in said L 3 is optionally - C ⁇ C-substitution; k is 1, 2, 3, or 4.
- L 3 is -(CH 2 ) k -, and a methylene group in the L 3 is optionally -O-, -NH- or - Group substitution of N(C 1 -C 6 alkyl)- (eg -N(CH 3 )-); k is 1, 2, 3 or 4.
- ring A in the LA is a 3-6 membered saturated cycloalkylene;
- ring B contains 1 or 2 nitrogen heteroatoms, a 4-7 membered saturated monocyclic ring Heterocycloalkylene;
- Ring C is a 4-7 membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, a 7-11 membered containing 1 or 2 nitrogen heteroatoms spiroheterocycloalkylene or fused heterocycloalkylene;
- X" is a bond or -C(O)-;
- L 3 is -(CH 2 ) k , k is 1, 2, 3, 4 or 5 (eg, k is 1, 2, 3 or 4).
- the LA is LA-1:
- Ring A , Ring B, Ring C, L3, X are as defined and described in LA.
- the LA is LA-2:
- ring A is The a-end is connected to S, and the b-end is connected to X"';
- X"' is -C(O)-
- Ring B is Wherein the c end is connected with X "', and the d end is connected with L 3 ;
- L 3 is -(CH 2 ) k -, wherein one or two CH 2 contained in said L 3 are each independently optionally -O-, -NH- or -N(C 1 -C 6 alkyl )- (eg -N(CH 3 )-) substitution; k is 1, 2, 3 or 4;
- Ring C is Wherein the e end is connected with L3, and the f end is connected with X" ;
- X" is a bond or -C(O)-.
- ring A is The a-end is connected to S, and the b-end is connected to X"'.
- ring B is Wherein the c-terminal is connected with X''', and the d - terminal is connected with L3.
- k is 2, 3 or 4.
- L 3 is -(CH 2 ) k -, wherein one CH 2 contained in the L 3 is optionally -O- substitution; k is 2, 3 or 4.
- L 3 in the LA, LA-1 and LA-2, L 3 can be -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -,
- the k" end is connected to ring B, and the k' end is connected to ring C.
- ring C is The e end is connected to L 3 and the f end is connected to X".
- the LA-2 is any of the following structures:
- the LA is LA-4:
- ring A is The a-end is connected to S, and the b-end is connected to X"';
- X"' is the key
- Ring B is a bond
- L 3 is -(CH 2 ) k -, wherein one or two CH 2 contained in said L 3 are each independently optionally -O-, -NH- or -N(C 1 -C 6 alkyl )- (eg -N(CH 3 )-) substitution; k is 1, 2, 3 or 4;
- Ring C is Wherein the e end is connected with L3, and the f end is connected with X" ;
- X is the key.
- ring A is The a-end is connected to S, and the b-end is connected to X"'.
- ring B is Wherein the c-terminal is connected with X''', and the d - terminal is connected with L3.
- k is 2, 3 or 4.
- L 3 is -(CH 2 ) k -, wherein one CH 2 included in the L 3 is optionally -O- Alternative; k is 2, 3, or 4.
- L 3 in the LA, LA-1 and LA-2, L 3 may be -(CH 2 ) 2 - or -(CH 2 ) 3 -.
- ring C is The e end is connected to L 3 and the f end is connected to X".
- the LA-4 is any of the following structures:
- the LA is any of the following structures:
- the compound of formula I is any of the following compounds:
- the deuterated compound is 1 in a compound structure (eg, L, eg, Ring A , Ring B, L3, Ring C in LA, LA-1, LA-2, LA-4). , 2, 3, 4, 5, 6, 7, 8, 9 or 10 H replaced by deuterium.
- the deuterated LA structure is
- the present invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or The preparation method of its pharmaceutically acceptable salt.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, and solvates , metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients.
- the present invention provides a method for degrading SOS1 protein, comprising making the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, The metabolite, prodrug and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted with the SOS1 protein.
- the present invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and /or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for treating or preventing SOS1-mediated diseases or disorders.
- the present invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and /or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for the treatment or prevention of a disease or disorder (cancer) caused by the interaction of SOS1 with Ras (eg KRAS) or SOS1 and Rac (eg KRAS) application.
- a disease or disorder cancer
- the present invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prevention of SOS1-mediated diseases or disorders (eg, cancer).
- SOS1-mediated diseases or disorders eg, cancer
- the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceuticals thereof Use of an acceptable salt of the above, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder (eg, cancer) caused by the interaction of SOS1 and Ras (eg, KRAS) or SOS1 and Rac (eg, KRAS).
- a disease or disorder eg, cancer
- a disease or disorder eg, cancer
- SOS1 and Ras eg, KRAS
- SOS1 and Rac eg, KRAS
- the present invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing cancer.
- the present invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or Its pharmaceutically acceptable salt, or its pharmaceutical composition is used in the preparation of treatment or prevention of pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, Acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer , ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma drug application.
- the present invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of the treatment or prevention of neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple freckles (NSML), capillary Vascular malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Leggers syndrome and hereditary gingival fibromatosis.
- NF1 neurofibromatosis type 1
- NS Noonan syndrome
- NML noonan syndrome with multiple freckles
- CM-AVM capillary Vascular malformation-arteriovenous malformation syndrome
- CS Costello syndrome
- CFC cardio-facial-cutaneous syndrome
- Leggers syndrome and hereditary gingival fibromato
- the present invention provides a method of treating or preventing a disease or disorder mediated by SOS1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, and/or a stereoisomer, enantiomer, non- Enantiomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
- the present invention provides a method of treating or preventing a disease or disorder (eg, cancer) modulated by the interaction of SOS1 and Ras (eg, KRAS) or SOS1 and Rac (eg, KRAS), comprising administering to a patient in need thereof a therapeutically effective amount of a formula Compound I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof , or its pharmaceutical composition.
- a disease or disorder eg, cancer
- SOS1 and Ras eg, KRAS
- SOS1 and Rac eg, KRAS
- the cancer may be selected from:
- Sarcomas angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibroids, lipomas and teratoma groups;
- Bronchial carcinoma squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma
- alveolar carcinoma bronchiolar carcinoma
- bronchial adenoma sarcoma
- lymphoma chondroma
- hamartoma interstitial carcinoma skin tumor
- Gastrointestinal esophagus squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma , carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine ( adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);
- Kidney adenocarcinoma, Wilms tumor, lymphoma, leukemia
- bladder and urethra squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (spermatogonia) tumor, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, mesenchymal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma
- kidney adenocarcinoma, Wilms tumor, lymphoma, leukemia
- bladder and urethra squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma
- prostate adenocarcinoma, sarcoma
- testis spermatogonia
- tumor teratoma, embryonal carcinoma, teratoma, choriocarcinoma, s
- liver cancer hepatocellular carcinoma
- cholangiocarcinoma hepatoblastoma
- angiosarcoma hepatocellular adenoma
- hemangioma hepatocellular adenoma
- Biliary tract gallbladder cancer, ampullary cancer, cholangiocarcinoma;
- Bone Osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, chondroma (extrachondral bone disease), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;
- Nervous system skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis malformations), meninges (meningiomas, meningiosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas) , ependymoma, germinoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibromas , meningioma, glioma, sarcoma);
- Gynecology Uterine (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granular-schingmocytoma, Sertoli stromal cell tumor, germ cell tumor, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, grape sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer);
- Hematology Hematology (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's Gold lymphoma (malignant lymphoma);
- Skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;
- Adrenal gland neuroblastoma.
- the cancer can be selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid cancer Leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer , prostate cancer, glioblastoma, kidney cancer and sarcoma.
- the present invention also provides a aforementioned compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or Use of a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of KRAS-mediated diseases or disorders.
- the present invention also provides a method of treating and/or preventing a KRAS-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, and/or a stereoisomer, enantiomer thereof isomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
- the KRAS may be a mutant KRAS.
- the mutant KRAS is preferably one or more of KRAS G12C, KRAS G12D, KRAS G13D and KRAS G12V.
- the present invention provides a compound of formula I, or a stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug or pharmaceutically acceptable compound thereof.
- INT-A and INT-B undergo reductive amination reaction to obtain the target compound; wherein the reducing reagents for the reductive amination include but are not limited to Pd/C, sodium borohydride, sodium cyanoborohydride, borane, triacetoxy Sodium borohydride.
- Ring B containing an NH group
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined and described in S6b
- Ring A, Ring B, Ring C, X" are as defined in LA
- E is as defined and described in the present invention, preferably E is E7, E7a, E7b, E7c, E7d, E7e , E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21-1bb , E21-1cc, E21-1dd, E21-1ee, E21-1ff, E21-1gg or E21-1hh.
- Substitution reaction occurs between INT-C and INT-D under alkaline conditions to obtain the target compound; wherein the base includes but not limited to triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate .
- E is as defined and described in the present invention, preferably E is E7, E7a, E7b, E7c, E7d, E7e, E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21-1bb, E21-1cc, E21-1dd, E21- 1ee, E21-1ff, E21-1gg or E21-1hh.
- Substitution reaction occurs between INT-E and INT-D under alkaline conditions to obtain the target compound; wherein the base includes but is not limited to triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate .
- E is as defined and described in the present invention, preferably E is E7, E7a, E7b, E7c, E7d, E7e, E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21-1bb, E21-1cc, E21-1dd, E21- 1ee, E21-1ff, E21-1gg or E21-1hh,.
- Alkyl refers to saturated aliphatic hydrocarbon groups, including straight or branched chain alkyl groups; C 1 -C 8 alkyl groups refer to alkyl groups containing 1-8 carbon atoms, such as methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2 - Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-tri Methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl , 2-methylpentyl, 3-methylpentyl,
- the alkyl group may be substituted or unsubstituted.
- the alkyl group is a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 alkyl.
- Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent;
- C 3 -C 11 cycloalkyl refers to a cycloalkyl group comprising 3 to 11 carbon atoms;
- C 3 -C 11 cycloalkyl refers to a cycloalkyl group including 3 to 8 carbon atoms;
- C 5 -C 10 -membered cycloalkyl refers to a cycloalkyl group including 5 to 10 carbon atoms;
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3 - C8 -membered cycloalkyl; more preferably C3 - C6 -membered cycloalkyl.
- Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
- “Spirocycloalkyl” refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings. They may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably 7-12 membered double-spirocycloalkyl groups.
- Non-limiting examples of spirocycloalkyl include:
- fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but None of the rings have a fully conjugated pi electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic fused cycloalkyl.
- fused cycloalkyl groups include:
- Bridged cycloalkyl refers to an all-carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, they may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system , according to the number of rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl.
- Non-limiting examples of bridged cycloalkyl groups include:
- the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydro Naphthyl, benzocycloheptyl, etc.
- the cycloalkyl group may be optionally substituted or unsubstituted.
- the cycloalkyl is C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 monocyclic or polycyclic (eg, spirocyclic , fused ring or bridged ring) cycloalkyl.
- Heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more (eg 2, 3, 4 or 5) ring atoms are selected from nitrogen, oxygen or S ( O) r (wherein r is the integer 0, 1 or 2), but does not contain ring moieties of -OO-, -OS- or -SS- and the remaining ring atoms are carbons.
- 3-11 membered heterocycloalkyl refers to a ring group containing 3 to 11 ring atoms
- 5-10 membered heterocycloalkyl refers to a ring group containing 5 to 10 ring atoms
- 3-8 membered heterocycloalkyl refers to a ring group containing 3 to 8 ring atoms, preferably "3-11 membered heterocycloalkyl” containing 1-2 heteroatoms selected from N, O or S, more preferably containing 1 or 2 3- to 11-membered heterocycloalkyl with N atoms.
- Monocyclic heterocycloalkyl is preferably a 3-8 membered monocyclic heterocycloalkyl containing 1-2 N heteroatoms; non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, piperidinyl, piperidine oxazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl and piperazinyl.
- Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups.
- “Spiroheterocycloalkyl” refers to a polycyclic heterocycloalkyl group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r (where r are integers 0, 1, 2) and the remaining ring atoms are carbon. They can contain one or more double bonds, but none of the rings have a fully conjugated pi electron system.
- the spirocycloalkyl groups are divided into single spiroheterocycloalkyl, double spiroheterocycloalkyl or polyspiroheterocycloalkyl, preferably containing 1-2 atoms selected from N, O or a saturated "3-11-membered bis-spiroheterocycloalkyl" of an S heteroatom; more preferably a saturated "7-11-membered bis-spiroheterocycloalkyl" containing 1 or 2 N atoms.
- spiroheterocycloalkyl include:
- “Fused heterocycloalkyl” refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but None of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon.
- the number of formed rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkanes, preferably "3-11-membered bicyclic fused heterocycloalkanes containing 1-3 heteroatoms selected from N, O or S"group"; more preferably a saturated "3-11 membered bicyclic fused heterocycloalkyl" containing 1 or 2 N atoms.
- fused heterocycloalkyl include:
- Bridged heterocycloalkyl refers to polycyclic heterocycloalkyl groups in which any two rings share two atoms that are not directly connected, they may contain one or more double bonds, but none of the rings have fully conjugated pi electrons System wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon.
- Bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic according to the number of constituent rings, non-limiting examples of bridged heterocycloalkyl include:
- heterocycloalkyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring linked to the parent structure is a heterocycloalkyl, non-limiting examples include:
- the heterocycloalkyl group can be optionally substituted or unsubstituted.
- the heterocycloalkyl is a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 membered monocyclic or polycyclic (eg spiro, fused or bridged) heterocyclic Cycloalkyl in which the number of heteroatoms may be 1, 2, 3, 4 or 5, each heteroatom being independently nitrogen, oxygen or S(O) r (where r is the integer 0, 1 or 2) .
- Aryl refers to an all-carbon monocyclic or fused polycyclic group (that is, rings that share adjacent pairs of carbon atoms) and a polycyclic group with a conjugated pi-electron system
- 6-10 membered aryl refers to a group containing 6 to 10 members.
- -10 carbon percarbon aryl groups such as phenyl and naphthyl; preferably phenyl.
- the aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include:
- the aryl group can be optionally substituted or unsubstituted. In some embodiments, the aryl group is a 6-10 membered aryl group.
- Heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2), 5-6 membered heteroatoms
- Aryl refers to a heteroaromatic system containing 5-6 ring atoms
- 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, preferably a 5-6 membered heteroaryl; more preferably contains 1 5-6 membered heteroaryl with 1 or 2 N atoms; non-limiting examples include furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazole, imidazole pyridyl, triazolyl, tetrazolyl, etc.; preferably pyridyl.
- the heteroaryl ring can be fused to an aryl, heterocyclo
- the heteroaryl group can be optionally substituted or unsubstituted.
- the heteroaryl group is a 5, 6, 7, 8, 9, or 10 membered heteroaryl group, wherein the number of heteroatoms can be 1, 2, 3, 4 or 5, each heteroatom
- the atoms are independently nitrogen, oxygen or S.
- Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
- C2-8 alkenyl refers to a straight or branched chain containing 2-8 carbons Alkenyl, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably "C 2-6 alkenyl", more preferably "C 2-4 alkene " base”.
- the alkenyl group may be substituted or unsubstituted.
- the alkenyl group is C2 , C3, C4 , C5 , C6 , C7 , C8 alkenyl.
- Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
- C2-8alkynyl refers to a straight or branched chain alkynyl group containing 2-8 carbons , including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C 2-6 alkynyl", more preferably "C 2-4 alkynyl " base”.
- the alkynyl group may be substituted or unsubstituted.
- the alkynyl group is C2 , C3, C4 , C5 , C6 , C7 , C8 alkynyl.
- Subgroup refers to a divalent group, such as alkylene refers to a divalent alkyl group, alkenylene refers to a divalent alkenyl group, alkynylene refers to a divalent alkynyl group, cycloalkylene refers to a divalent cycloalkyl group, and Heterocycloalkyl refers to divalent heterocycloalkyl, arylene refers to divalent aryl, heteroarylene refers to divalent heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane Radyl, aryl, heteroaryl are as defined above, and the subunits may be optionally substituted or unsubstituted.
- Haloalkyl refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein the alkyl group is as defined above, non-limiting examples include difluoromethyl, dichloromethyl , dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
- Hydroxyalkyl refers to an alkyl group optionally substituted with one or more -OH, wherein the alkyl group is as defined above, non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl base.
- Alkoxy refers to -O-alkyl, wherein the alkyl group is as defined above, non-limiting examples include methoxy, ethoxy, isopropoxy, t-butoxy, and the like.
- Cycloalkoxy refers to -O-cycloalkyl, wherein the cycloalkyl is as defined above, non-limiting examples include cyclopropanoxy, cyclobutanoxy, cyclopentyloxy, cyclohexane Oxygen, etc.
- Heterocycloalkoxy refers to -O-heterocycloalkyl, wherein the heterocycloalkyl is as defined above, non-limiting examples include azetidinyloxy, azetidineoxy, piperidine pyridinyloxy, piperazinyloxy, oxolanyloxy, oxohexyloxy, and the like.
- -C(O) C1 - C3 alkyl refers to -C(O) -CH3 , -C (O) -CH2CH3 , and the like.
- Cyano refers to -CN.
- Carboxyl or “carboxylic acid” refers to -COOH.
- Halogen refers to fluorine, chlorine, bromine or iodine.
- Pd( PPh3 ) 2Cl2 refers to (dichlorobis(triphenylphosphonium)palladium).
- TAA triethylamine
- EA or EtOAc refers to ethyl acetate.
- THF tetrahydrofuran
- NaBH4 refers to sodium borohydride
- DCM dichloromethane
- Tf2O refers to trifluoromethanesulfonic anhydride.
- (Bpin) 2 refers to bipinacol biborate.
- Pd(dppf) 2 Cl 2 refers to 1,1'-bisdiphenylphosphinoferrocene palladium dichloride.
- KAc refers to potassium acetate
- DMF N,N-dimethylformamide
- NBS N-bromosuccinimide
- MeOH refers to methanol
- Pd/C refers to palladium/carbon
- Pd(OH) 2 /C refers to palladium hydroxide/carbon.
- DMSO dimethyl sulfoxide
- HATU refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
- TFA trifluoroacetic acid
- NMP refers to N-methylpyrrolidone
- IBX refers to 2-iodoylbenzoic acid.
- DIEA refers to N,N-diisopropylethylamine.
- STAB sodium triacetoxyborohydride
- T3P refers to 2,4,6-tripropyl-1,3,5,2,4,6 - trioxytriphosphoric acid-2,4,6-trioxide.
- NaOH sodium hydroxide
- DMAP refers to 4-dimethylaminopyridine.
- TPSCl refers to 2,4,6-triisopropylbenzenesulfonyl chloride.
- DPBS Dulbecco's Phosphate Buffered Saline.
- Dess-Martin refers to Dess-Martin reagents.
- PBS refers to phosphate buffered saline.
- SDS-PAGE refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
- PVDF polyvinylidene fluoride
- PE refers to petroleum ether
- NaHCO3 refers to sodium bicarbonate.
- Na2SO4 refers to sodium sulfate .
- NH4Cl refers to ammonium chloride.
- HCl refers to hydrochloric acid
- DCC refers to N,N'-dicyclohexylcarbodiimide.
- Ti(OEt) 4 refers to tetraethyl titanate.
- L-Selectride refers to lithium triisobutylborohydride.
- BOP means benzotriazol-1-oxytris(dimethylamino)phosphorus hexafluorophosphate
- DBU refers to 1,8-diazacyclo[5,4,0]undecene-7
- LiOH.H 2 O refers to lithium hydroxide monohydrate
- EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
- Ac2O refers to acetic anhydride.
- HOAc refers to acetic acid
- Halsch-ester refers to diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.
- DMA dimethylacetamide
- NiBr 2 (dtbpy) refers to 4,4-di-tert-butylbipyridine nickel dibromide.
- K2CO3 refers to potassium carbonate.
- 9-BBN refers to 9-borabicyclo[3.3.1]nonane.
- MTBE refers to methyl tert-butyl ether
- LiOH refers to lithium hydroxide
- DCE dichloroethane
- NaBH3CN refers to sodium cyanoborohydride
- CBr4 refers to carbon tetrabromide
- PPh3 refers to triphenylphosphine.
- n-BuLi refers to n-butyllithium
- NaH sodium hydrogen
- i-PrOH refers to isopropanol.
- ACN refers to acetonitrile
- NH4HCO3 refers to ammonium bicarbonate .
- m-CPBA refers to meta-chloroperoxybenzoic acid.
- KI refers to potassium iodide
- IPA isophthalic acid
- N2H4 - H2O refers to hydrazine hydrate.
- NMI N-methylimidazole
- TCFH means tetramethylchlorourea hexafluorophosphonate
- Ruphos Pd G2 means chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl) -2-yl)palladium(II).
- K3PO4 refers to potassium phosphate .
- (Boc) 2 O refers to di-tert-butyl dicarbonate.
- Prep-HPLC refers to preparative high performance liquid chromatography.
- Optional means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not occur.
- a heterocycloalkyl group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the specification includes the case where the heterocycloalkyl group is substituted with an alkyl group and the case where the heterocycloalkyl group is not substituted with an alkyl group replaced situation.
- Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are independently of one another substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
- the term "optionally substituted” as used herein can be unsubstituted or substituted; when substituted, the substituents can be one or more (eg 2, 3, 4, 5 or 6) independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo, cycloalkyl, heterocycloalkyl, aryl and Heteroaryl, the alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl optionally substituted by one or more (eg 2, 3, 4, 5 or 6) cycloalkyl, heterocycloalkyl, aryl and heteroaryl substituted; the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more selected
- “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
- the present invention also provides pharmaceutically acceptable salts of the compounds of formula (I).
- pharmaceutically acceptable salts refers to relatively nontoxic acid or base addition salts of compounds of the present invention.
- the acid addition salts are salts of the compounds of formula (I) of the present invention with suitable inorganic or organic acids. These salts can be prepared during the final isolation and purification of the compounds, or the purified compounds of formula (I) can be used as It is prepared by reacting its free base form with a suitable organic or inorganic acid.
- Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearic acid salt, laurosilicate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, rich Maleate, succinate, tartrate, benzoate, mesylate, p-toluenesulfonate, gluconate, lactobionate, lauryl sulfonate and the like.
- the base addition salts are salts of compounds of formula (I) with suitable inorganic or organic bases, including, for example, salts with alkali metals, alkaline earth metals, quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, Calcium salts, magnesium salts, tetramethyl quaternary ammonium salts, tetraethyl quaternary ammonium salts, etc.; amine salts include salts formed with ammonia ( NH3 ), primary, secondary or tertiary amines, such as methylamine salts, dimethylamine Amine salt, trimethylamine salt, triethylamine salt, ethylamine salt, etc.
- suitable inorganic or organic bases including, for example, salts with alkali metals, alkaline earth metals, quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, Calcium salts, magnesium salts, tetramethyl quatern
- the compounds of the present invention can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (in powders, ointments or drops) , or intratumoral administration.
- the compounds of the present invention may be administered at a dose of approximately 0.05-300 mg/kg body weight/day, preferably 10-300 mg/kg body weight/day, more preferably 10-200 mg/kg body weight/day.
- the compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders, granules, and the like.
- the compounds of formula (I) of the present invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (1 ) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, etc.; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabino glue, etc.; (3) humectants, such as glycerin, etc.; (4) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, some complex silicates and sodium carbonate, etc.; (5) slow Sol
- the solid dosage forms such as tablets, dragees, capsules, pills and granules can be coated or microencapsulated with coatings and shell materials such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
- liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like.
- liquid dosage forms may contain inert diluents conventionally employed in the art such as water and other solvents, solubilizers and emulsifiers such as ethanol, isopropanol , ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or the like mixture, etc.
- the liquid dosage forms of the present invention may also contain conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening
- Such suspending agents include, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan only, microcrystalline cellulose, aluminum methoxide and agar, and the like or mixtures of these substances.
- the compounds of the present invention, or pharmaceutically acceptable salts thereof can be formulated in dosage forms for parenteral injection including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and for reconstitution Sterile powder for sterile injectable solution or dispersion.
- Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- the compounds of the present invention, or pharmaceutically acceptable salts thereof may also be formulated for topical administration in dosage forms including, for example, ointments, powders, suppositories, drops, propellants, inhalants, and the like.
- dosage forms including, for example, ointments, powders, suppositories, drops, propellants, inhalants, and the like.
- the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, as the active ingredient is under sterile conditions together with a physiologically acceptable carrier and optionally a preservative, buffer, or propellant which may be required if necessary mix.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent.
- the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof is usually admixed with a pharmaceutically acceptable carrier, excipient or diluent.
- compositions of the present invention can be formulated into conventional pharmaceutical preparations according to conventional preparation methods. For example, tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, propellants, and the like.
- the compounds of the present invention, or pharmaceutically acceptable salts thereof, can be administered alone, or (if desired) in combination with other pharmaceutically acceptable therapeutic agents, such as other antineoplastic agents.
- the ingredients to be combined may be administered simultaneously or sequentially, in a single formulation or in separate formulations.
- the combination may include not only a combination of a compound of the present invention and one other active agent, but also a combination of a compound of the present invention and two or more other active agents.
- other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrading agent formula (I) compound can be: EGFR and/or its mutant inhibitors, ErbB2 (Her2) and/or its mutants Inhibitor, ALK and/or its mutant inhibitor, MEK and/or its mutant inhibitor, Kras and/or its mutant inhibitor, BCR-ABL and/or its mutant inhibitor, FGFR1/FGFR2/FGFR3 and/or its mutant inhibitors, ROS1 and/or its mutant inhibitors, c-MET and/or its mutant inhibitors, AXL and/or its mutant inhibitors, NTRK1 and/or its mutant inhibitors , RET and/or mutant inhibitors, taxanes, platinum-containing compounds, antimetabolites, mitotic kinase inhibitors, immunotherapeutics, antiangiogenic drugs, topoisomerase inhibitors, A-Raf/B- Raf/C-RAf and/or its mutant inhibitors, ERK and/or its mutant inhibitors,
- other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrader compound of formula (I) can be: afatinib, erlotinib, gefitinib (gefitinib), lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816, trastuzumab, Pertuzumab, crizotinib, alectinib, entrectinib, brigatinib, trametinib, cobiratinib Cobimetinib, binimetinib, selumetinib, refametinib, imatinib, dasatinib, nilotinib ( nilotinib, nintedanib, crizotinib, lorlatinib, ceritinib, merestinib, paclitaxel,
- the SOS1 kinase activity test experiment proves that the compound of formula I of the present invention can effectively bind to SOS1 target protein or produce an inhibitory effect
- Western-Blot proves that the compound of formula I of the present invention can effectively and specifically degrade NCI- SOS1 protein in H358 cells.
- the acceptable salt can effectively degrade the SOS1 protein, so as to achieve the effect of preventing or treating diseases or disorders caused by the interaction of SOS1 or SOS1 and Ras or SOS1 and Rac.
- the concentrate was dissolved in THF (180 mL), and hydrochloric acid (100 mL, 6M) was added, followed by stirring at room temperature for 3 h. The mixture was then quenched with water (300 mL) and extracted with EA (200 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. rough production
- the compound was purified by column chromatography to obtain the target product 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-one.
- Step 2 Preparation of (R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propyl-2-sulfinamide
- Step 3 (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propyl-2-sulfinamide preparation
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Abstract
一种SOS1降解剂及其制备方法和应用。具体地,涉及一种式Ⅰ化合物:S-L-E(Ⅰ);其中S为能够抑制SOS1蛋白活性或与SOS1蛋白相结合的小分子化合物;L为连接链,其通过共价键连接S和E;E为E7a所示结构。式I化合物能够降解和/或抑制细胞中的SOS1蛋白,可用于治疗和/或预防由SOS1介导的或由SOS1与Ras或SOS1与Rac相互作用所引起的相关疾病或病症。
Description
本发明属于医药技术领域,具体的,本发明涉及SOS1降解剂,及其制备方法和其作为预防和/或治疗癌症治疗剂的应用。
SOS1(son of sevenless homolog 1)蛋白是一种在细胞中广泛表达的调控蛋白,作为信号通路中的关键蛋白,SOS1在细胞内许多信号转导通路中起着重要的调控作用,例如参与调控Ras和Rac信号通路。SOS1由1333个氨基酸组成,在其C端包含一个富含脯氨酸的结构域(PxxP),该结构域可与Ras通路中的生长因子受体结合蛋白2(growth factor receptor-bound protein 2,Grb2)相结合,形成Grb2和SOS1的复合物,从而将SOS1带至细胞膜Ras蛋白附近,SOS1催化Ras与GTP的结合,促进Ras的激活,进而激活多条下游信号通路,例如Ras-Raf-Mek-Erk、Ras-PI3K-AKT-mTOR。PxxP也可与Rac通路中的E3B1等蛋白的SH3(Src homology 3)结构域相结合,形成EPS8-E3B1-SOS1复合物,EPS8-E3B1-SOS1复合物通过EPS8连接肌动蛋白丝,引起GTP的转换,从而激活Rac,随后激活JNK和MAPK等信号通路。
Ras突变基因被认为是人类癌症具有高发生率的主要致癌基因,研究表明,20-30%的肿瘤患者都存在着Ras的突变,其中KRas的突变占了85%,NRas和HRas分别占12%和3%。然而由于GTP对其结合位点的皮摩尔亲和力,以及Ras蛋白表面光滑,缺乏其他合适的结合口袋,因此,直接作用于Ras抑制其活性被认为是极具挑战性的。
SOS1的异常表达或突变与临床疾病的发生也有着密切的关系。研究表明,在NS患者、CFC患者体内都存在SOS1的突变,HGF1是一种罕见的常染色体显性遗传病,其病因也与SOS1的PxxP结构域突变有关,此外,SOS1的异常表达或突变与癌症的发生也有关系。
WO2018172250A1、WO2020173935A1、WO2019201848A1、WO2020180768A1、WO2020180770A1、WO2019122129A1和EP3558979A1公开了几类SOS1抑制剂,但目前为止,未有SOS1降解剂的相关报道。蛋白降解靶向嵌合体(Proteolysis Targeting Chimeria,PROTAC)是一种不同于传统小分子抑制剂的技术,传统小分子抑制剂通常需要作用于靶蛋白的活性位点才能抑制其活性,而PROTAC为一种异质双功能分子,其一端为可识别靶蛋白的小分子抑制剂,通过连接链,另一端为可识别E3泛素连接酶的E3泛素连接酶配体,这种双功能分子在体内识别靶蛋白和E3泛素连接酶,将靶蛋白和E3泛素连接酶拉近,形成三元复合物,将靶蛋白泛素化后,在体内通过泛素-蛋白酶体途径将靶蛋白降解。相较于传统小分子抑制剂,一方面PROTAC只需要将靶蛋白与E 3泛素连接酶拉近,使底物降解,这种作用模式使得这种技术可以应用于一些不可成药靶点;另一方面,由于靶蛋白在被降解后,PROTAC分子还可释放出来继续参与下一蛋白的降解过程,因此这种具有催化效果的降解作用,使得较少的PROTAC药物剂量就可以实现高效的降解;再一方面,传统的小分子抑制剂易产生耐药性常常是因为发生了点突变,使得小分子抑制剂失去了对靶点的抑制作用,而PROTAC可以直接将靶蛋白降解,在一定程度上能过避免点突变产生的耐药性。因此,相较于传统小分子抑制剂,运用PROTAC技术进行新药小分子研发具有很高的优势和可行性。
发明内容
本发明提供了式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐
S-L-E
Ⅰ
其中:
S为能够抑制SOS1蛋白活性或与SOS1蛋白相结合的小分子化合物;
L为连接链,其通过共价键连接S和E;
E为E7a;
其中所述E7a中:
W为CH
2、CR
aR
b、C(S)、C(O)或SO
2;
X为H
2、CH
2、O或S;
Z为H
2、CH
2、O或者S;
G选自氢、C
1-C
6烷基、OH、任选被R′取代的-CH
2-杂环烷基、任选被R′取代的-CH
2-苯基;
Q
1、Q
2、Q
3、Q
4各自独立的为碳、氮或者氮氧化物;
A为氢、C
1-C
6烷基、环烷基或卤素;
R独立的选自氢、羟基、卤素、-NH
2、-N(C
1-C
6烷基)
1-2、C
1-C
6烷基、C
1-C
6烷氧基、C
1-C
6卤代烷基、-CONR′R″、-OR′、-NR′R″、-SR′、-SO
2R′、-SO
2NR′R″、-CR′R″、-CR′NR′R″、芳基、杂芳基、C
3-C
8环烷基、3-8元杂环烷基、-P(O)(OR′)R″、-P(O)R′R″、-OP(O)(OR′)R″、-Cl、-F、-Br、-I、-CF
3、-CN、-NR′SO
2NR′R″、-NR′C(O)NR′R″、-C(O)NR′C(O)R″、-NR′C(=N-CN)NR′R″、-C(=N-CN)NR′R″、-NR′C(=N-CN)R″、-NR′C(=C-NO
2)NR′R″、-SO
2NR′COR″、-NO
2、-COR′、-C(C=N-OR′)R″、-CR′=CR′R″、-CCR′、-S(C=O)(C=N-R′)R″、-SF
5或-OCF
3;
R′和R″各自独立的选自键、氢、C
1-C
6烷基、环烷基、芳基、杂芳基或杂环烷基;
n″为1-4的整数;
-----为键,其可为R立体异构体、S立体异构体或非立体异构体。本发明提供了式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐
S-L-E
Ⅰ
其中,S和L的结构如下文所定义;
E为E7a,E7a的结构如上文所定义。
本发明某些实施方案中,所述E7a中,W为CH
2或C(O)。
本发明某些实施方案中,所述E7a中,X为O或S。
本发明某些实施方案中,所述E7a中,X为O。
本发明某些实施方案中,所述E7a中,Z为O。
本发明某些实施方案中,所述E7a中,G为氢。
本发明某些实施方案中,所述E7a中,Q
1、Q
2、Q
3、Q
4各自独立的为碳或氮。
本发明某些实施方案中,所述E7a中,Q
1为碳。
本发明某些实施方案中,所述E7a中,Q
2为碳。
本发明某些实施方案中,所述E7a中,Q
3为碳。
本发明某些实施方案中,所述E7a中,Q
4为碳。
本发明某些实施方案中,所述E7a中,Q
1、Q
2、Q
3、Q
4为碳。
本发明某些实施方案中,所述E7a中,A为氢。
本发明某些实施方案中,所述E7a中,R为氢。
本发明某些实施方案中,所述E为E7a';
其中,所述E7a'中,Q
1、Q
2、Q
4、X、W、G、Z、R、n”、A和-----的定义如E7a中所定义和描述。
本发明某些实施方案中,所述E为E7a”;
其中,所述E7a”中,Q
1、Q
2、Q
3、X、W、G、Z、R、n”、A和-----的定义如E7a中所定义和描述。
本发明式Ⅰ化合物、其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐的一个优选实施方案中,E为E7a-1:
其中所述E7a-1中:
Q
1、Q
2、Q
3和Q
4各自独立的为碳或氮;
W为C(O)或CH
2;
A为氢、C
1-C
6烷基或卤素(例如A为氢);
R选自氢、羟基、卤素、-NH
2、-N(C
1-C
6烷基)
1-2、C
1-C
6烷基、C
1-C
6烷氧基、C
1-C
6卤代烷基;
n″为1、2、3或4;
-----为键,其可为R立体异构体、S立体异构体或非立体异构体。
本发明式Ⅰ化合物、其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐的一个优选实施方案中,E为E7a-2:
其中所述E7a-2中:
W为CH
2或C(O);
A为氢、甲基、Cl或F(例如A为氢);
R各自独立的选自氢、羟基、NH
2、C
1-C
6烷基或C
1-C
6烷氧基;
n″为1、2、3或4;
-----为键,其可为R立体异构体、S立体异构体或非立体异构体。
本发明某些实施方案中,当-----键连接的碳原子具有手性时,其为R构型、S构型或其混合(例如40%-60%R构型和60%-40%S构型的混合物)。
本发明式Ⅰ化合物、其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐的一个优选实施方案中,E为如下任一结构:
其中,*标记的碳原子为R构型、S构型或其混合(例如40%-60%R构型和60%-40%S构型的混合物)。
本发明式Ⅰ化合物、其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐的一个优选实施方案中,E为如下结构:
其中,*标记的碳原子为R构型、S构型或其混合(例如40%-60%R构型和60%-40%S构型的混合物)。
本发明式Ⅰ化合物、其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐的一个优选实施方案中,E为如下结构:
其中,*标记的碳原子为R构型、S构型或其混合(例如40%-60%R构型和60%-40%S构型的混合物)。本发明式Ⅰ化合物、其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐的一个优选实施方案中,E为如下任一结构:
本发明式Ⅰ化合物、其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐的一个优选实施方案中,E为E8r:
其中所述E8r中:
Q
1、Q
2、Q
3、Q
4各自独立的为碳、N、或者被R’取代的N,或者氮氧化物。
本发明式Ⅰ化合物、其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐的一个优选实施方案中,E为E9:
其中所述E9中:
R’是H。
优选的,本发明某些实施方式中,所述S为S1:
其中所述S1中:
R
1选自氢、卤素、-OH、-CN、-NO
2、C
1-C
6烷基巯基或-NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
1选自C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷氧基、C
3-C
6杂环烷氧基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、C
1-C
6卤代烷基、-COOH、-COOR
c;所述R
c为-C
1-C
6烷基、C
3-C
6烯基、C
3-C
6炔基、C
3-C
8环烷基或-C
4-C
8环烯基;
R
1为-NS(O)(R
d)(R
e),所述R
d和R
e各自独立的为C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、6-10元芳基或5-10元杂芳基;
R
1为-NHC(O)-(C
1-C
6烷基)、-NHC(O)-NR
aR
b,所述R
a和R
b各自独立的为氢、-C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
1为-NH-(CH
2)
k-NH-C(O)-R
aa,所述R
aa为C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基(例如所述R
aa为C
1-C
6烷基),且k为1或者2;
R
1为-NH-(CH
2)
i-R
f,所述i为0,1或者2且R
f为4-7元杂环烷基、杂芳基、C
1-C
6烷基磺酰基;
此外以上所述C
1-C
6烷基、C
1-C
6烷氧基、4-7元杂环烷基和杂芳基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-NO
2、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、4-7元杂环烷基、C
1-C
6烷氧基、C
1-C
6卤代烷基、C
1-C
6卤代烷氧基、C
1-C
6烷基磺酰基、苯基、苄基、杂芳基、-(CH
2)-杂芳基、-NHC(O)(C
1-C
6烷基)、C
3-C
8环烷氧基、苯氧基、杂芳基氧基或者-NR
aR
b的基团取代;所述R
a和R
b各自独立的选自氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
1为-O-(CH
2)
z-苯基、-O-(CH
2)
z-(4-7元杂环烷基)、-O-(CH
2)
z-杂芳基,所述z为0,1或2,所述苯基、杂环烷基和杂芳基任选的被选自-OH、杂环烷基或者杂环烯基取代,且能被甲基或者氧代基取代;
或者R
1为
或者相邻2个R
1与它们各自连接的碳原子一起形成5-7元环烷基或5-7元杂环烷基;
且所述x为1、2或者3;
A
1为C
4-C
12环烷基、杂环烷基、芳基(例如苯基)或杂芳基(例如噻吩基);
R
2为氢、-OH、氧代、卤素、-CN、C
1-C
6烷基、C
1-C
6烷氧基、C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8环烷基、-C
3-C
8环烷氧基、-C
3-C
8卤代环烷氧基、-C
4-C
8环烯基、4-7元杂环烷基、-O-CH
2-4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、-C
1-C
6卤代烷基、-C
1-C
6卤代烷氧基、-C
1-C
6烷基磺酰基;
R
2为-NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基或-C(O)C
1-C
3烷基;
R
2为-C(O)NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2为-C(O)OR
g,所述R
g为氢或C
1-C
6烷基;
R
2为-OR
h;所述R
h为C
1-C
6烷基;
R
2为-(CH
2)NR
aR
b,所述R
a和R
b各自独立的氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
且w为1、2、3或者4(例如,所述w为1、2或3);
所述A
2(R
3)
Y为氢;
或者A
2为C
4-C
12环烷基、杂环烷基、芳基(例如苯基)或杂芳基,且
R
3为氢、卤素、-OH、氧代、-CN、-NO
2、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、C
7-C
8环炔基、4-7元杂环烷基、5-10元杂环烯基、苯基、杂芳基、C
1-C
6卤代烷基;
所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-C
1-C
6烷基、-C
1-C
6烷氧基、-C
1-C
6卤代烷基、苯基、杂芳基或-C(O)NR
iR
j的取代基取代,所述R
i和R
j各自独立的为氢或者C
1-C
6烷基;
或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR
kR
l取代,所述R
k和R
l各自独立的为氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
1-C
6烷基磺酰基、苯基、杂芳基、-CH
2-C(O)-R
m、-C(O)R
p或4-7元杂环烷基,且所述烷基、炔基、烯基、环烷基、苯基、杂芳基和杂环烷基各自独立的任选的被1个、2个或3个选自C
1-C
6卤代烷基、-OH、氧代基、苯基、-CN、C
1-C
6烷氧基或杂芳基取代,且所述杂芳基任选被甲基取代;且所述R
m为双环杂芳基、C
1-C
6烷氧基或者-NR
nR
o,所述R
n和R
o各自独立的为氢、C
1-C
6烷基或者苯基,所述烷基任选被C
1-C
6烷氧基或者苯基取代,或者-NR
nR
o为4-7元氮杂环烷基,所述氮杂环烷基通过N原子连接分子其他部位,且还包含1个或者多个选自N或者O的杂原子;所述R
p选自C
1-C
6烷氧基、任选被1个、2个或者3个选自-OH或者C
1-C
6烷氧基取代的C
1-C
6烷基、单环或双环杂芳基、4-7元杂环烷基或者R
p为-CH
2-NR
qR
r,所述R
q和R
r各自独立的选自氢、苯基或者任选被F取代的C
1-C
6烷基;
或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR
sR
t取代,所述-NR
sR
t为通过氮原子连接至分子其他部位的4-7元氮杂环烷基或者通过氮原子连接至分子其他部位的6-10元氮螺杂环烷基,且进一步包括最多两个选自N或者O的杂原子,且任选的被1个、2个或者3个选自-OH、氧代基、C
1-C
6烷基、C
1-C
6羟基烷基、-C(O)OR
z的取代基取代,所述R
z为C
1-C
6烷基、卤素、-N(C
1-C
6烷基)
2、-CH
2N(C
1-C
6烷基)
2、-C(O)NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
或者R
3为C(O)R
v、-C(O)NH
2、-C(O)NHR
v、-C(O)NR
vR
w、-C(O)OR
v,所述R
v和R
w各自独立的为氢、C
1-C
4烷基、C
1-C
4卤代烷基、苯基或者-(CH
2)
2NR
xR
y,所述R
x和R
y各自独立的为氢、C
1-C
4烷基或者-(CH
2)
2N(CH
3)
2;
或者R
3为-NH
2、-NHR
z、-NR
zR
za、-NHC(O)R
z、-NHC(O)OR
z、-NHS(O)
2R
z、4-7元杂环烷基、杂芳基、螺杂环烷基、稠杂环烷基、桥杂环烷基,所述R
z和R
za各自独立的为C
1-C
4烷基、C
1-C
4卤代烷基或者苯基;
或者R
3为C
1-C
6烷氧基、C
1-C
6卤代烷氧基、-O(CH
2)
s-C
3-C
8环烷基、-O(CH
2)
s-苯基、-O(CH
2)
s-杂环烷基、-O(CH
2)
s-杂芳基,所述s为0、1、2或者3;
或者R
3为-S(O)
2R
z、-S(O)
2NH
2、-S(O)
2NHR
z、-S(O)
2NR
zR
za,所述R
z和R
za各自独立的为C
1-C
4烷基、C
1-C
4卤代烷基或者苯基;
Y为0、1、2、3、4或5(例如,Y为0、1、2或3);
L'为键、-(CH
2)
k-、-O(CH
2)
k-、-(CH
2)
k-O-或者-O-(CH
2)
k-O-(例如,L'为键、-(CH
2)
k-或者-O(CH
2)
k-),所述k为0、1、2或者3,或者L'为-CH=CH-(CH
2)
n-,所述n为0、1或者2;
R
4、R
5各自独立的为C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基或C
3-C
6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C
1-C
6烷氧基、C
3-C
6环烷基、C
3-C
6环烷氧基或卤素取代。
优选的,本发明某些实施方式中,所述S1中R
4、R
5各自独立的为甲基。
在一些实施方案中,所述S1各基团的定义中,所述R
a和R
b在任一处出现时各自独立的为氢或C
1-C
6烷基。
在一些实施方案中,所述S1各基团的定义中,所述R
d和R
e在任一处出现时各自独立的为氢或C
1-C
6 烷基。
本发明某些实施方式中,所述S1中,R
5为C
1-C
6烷基,例如甲基。
本发明某些实施方式中,所述S1中,R
4为C
1-C
6烷基,例如甲基。
本发明某些实施方式中,所述S1中,R
1为氢或C
1-C
6烷氧基。
本发明某些实施方式中,所述S1中,A
1为芳基或杂芳基。
本发明某些实施方式中,所述S1中,A
1为芳基,例如苯基。
本发明某些实施方式中,所述S1中,A
1为杂芳基,例如噻吩基。
本发明某些实施方式中,所述S1中,R
2为氢、卤素、C
1-C
6烷基或-C
1-C
6卤代烷基。
本发明某些实施方式中,所述S1中,L'为键。
本发明某些实施方式中,所述S1中,A
2(R
3)
Y为氢。
本发明某些实施方式中,所述S1中,A
2为芳基,例如苯基。
本发明某些实施方式中,所述S1中,R
3为氢、卤素或C
1-C
6烷基,所述烷基任选被-NR
kR
l取代;所述R
k和R
l各自独立的为氢或C
1-C
6烷基。本发明某些实施方式中,所述S7中,R
3为氢、F、Cl、甲基或乙基,所述甲基和乙基被-NR
kR
l取代;所述R
k为甲基或乙基,R
l为氢、甲基或乙基。
本发明某些实施方式中,所述S1中,R
3为氢、Cl、-CH
2NHCH
3或-CH
2N(CH
3)
2。
本发明某些实施方式中,所述S1中,A
1为芳基,L'为键,A
2(R
3)
Y为氢。
本发明某些实施方式中,所述S1中,A
1为杂芳基,L'为键,A
2为芳基,R
3为氢、卤素或C
1-C
6烷基,所述烷基任选被-NR
kR
l取代;所述R
k和R
l各自独立的为氢或C
1-C
6烷基。
本发明某些实施方式中,所述S为S1':
其中,所述S1'中,R
1、R
2、R
3、R
4、R
5、L'、A
1、A
2、w、x和Y的定义如S1中所述。
本发明某些实施方式中,所述S为S1”:
其中,所述S1”中,R
1、R
2、R
3、R
4、R
5、L'、A
1、A
2、w和Y的定义如S1中所述。
本发明某些实施方式中,所述S1'或S1”中,R
1为氢、C
1-C
6烷基或C
1-C
6烷氧基,所述C
1-C
6烷基和C
1-C
6烷氧基任选的被C
1-C
6烷氧基(例如甲氧基)取代。
本发明某些实施方式中,所述S为-X-S1',S1'的结构如上所述;X为O、NH或者S,优选为O。
本发明某些实施方式中,所述S为-X-S1”,S1”的结构如上所述;X为O、NH或者S,优选为O。
优选的,本发明某些实施方式中,所述S为S1a
其中所述S1a中:
R
1选自氢、-OCH
3、-OCH
2CH
3、
-CH
2OH、-C(O)OH、-C(O)OCH
3、-Br、-OCH(CH
3)
2、-O(CH
2)
2CH(CH
3)
2、-O(CH
2)
3CH
3、-O(CH
2)
2OCH
3、
-O(CH
2)-苯基、-N=S(O)(CH
3)
2、-CH
3、环丙基、-N(CH
3)
2、-NHCH
3、-NH
2、
-C(CH
3)
2-OH、
-NH(CH
2)-NH-C(O)CH
3、-NH(CH
2)-吗啡啉、-NH-C(O)CH
3、-NH-C(O)NHCH
3、-NH-C(O)-N(CH
3)
2、硝基、-NH-S(O)
2CH
3、-N=S(O)(CH
3)
2、羟基、-O-(CH
2)
2-S(O)
2CH
3、-F、
环丙氧基、环丁氧基、环戊氧基、环己氧基、氮杂环丁烷基、氮杂环戊烷基、哌啶基、哌嗪基、氧杂环丁烷、氧杂环戊烷基、氧杂环己烷基、硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、氮杂环丁烷氧基、氮杂环戊烷氧基、哌啶基氧基、哌嗪基氧基、氧杂环丁烷氧基、氧杂环戊烷氧基、氧杂环己烷氧基、硫杂环丁烷氧基、硫杂环戊烷氧基、硫杂环己烷氧基、
-OCH
2CH
2CH
3、-OCH
2CH
2CH
2N(CH
3)
2、-OCH
2CH
2CH
2OH、
-OCH
2CH
2NC(O)CH
3、-OCH
2CH
2N(CH
3)
2、-OCH
2CH
2OH、
-SCH
3、-N(CH
3)
2、
x为1或者2;
R
2选自:氢、羟基、氧代基、氰基、环丙基、1,1-二甲基环丙基、-C(=CH
2)CH
3、-C(CH
3)(=CH
2)CH
3、-CH=CH(CH
2)
2CH
3、-CH=CHCH
3、-CH=CH-环丙基、-C(O)NH
2、-C(O)OCH
3、-S(O)
2CH
3、-OCH
3、-CH
2NH
2、三氟甲基、甲基、三氟甲氧基、或卤素(F、Cl、Br)、-NH
2、-NHC(O)CH
3、-NHCH
2CH
3或-NHCH(CH
3)
2;
w为1、2或者3;
R
3选自-C(O)NH(CH
2)
2CH
3、-C(O)N(CH
3)
2、-C(O)NH
2、-C(O)NH(CH
2)
2N(CH
3)
2、-CH
2C(O)NH
2、氢、-F、-Cl、-Br、氰基、-CF
3、-CH
3、-CH
2CH
3、-CH=CH
2、-CH
2CN、-CH(CH
3)-NH
2、-CH=CH-CN、-C(O)-OH、-C(O)OCH
3、-C(O)CH
3、-C(CH
3)
2-C(O)-OCH
3、-C(CH
3)
2-CN、氧代基、羟基、环丙基、环丁基、环戊基、-NH
2、-NH-C(O)CH
3、-NH-S(O)
2CH
3、-NH-C(O)OC(CH
3)
3、
-S(O)
2CH
3、-S(O)
2NCH
3、-S(O)
2NH
2、-OCH
2CH
3、-O(CH
2)
2CH
3、-OCF
3、
-OCH
2环丙基、-OCH
3、-O(CH
2)
3CH
3、-OCH
2苯基、-O-苯基、-(CH
2)-OH、-(CH
2)
2-OH、-(CH
2)-OCH
3、-(CH
2)-OCH
2CH
3、-CH(OH)-CH
2-苯基、-CH(OH)-CH
2CH
3、-CH(OH)-CH
2CH
2CH
3、-CH(OH)-CH
2CH
2CH
2CH
3、-CH(OH)-CH(CH
3)
2、-CH(OH)-苯基、-CH(OH)-CN、-CH(OH)-CH
2-OH、-CH(OH)-CF
3、-CH(OH)-(CH
2)
2-苯基、*-CH(OH)-C≡CH、-CH(NH
2)-CH
2-C(O)OH、-CH
2-NH-S(O)
2-CH
3、-CH
2-NH-(CH
2)
3CH
3、-CH
2-NH-CH
3、-CH
2-N(CH
3)
2、-CH
2-NH-CH
2CH
3、-CH(CH
3)-NH
2、-CH
2-NH
2、-CH
2CH
2-NH
2、-CH
2NH-CH
2-苯基、-CH
2N(CH
2CH
3)
2、-CH
2NH-环丙基、-CH
2NH-环丁基、-CH
2NH-环戊基、-CH
2NH-吡啶基、-CH
2NH-苯基、-CH
2NH-(CH
2)
2-OH、-CH
2N(CH
3)-(CH
2)
2-OH、-CH
2NH-CH
2-CN、-CH
2N(CH
3)-CH
2-CN、-CH
2N(CH
3)-CH
2-CF
3、-CH
2N(CH
3)-CH
2-CF
2H、-CH
2NH-CH
2-CF
2H、-CH
2NH-(CH
2)
2-OCH
3、
-CH
2NH-C(O)-OC(CH
3)
3、-CH
2CH
2NH-C(O)-OC(CH
3)
3、-CH
2NH-C(O)-CH
2NOH、-CH
2NH-C(O)-CH
2OCH
3、-CH(CH
3)NH-C(O)-OC(CH
3)
3、-CH
2NH-C(O)-CH
3、
-CH
2NHCH
2-C(O)-NH
2、-CH
2NHCH
2-C(O)-(CH
3)
2、-CH
2NHCH
2-C(O)-OCH
3、-CH
2NHCH
2-C(O)-NHCH
3、-CH
2NHCH
2-C(O)-NH(CH
2)
2-OCH
3、-CH
2NHCH
2-C(O)-NHCH
2-苯基、
-CH
2NHCH
2-C(O)-NH-苯基、
-CH
2NH-C(O)-CH
2NH-苯基、
或-CH
2NH-C(O)-CH
2NH-CH
2CF
3;
Y为1或者2;
L'为键、-(CH
2)
k-或者-O(CH
2)
k-,所述k为1或者2,或者L'为-CH=CH-(CH
2)
n-,所述n为0、1或者2。
在一些实施方案中,所述S1a中,R
2选自:氢、羟基、氧代基、氰基、环丙基、1,1-二甲基环丙基、-C(=CH
2)CH
3、-C(CH
3)(=CH
2)CH
3、-CH=CH(CH
2)
2CH
3、-CH=CHCH
3、-CH=CH-环丙基、-C(O)NH
2、-C(O)OCH
3、-S(O)
2CH
3、-OCH
3、-CH
2NH
2、三氟甲基、甲基、三氟甲氧基、卤素(F、Cl、Br)。
本发明某些实施方式中,所述S1a中,w为1或者2。
本发明某些实施方式中,所述S1a中,R
1为氢、-CH
3、-OCH
3、-OCH
2CH
3、-OCH(CH
3)
2、-O(CH
2)
2CH(CH
3)
2或-O(CH
2)
3CH
3,例如-OCH
3。
本发明某些实施方式中,所述S1a中,R
2为氢、卤素、-NH
2、C
1-C
6烷基或-C
1-C
6卤代烷基。
本发明某些实施方式中,所述S1a中,L'为键。
本发明某些实施方式中,所述S1a中,A
2(R
3)
Y为氢。
本发明某些实施方式中,所述S1a中,R
3为氢、-F、-Cl、-Br、-CH
2-NH-(CH
2)
3CH
3、-CH
2-NH-CH
3、-CH
2-N(CH
3)
2或-CH
2-NH-CH
2CH
3。
本发明某些实施方式中,所述S1a中,R
3为氢、Cl、-CH
2NHCH
3或-CH
2N(CH
3)
2。
本发明某些实施方式中,所述S1a中,A
1为
L'为键,A
2为
R
3为氢、-F、-Cl、-Br、-CH
2-NH-(CH
2)
3CH
3、-CH
2-NH-CH
3、-CH
2-N(CH
3)
2或-CH
2-NH-CH
2CH
3。
本发明某些实施方式中,所述S为S1a':
其中,所述S1a'中,R
1、R
2、R
3、L'、A
1、A
2、w、x和Y的定义如S1或S1a中所述。
本发明某些实施方式中,所述S为S1a”:
其中,所述S1a”中,R
1、R
2、R
3、L'、A
1、A
2、w和Y的定义如S1或S1a中所述。
本发明某些实施方式中,所述S1a'、S1a”中,R
1为氢、C
1-C
6烷基或C
1-C
6烷氧基,所述C
1-C
6烷基和C
1-C
6烷氧基任选的被C
1-C
6烷氧基(例如甲氧基)取代。
本发明某些实施方式中,所述S为-X-S1a',S1a'的结构如上所述;X为O、NH或者S,优选为O。
本发明某些实施方式中,所述S为-X-S1a”,S1a”的结构如上所述;X为O、NH或者S,优选为O。
更优选的,本发明某些实施方式中,所述S1为WO2018172250A1(其全文通过引用的方式并入本文中)中实施例1(Example 1)至实施例458(Example 458)的具体化合物。
优选的,本发明某些实施方式中,所述S为S2:
其中所述S2中:
R
1为氢、卤素、-OH、-CN、-NO
2、C
1-C
6烷基巯基或-NR
aR
b;所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
1选自C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷氧基、C
3-C
6杂环烷氧基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、C
1-C
6卤代烷基、-COOH、-COOR
c;所述R
c为-C
1-C
6烷基、C
3-C
6烯基、C
3-C
6炔基、C
3-C
8环烷基或-C
4-C
8环烯基;
R
1为-NS(O)(R
d)(R
e),所述R
d和R
e各自独立的为C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基;
R
1为-NHC(O)-(C
1-C
6烷基)、-NHC(O)-NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
1为-NH-(CH
2)
k-NH-C(O)-(C
1-C
6烷基),所述k为1或者2;
R
1为-NH-(CH
2)
i-R
f,所述i为0、1或者2且R
f为4-7元杂环烷基、杂芳基、C
1-C
6烷基磺酰基;
此外以上所述C
1-C
6烷基、C
1-C
6烷氧基、4-7元杂环烷基和杂芳基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-NO
2、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、4-7元杂环烷基、C
1-C
6烷氧基、C
1-C
6卤代烷基、C
1-C
6卤代烷氧基、C
1-C
6烷基磺酰基、苯基、苄基、杂芳基、-(CH
2)-杂芳基、-NHC(O)(C
1-C
6烷基)、C
3-C
8环烷氧基、苯氧基、杂芳基氧基或者-NR
aR
b的基团取代;所述R
a和R
b各自独立的选自氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
1为-O-(CH
2)
z-苯基、-O-(CH
2)
z-(4-7元杂环烷基)、-O-(CH
2)
z-杂芳基,所述z为0,1或2,所述苯基、杂环烷基和杂芳基任选的被选自-OH、杂环烷基或者杂环烯基取代,且能被甲基或者氧代基取代;
或者R
1为
或者R
1为
或者相邻2个R
1与它们各自连接的碳原子一起形成5-7元环烷基或5-7元杂环烷基;
且所述x为1、2、3或者4(例如,所述x为1、2或3);
A
1为C
4-C
12环烷基、杂环烷基、芳基或杂芳基;
R
2为氢、-OH、氧代、卤素、-CN、C
1-C
6烷基、C
1-C
6烷氧基、C
2-C
6烯基、-C
2-C
6炔基、-C
3-C
8环烷基、-C
3-C
8环烷氧基、-C
3-C
8卤代环烷氧基、-C
4-C
8环烯基、4-7元杂环烷基、-O-CH
2-4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、-C
1-C
6卤代烷基、-C
1-C
6卤代烷氧基、-C
1-C
6烷基磺酰基;
R
2为-NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2为-C(O)NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2为-C(O)OR
g,所述R
g为氢或C
1-C
6烷基;
R
2为-OR
h;所述R
h为C
1-C
6烷基;
R
2为-(CH
2)NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
且w为1、2、3或者4(例如,所述w为1或者2);
所述A
2(R
3)
Y为氢;
或者A
2为C
4-C
12环烷基、杂环烷基、芳基或杂芳基,且
R
3为氢、卤素、-OH、氧代、-CN、-NO
2、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、C
2-C
8环炔基、4-7元杂环烷基、5-10元杂环烯基、苯基、杂芳基、C
1-C
6卤代烷基;
所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-C
1-C
6烷基、-C
1-C
6烷氧基、-C
1-C
6卤代烷基、苯基、杂 芳基或-C(O)NR
iR
j的取代基取代,所述R
i和R
j各自独立的为氢或者C
1-C
6烷基;
或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR
kR
l取代,所述R
k和R
l各自独立的为氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
1-C
6烷基磺酰基、苯基、杂芳基、-CH
2-C(O)-R
m、-C(O)R
p或4-7元杂环烷基,且所述烷基、炔基、烯基、环烷基、苯基、杂芳基和杂环烷基各自独立的任选的被1个、2个或3个选自C
1-C
6卤代烷基、-OH、氧代基、苯基、-CN、C
1-C
6烷氧基或杂芳基取代,且所述杂芳基任选被甲基取代;且所述R
m为双环杂芳基、C
1-C
6烷氧基或者-NR
nR
o,所述R
n和R
o各自独立的为氢、C
1-C
6烷基或者苯基,所述烷基任选被C
1-C
6烷氧基或者苯基取代,或者-NR
nR
o为4-7元氮杂环烷基,所述氮杂环烷基通过N原子连接分子其他部位,且还包含1个或者多个选自N或者O的杂原子;所述R
p选自C
1-C
6烷氧基、任选被1个、2个或者3个选自-OH或者C
1-C
6烷氧基取代的C
1-C
6烷基、单环或双环杂芳基、4-7元杂环烷基或者R
p为-CH
2-NR
qR
r,所述R
q和R
r各自独立的选自氢、苯基或者任选被F取代的C
1-C
6烷基;
或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR
sR
t取代,所述-NR
sR
t为通过氮原子连接至分子其他部位的4-7元氮杂环烷基或者通过氮原子连接至分子其他部位的6-10元氮螺杂环烷基,且进一步包括最多两个选自N或者O的杂原子,且任选的被1个、2个或者3个选自-OH、氧代基、C
1-C
6烷基、C
1-C
6羟基烷基、-C(O)OR
z的取代基取代,所述R
z为C
1-C
6烷基、卤素、-N(C
1-C
6烷基)
2、-CH
2N(C
1-C
6烷基)
2、-C(O)NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
或者R
3为C(O)R
v、-C(O)NH
2、-C(O)NHR
v、-C(O)NR
vR
w、-C(O)OR
v,所述R
v和R
w各自独立的为氢、C
1-C
4烷基、C
1-C
4卤代烷基、苯基或者-(CH
2)
2NR
xR
y,所述R
x和R
y各自独立的为氢、C
1-C
4烷基或者-(CH
2)
2NH(CH
3)
2;
或者R
3为-NH
2、-NHR
z、-NR
zR
za、-NHC(O)R
z、-NHC(O)OR
z、-NHS(O)
2R
z、4-7元杂环烷基、杂芳基、螺杂环烷基、稠杂环烷基、桥杂环烷基,所述R
z和R
za各自独立的为C
1-C
4烷基、C
1-C
4卤代烷基或者苯基;
或者R
3为C
1-C
6烷氧基、C
1-C
6卤代烷氧基、-O(CH
2)
s-C
3-C
8环烷基、-O(CH
2)
s-苯基、-O(CH
2)
s-杂环烷基、-O(CH
2)
s-杂芳基,所述s为0、1、2或者3;
或者R
3为-S(O)
2R
z、-S(O)
2NH
2、-S(O)
2NHR
z、-S(O)
2NR
zR
za,所述R
z和R
za各自独立的为C
1-C
4烷基、C
1-C
4卤代烷基或者苯基;
Y为0、1、2、3、4或5(例如,所述Y为0、1、2或3);
L'为键、-(CH
2)
k-、-O(CH
2)
k-、-(CH
2)
k-O-或者-O-(CH
2)
k-O-(例如,所述L'为键、-(CH
2)
k-或-O(CH
2)
k-),所述k为0、1、2或者3,或者L'为-CH=CH-(CH
2)
n-,所述n为0、1或者2;
R
4、R
5各自独立的为C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基或C
3-C
6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C
1-C
6烷氧基、C
3-C
6环烷基、C
3-C
6环烷氧基或卤素取代;
T和V都为N,或者T为C,V为N,或者T为N,V为C。
优选的,本发明某些实施方式中,所述S2中R
4、R
5各自独立的为甲基。
在一些实施方案中,所述S2各基团的定义中,所述R
a和R
b在任一处出现时各自独立的为氢或C
1-C
6烷基。
本发明某些实施方式中,所述S2中,T和V都为N。
本发明某些实施方式中,所述S2中,T为C,V为N。
本发明某些实施方式中,所述S2中,T为N,V为C。
本发明某些实施方式中,所述S2中,R
5为C
1-C
6烷基,例如甲基。
本发明某些实施方式中,所述S2中,R
4为C
1-C
6烷基,例如甲基。
本发明某些实施方式中,所述S2中,R
1为氢或C
1-C
6烷氧基。
本发明某些实施方式中,所述S2中,A
1为芳基或杂芳基。
本发明某些实施方式中,所述S2中,A
1为芳基,例如苯基。
本发明某些实施方式中,所述S2中,A
1为杂芳基,例如噻吩基。
本发明某些实施方式中,所述S2中,R
2为氢、卤素、C
1-C
6烷基或-C
1-C
6卤代烷基。
本发明某些实施方式中,所述S2中,L'为键。
本发明某些实施方式中,所述S2中,A
2(R
3)
Y为氢。
本发明某些实施方式中,所述S2中,A
2为芳基,例如苯基。
本发明某些实施方式中,所述S2中,R
3为氢、卤素或C
1-C
6烷基,所述烷基任选被-NR
kR
l取代;所述R
k和R
l各自独立的为氢或C
1-C
6烷基。本发明某些实施方式中,所述S7中,R
3为氢、F、Cl、甲基或乙基,所述甲基和乙基被-NR
kR
l取代;所述R
k为甲基或乙基,R
l为氢、甲基或乙基。
本发明某些实施方式中,所述S2中,R
3为氢、Cl、-CH
2NHCH
3或-CH
2N(CH
3)
2。
本发明某些实施方式中,所述S2中,A
1为芳基,L'为键,A
2(R
3)
Y为氢。
本发明某些实施方式中,所述S2中,A
1为杂芳基,L'为键,A
2为芳基,R
3为氢、卤素或C
1-C
6烷基,所述烷基任选被-NR
kR
l取代;所述R
k和R
l各自独立的为氢或C
1-C
6烷基。
本发明某些实施方式中,所述S为S2':
其中,所述S2'中,T、V、R
1、R
2、R
3、R
4、R
5、L'、A
1、A
2、w、x和Y的定义如S2中所述。
本发明某些实施方式中,所述S为S2”:
其中,所述S2”中,R
2、R
3、R
4、R
5、L'、A
1、A
2、w和Y的定义如S2中所述。
本发明某些实施方式中,所述S2、S2'、S2”中,R
1为氢、C
1-C
6烷基或C
1-C
6烷氧基,所述C
1-C
6烷基和C
1-C
6烷氧基任选的被C
1-C
6烷氧基(例如甲氧基)取代。
本发明某些实施方式中,所述S为-X-S2',S2'的结构如上所述;X为O、NH或者S,优选为O。
本发明某些实施方式中,所述S为-X-S2”,S2”的结构如上所述;X为O、NH或者S,优选为O。
优选的,本发明某些实施方式中,所述S为S2a,
其中所述S2a中:
T和V都为N,或者T为C,V为N,或者T为N,V为C;
R
1选自氢、-OCH
3、-OCH
2CH
3、
-CH
2OH、-C(O)OH、-C(O)OCH
3、-Br、-OCH(CH
3)
2、-O(CH
2)
2CH(CH
3)
2、-O(CH
2)
3CH
3、-O(CH
2)
2OCH
3、
-O(CH
2)
z-苯基、-N=S(O)(CH
3)
2、-CH
3、环丙基、-N(CH
3)
2、-NHCH
3、-NH
2、
-C(CH
3)
2-OH、
-NH(CH
2)-NH-C(O)CH
3、-NH(CH
2)-吗啡啉、-NH-C(O)CH
3、-NH-C(O)NHCH
3、-NH-C(O)-N(CH
3)
2、硝基、-NH-S(O)
2CH
3、-N=S(O)(CH
3)
2、羟基、-O-(CH
2)
2-S(O)
2CH
3、-F、
环丙氧基、环丁氧基、环戊氧基、环己氧基、氮杂环丁烷基、氮杂环戊烷基、哌啶基、哌嗪基、氧杂环丁烷、氧杂环戊烷基、氧杂环己烷基、硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、氮杂环丁烷氧基、氮杂环戊烷氧基、哌啶基氧基、哌嗪基氧基、氧杂环丁烷氧基、氧杂环戊烷氧基、氧杂环己烷氧基、硫杂环丁烷氧基、硫杂环戊烷氧基、硫杂环己烷氧基、
-OCH
2CH
2CH
3、-OCH
2CH
2CH
2N(CH
3)
2、-OCH
2CH
2CH
2OH、
-OCH
2CH
2NC(O)CH
3、-OCH
2CH
2N(CH
3)
2、-OCH
2CH
2OH、
-SCH
3、-N(CH
3)
2、
z为1或者2;
x为1或者2;
R
2选自:氢、羟基、氧代基、氰基、环丙基、1,1-二甲基环丙基、-C(=CH
2)CH
3、-C(CH
3)(=CH
2)CH
3、-CH=CH(CH
2)
2CH
3、-CH=CHCH
3、-CH=CH-环丙基、-C(O)NH
2、三氟甲基、甲基、三氟甲氧基、-C(O)OCH
3、-S(O)
2CH
3、-OCH
3、-CH
2NH
2或卤素(F、Cl、Br);
w为1、2或者3;
R
3选自-C(O)NH(CH
2)
2CH
3、-C(O)N(CH
3)
2、-C(O)NH
2、-C(O)NH(CH
2)
2N(CH
3)
2、-CH
2C(O)NH
2、氢、-F、-Cl、-Br、氰基、-CF
3、-CH
3、-CH
2CH
3、-CH=CH
2、-CH
2CN、-CH(CH
3)-NH
2、-CH=CH-CN、-C(O)-OH、-C(O)OCH
3、-C(O)CH
3、-C(CH
3)
2-C(O)-OCH
3、-C(CH
3)
2-CN、氧代基、羟基、环丙基、环丁基、环戊基、-NH
2、-NH-C(O)CH
3、-NH-S(O)
2CH
3、-NH-C(O)OC(CH
3)
3、
-S(O)
2CH
3、-S(O)
2NCH
3、-S(O)
2NH
2、-OCH
2CH
3、-O(CH
2)
2CH
3、-OCF
3、
-OCH
2环丙基、-OCH
3、-O(CH
2)
3CH
3、-OCH
2苯基、-O-苯基、-(CH
2)-OH、-(CH
2)
2-OH、-(CH
2)-OCH
3、-(CH
2)-OCH
2CH
3、-CH(OH)-CH
2-苯基、-CH(OH)-CH
2CH
3、-CH(OH)-CH
2CH
2CH
3、-CH(OH)-CH
2CH
2CH
2CH
3、-CH(OH)-CH(CH
3)
2、-CH(OH)-苯基、-CH(OH)-CN、-CH(OH)-CH
2-OH、-CH(OH)-CF
3、-CH(OH)-(CH
2)
2-苯基、*-CH(OH)-C≡CH、-CH(NH
2)-CH
2-C(O)OH、-CH
2-NH-S(O)
2-CH
3、-CH
2-NH-(CH
2)
3CH
3、-CH
2-NH-CH
3、-CH
2-N(CH
3)
2、-CH
2-NH-CH
2CH
3、-CH(CH
3)-NH
2、-CH
2-NH
2、-CH
2CH
2-NH
2、-CH
2NH-CH
2-苯基、-CH
2N(CH
2CH
3)
2、-CH
2NH-环丙基、-CH
2NH-环丁基、-CH
2NH-环戊基、-CH
2NH-吡啶基、-CH
2NH-苯基、-CH
2NH-(CH
2)
2-OH、-CH
2N(CH
3)-(CH
2)
2-OH、-CH
2NH-CH
2-CN、-CH
2N(CH
3)-CH
2-CN、-CH
2N(CH
3)-CH
2-CF
3、-CH
2N(CH
3)-CH
2-CF
2H、-CH
2NH-CH
2-CF
2H、-CH
2NH-(CH
2)
2-OCH
3、
-CH
2NH-C(O)-OC(CH
3)
3、-CH
2CH
2NH-C(O)-OC(CH
3)
3、-CH
2NH-C(O)-CH
2NOH、-CH
2NH-C(O)-CH
2OCH
3、-CH(CH
3)NH-C(O)-OC(CH
3)
3、-CH
2NH-C(O)-CH
3、
CH
2NHCH
2-C(O)-NH
2、-CH
2NHCH
2-C(O)-(CH
3)
2、-CH
2NHCH
2-C(O)-OCH
3、-CH
2NHCH
2-C(O)-NHCH
3、-CH
2NHCH
2-C(O)-NH(CH
2)
2-OCH
3、-CH
2NHCH
2-C(O)-NHCH
2-苯基、
-CH
2NHCH
2-C(O)-NH-苯基、
-CH
2NH-C(O)-CH
2NH-苯基、
或-CH
2NH-C(O)-CH
2NH-CH
2CF
3;
Y为1或者2;
L'为键、-(CH
2)
k-或者-O(CH
2)
k-,所述k为1或者2,或者L'为-CH=CH-(CH
2)
n,所述n为0或者1。
更优选的,本发明某些实施方式中,所述S2为WO2019201848A1(其全文通过引用的方式并入本文中)中实施例1(Example 1)至实施例100(Example 100)的具体化合物。
本发明某些实施方式中,所述S2a中,w为1或者2。
本发明某些实施方式中,所述S2a中,R
1为氢、甲基、-OCH
3、-OCH
2CH
3、-OCH(CH
3)
2、-O(CH
2)
2CH(CH
3)
2或-O(CH
2)
3CH
3,例如-OCH
3。
本发明某些实施方式中,所述S2a中,R
2为氢、卤素、-NH
2、C
1-C
6烷基或-C
1-C
6卤代烷基。
本发明某些实施方式中,所述S2a中,L'为键。
本发明某些实施方式中,所述S2a中,A
2(R
3)
Y为氢。
本发明某些实施方式中,所述S2a中,R
3为氢、-F、-Cl、-Br、-CH
2-NH-(CH
2)
3CH
3、-CH
2-NH-CH
3、-CH
2-N(CH
3)
2或-CH
2-NH-CH
2CH
3。
本发明某些实施方式中,所述S2a中,R
3为氢、Cl、-CH
2NHCH
3或-CH
2N(CH
3)
2。
本发明某些实施方式中,所述S2a中,A
1为
L'为键,A
2为
R
3为氢、-F、-Cl、-Br、-CH
2-NH-(CH
2)
3CH
3、-CH
2-NH-CH
3、-CH
2-N(CH
3)
2或-CH
2-NH-CH
2CH
3。
本发明某些实施方式中,所述S为S2a',
其中,所述S2a'中,T、V、R
1、R
2、R
3、L'、A
1、A
2、w、x和Y的定义如S2或S2a中所述。
本发明某些实施方式中,所述S为S2a”,
其中,所述S2a”中,T、V、R
2、R
3、L'、A
1、A
2、w和Y的定义如S2或S2a中所述。
本发明某些实施方式中,所述S2a'、S2a”中,R
1为氢、C
1-C
6烷基或C
1-C
6烷氧基,所述C
1-C
6烷基和C
1-C
6烷氧基任选的被C
1-C
6烷氧基(例如甲氧基)取代。
本发明某些实施方式中,所述S为-X-S2a',S2a'的结构如上所述;X为O、NH或者S,优选为O。
本发明某些实施方式中,所述S为-X-S2a”,S2a”的结构如上所述;X为O、NH或者S,优选为O。
优选的,本发明某些实施方式中,所述S为S3:
其中所述S3中:
Q
1和Q
2各自独立的CH或者N;
Q
3、Q
4和Q
7各自独立的为C或者N,所述Q
3和Q
4至少有一个为C,所述Q
3、Q
4和Q
7不全部为N;
Q
5为CH、N、NH、O或者S;
Q
6为CH、N、NH、N(C
1-C
6烷基)、N(C
1-C
6杂烷基)、N(3-7元环烷基)、N(3-7元杂环)、O或者S;
所述Q
1、Q
2、Q
3、Q
4、Q
5、Q
6和Q
7中至少有一个为N、NH、O或者S;
R
1选自氢、C
1-C
6烷基、C
1-C
6烷氧基、卤素、-NHR
1a、-OR
1a、C
3-C
6环烷基、C
3-C
6环烷氧基或者-CN;所述C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基和C
3-C
6环烷氧基任选的被选自卤素、-NHR
1a或-OR
1a的取代基取代;所述R
1a为氢、C
1-C
6烷基、3-6元杂环或者C
1-C
6卤代烷基;
L
2选自键、-C(O)-、-C(O)O-、-C(O)NH(CH
2)
o-、-S(O)
2-、-S(O)-、-S(=O)(=NH)-、-S(=O)[=N(C
1-C
6烷基)]-、-N(C
1-C
6烷基)-、-C(O)(CH
2)
p-、-(CH
2)
p-或者O;所述o为0、1或者2;所述p为1至6的整数;
R
2选自氢、卤素、-CN、-NO
2、C
1-C
6烷基巯基、C
2-C
6炔基、C
1-C
6烷基、C
2-C
6烯基、-NR
2bR
2c、-OR
2a、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基;所述C
1-C
6烷基、C
2-C
6烯基、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基和5-10元杂芳基各自独立的任选的被选自C
1-C
6烷基、C
1-C
6卤代烷基、-OH、-OR
2a、氧代基、卤素、-C(O)R
2a、-C(O)OR
2a、-C(O)NR
2bR
2c、-CN、-NR
2bR
2c、3-6元环烷基、3-7元杂环烷基、6-10元芳基或5-10元杂芳基的取代基取代;所述R
2a为氢、C
1-C
6烷基、C
1-C
6卤代烷基、3-7元杂环烷基、或者-(CH
2)
rOCH
3,所述r为1、2或者3;
所述R
2b为氢或C
1-C
6烷基;
所述R
2c为氢或C
1-C
6烷基;
R
2为-NHC(O)-(C
1-C
6烷基)、-NHC(O)-NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基(例如,所述R
a和R
b各自独立的为氢或C
1-C
6烷基);
R
2为-NH-(CH
2)
k-NH-C(O)-(C
1-C
6烷基),所述k为1或者2;
R
2为-NH-(CH
2)
i-R
f,所述i为0,1或者2且R
f为4-7元杂环烷基、杂芳基、C
1-C
6烷基磺酰基;
R
3和R
4各自独立的为氢、C
1-C
6烷基、C
1-C
6烷氧基或C
3-C
6环烷氧基;所述R
3和R
4至少有一个不为氢,或者所述R
3和R
4和其所连接的原子一起形成3-6元环烷基;所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C
1-C
6烷氧基、C
3-C
6环烷基、C
3-C
6环烷氧基或卤素取代;
A为任选取代的(例如任选1个或多个R
2取代,R
2的定义如S1中所述)6-元芳基或者任选取代的(例如任选1个或多个R
2取代,R
2的定义如S1中所述)5-6元杂芳基。
优选的,本发明某些实施方式中,所述S为S3a,
其中所述S3a中:
Q
1和Q
2各自独立的CH或者N;
Q
3和Q
4各自独立的为C或者N,所述Q
3和Q
4至少有一个为C;
Q
6为CH、N、NH、O或者S;
Q
5为CH、N、NH、O或者S;
所述Q
1、Q
2、Q
3、Q
4、Q
5和Q
6中至少有一个为N、NH、O或者S;
R
1选自氢、C
1-C
6烷基、卤素、-OR
1a、环丙基或者-CN;所述R
1a为氢或C
1-C
6烷基;
L
2选自键、-C(O)-、-C(O)O-、-C(O)NH(CH
2)
o-、-S(O)
2-、-C(O)(CH
2)
p-、-(CH
2)
p-或者O;所述o为0、1或者2;所述p为1至6的整数;
R
2选自氢、-(CH
2)
qCH
3、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基;所述q为1至5的整数;所述3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基和5-10元杂芳基各自独立的任选的被选自C
1-C
6烷基、-OH、卤素、-C(O)R
2a、-C(O)NR
2bR
2c的取代基取代;所述R
2a为C
1-C
6烷基或者-(CH
2)
rOCH
3,所述r为1、2或者3;所述R
2b为氢或C
1-C
6烷基;所述R
2c为氢或C
1-C
6烷基;
R
3和R
4各自独立的为氢或C
1-C
6烷基,所述R
3和R
4至少有一个不为氢,或者所述R
3和R
4和其所连接的原子一起形成3-6元环烷基;
A为任选取代的(例如任选1个或多个R
2取代,R
2的定义如S1中所述)苯基或者任选取代的(例如任选1个或多个R
2取代,R
2的定义如S1中所述)5-6元杂芳基。
更优选的,本发明某些实施方式中,所述S3为WO2020180768A1(其全文通过引用的方式并入本文中)中实施例1(Example 1)至实施例103(Example 103)的具体化合物。
优选的,本发明某些实施方式中,所述S为S4:
其中所述S4中:
Q
1为CH或者N;
Q
4为CH、C或者N;
每个Q
2各自独立的为C-R
1或者N,所述Q
2其中一个为N另一个Q
2为C-R
1;
每个Q
3和Q
5分子独立的为C(R
QC)
2、NR
QN、C(O)、O、S或者SO
2,所述R
QC各自独立的为氢、 F、Cl、Br、或者6-10元芳基,所述R
QN各自独立的为氢、C
1-C
6烷基或者6-10元芳基;
所述Q
1、Q
2、Q
3、Q
4、和Q
5至少有一个是N、NR
QN、O或者SO
2;
m为0、1、2或者3;
n为0、1、2或者3;
且当m为0时,n不是0;
R
1选自氢、C
1-C
6烷基、卤素、-C(O)NHR
1a、-NHR
1a、-OR
1a、环丙基、氮杂环丁烷或者-CN;所述C
1-C
6烷基和氮杂环丁烷任选的被选自卤素、R
1a、-NHR
1a或-OR
1a的取代基取代;所述R
1a为氢、C
1-C
6烷基、环丙基、3-6元杂环或者C
1-C
6卤代烷基;
L
2选自键、-C(O)-、-C(O)O-、-C(O)NH(CH
2)
o-、-S(O)
2-、-S(O)-、-S(=O)(=NH)-、-S(=O)[=N(C
1-C
6烷基)]-、-N(C
1-C
6烷基)-、-C(O)(CH
2)
p-、-(CH
2)
p-或者O;所述o为0、1或者2;所述p为1至6的整数;
R
2选自氢、C
1-C
6烷基、-NR
2bR
2c、-OR
2a、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基;所述C
1-C
6烷基、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基和5-10元杂芳基各自独立的任选的被选自C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6羟基烷基、C
1-C
6甲氧基烷基、-OH、-OR
2a、氧代基、卤素、=N、-C(O)R
2a、-C(O)OR
2a、-C(O)NR
2bR
2c、-S(O)
2R
2a、-CN、-NR
2bR
2c、3-6元环烷基、3-7元杂环烷基、6-10元芳基或5-10元杂芳基的取代基取代;所述R
2a为氢、C
1-C
6烷基、C
1-C
6卤代烷基、3-7元杂环烷基、或者-(CH
2)
rOCH
3,所述r为1、2或者3;
所述R
2b为氢或C
1-C
6烷基;
所述R
2c为氢或C
1-C
6烷基;
R
3和R
4各自独立的为氢、任选被卤素、-OH取代的C
1-C
6烷基,所述R
3和R
4至少有一个为氢,或者所述R
3和R
4和其所连接的原子一起形成3-6元环烷基;
A为任选取代的(例如任选1个或多个R
2取代,R
2的定义如S1中所述)6-元芳基或者任选取代的(例如任选1个或多个R
2取代,R
2的定义如S1中所述)5-6元杂芳基;
优选的,本发明某些实施方式中,所述S为S4a
其中所述S4a中:
Q
1为CH或者N;
Q
4为CH、C或者N;
每个Q
2各自独立的为CR
1或者N;
每个Q
3和Q
5分子独立的为C(R
QC)
2、NR
QN、C(O)、O、S或者SO
2,所述R
QC各自独立的为氢、F、Cl、Br、或者6-10元芳基,所述R
QN各自独立的为氢、C
1-C
6烷基或者6-10元芳基;
所述Q
1、Q
2、Q
3、Q
4、和Q
5至少有一个是N、NR
QN、O或者SO
2;
R
1选自氢、C
1-C
6烷基、卤素、环丙基、氰基或-OR
1a,所述R
1a为氢或C
1-C
6烷基;
L
2选自键、-C(O)-、-C(O)O-、-C(O)NH(CH
2)
o-、-S(O)
2-、-C(O)(CH
2)
p-、-(CH
2)
p-或者O;所述o为0、1或者2;所述p为1至6的整数;
R
2选自氢、-(CH
2)
qCH
3、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基;所述q为1至5的倍数;所述3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基各自独立的任选的被选自C
1-C
6烷基、羟基、卤素、-C(O)R
2a或-C(O)NR
2bR
2c的基团取代;所述R
2a选自C
1-C
6烷基或-(CH
2)
rOCH
3;所述r为1、2或者3;所述R
2b和R
2c各自独立的为氢或C
1-C
6烷基;
R
3和R
4各自独立的为氢或C
1-C
6烷基,所述R
3和R
4至少有一个为氢,或者所述R
3和R
4和其所连接的原子一起形成3-6元环烷基;
A为任选取代的(例如任选1个或多个R
2取代,R
2的定义如S1中所述)6-元芳基或者任选取代的(例如任选1个或多个R
2取代,R
2的定义如S1中所述)5-6元杂芳基。
优选的,本发明某些实施方式中,所述S4a中R
3和R
4各自独立的为氢或甲基,所述R
3和R
4至少有一个为氢。
更优选的,本发明某些实施方式中,所述S4为WO2020180770A1(其全文通过引用的方式并入本文中)中实施例1(Example 1)至实施例540(Example 540)的具体化合物。
优选的,本发明某些实施方式中,所述S为S5:
其中所述S5中:
所述R
1为氢或R
a1;
R
a1选自C
1-C
6烷基、C
1-C
6卤代烷基、C
2-C
6烯基、C
1-C
6炔基、C
3-C
10环烷基、C
4-C
10环烯基、3-10元杂环烷基、C
6-C
10元芳基或者5-10元杂芳基,所述C
1-C
6烷基、C
1-C
6卤代烷基、C
2-C
6烯基、C
1-C
6炔基、C
3-C
10环烷基、C
4-C
10环烯基、3-10元杂环烷基、C
6-C
10元芳基和5-10元杂芳基任选的被1个或多个相同的或者不同的R
b1和/或R
c1取代;
每个R
b1各自独立的为-OR
c1、-NR
c1R
c1、卤素、-CN、-C(O)R
c1、-C(O)OR
c1、-C(O)NR
c1R
c1、-S(O)
2R
c1、-S(O)
2NR
c1R
c1、-NHC(O)R
c1、-N(C
1-C
4烷基)C(O)R
c1、-NHC(O)OR
c1或者-N(C
1-C
4烷基)C(O)OR
c1;
每个R
c1各自独立的为氢、C
1-C
6烷基、C
1-C
6卤代烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
4-C
10环烯基、3-10元杂环烷基、C
6-C
10芳基或者5-10元杂芳基;所述C
1-C
6烷基、C
1-C
6卤代烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
4-C
10环烯基、3-10元杂环烷基、C
6-C
10芳基和5-10元杂芳基各自独立的任选的被1个或者多个相同的或者不同的R
d1和/或R
e1;
每个R
d1各自的独立为-OR
e1、-NR
e1R
e1、卤素、-CN、-C(O)R
e1、-C(O)OR
e1、-C(O)NR
e1R
e1、-S(O)
2R
e1、-S(O)
2NR
e1R
e1、-NHC(O)R
e1、-N(C
1-C
4烷基)C(O)R
e1、-NHC(O)OR
e1或者-N(C
1-C
4烷基)C(O)OR
e1;
每个R
e1各自独立的为氢、C
1-C
6烷基、C
1-C
6卤代烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
4-C
10环烯基、3-10元杂环烷基、C
6-C
10芳基或者5-10元杂芳基;
R
2选自氢、C
1-C
4烷基、C
3-C
6环烷基、3-6元杂环烷基或者卤素;
环A选自C
6-C
10芳基、5-10元杂芳基或者9-10元双杂环烷基;
p为1、2或3;
每个R
4各自独立的为氢、羟基、氧代、卤素、氰基、C
1-C
4烷基、-NH
2、C
1-C
4卤代烷基、C
2-C
4烯基、C
2-C
4炔基、C
1-C
4羟基烷基、羟基-C
1-C
4卤代烷基、C
3-C
6环烷基、C
3-C
6环烷氧基、3-6元杂环烷基、C
3-C
6羟基环烷基,被3-6元杂环烷基取代的C
1-C
4卤代烷基,被羟基、卤素、-NH
2、-S(O)
2-(C
1-C
4烷基)或者氧代基取代的3-6元杂环烷基,且氧代基仅在非芳香环上取代;
R
4为-NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
4为-C(O)NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
4为-C(O)OR
g,所述R
g为氢或C
1-C
6烷基;
R
4为-OR
h;所述R
h为C
1-C
6烷基;
或者R
4为-(CH
2)NR
aR
b,所述R
a和R
b各自独立的氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
3和R
5各自独立的为氢、C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基或C
3-C
6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C
1-C
6烷氧基、C
3-C
6环烷基、C
3-C
6环烷氧基或卤素取代。
优选的,本发明某些实施方式中,所述S5中R
5为甲基。
在一些实施方案中,所述S5各基团的定义中,所述R
a和R
b在任一处出现时各自独立的为氢或C
1-C
6烷基。
本发明某些实施方式中,所述S为S5':
其中所述S5'中,所述R
2、R
3、R
4、R
5、环A和p如S5中所定义和描述。
本发明某些实施方式中,所述S为-X-S5',S5'的结构如上所述;X为O、NH或S,优选为O。
优选的,本发明某些实施方式中,所述S为S5a:
其中,所述R
1、R
2、R
3、R
4、环A和p如S5中所定义和描述。
本发明某些实施方式中,所述S为S5a':
其中所述S5a'中,所述R
2、R
3、R
4、R
5、环A和p如S5a中所定义和描述。
本发明某些实施方式中,所述S为-X-S5a',S5a'的结构如上所述;X为O、NH或S,优选为O。
更优选的,本发明某些实施方式中,所述S5为WO2019122129A1(其全文通过引用的方式并入本文中)中I-1至I-179的具体化合物。
优选的,本发明某些实施方式中,所述S为S6:
其中所述S6中:
R
2选自氢、卤素、-OH、-CN、-NO
2、C
1-C
6烷基巯基或-NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2选自C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷氧基、C
3-C
6杂环烷氧基(例如
)、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、4-7元杂环烷基(例如
)、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、C
1-C
6卤代烷基、-COOH、-COOR
c;所述R
c为-C
1-C
6烷基、C
3-C
6烯基、C
3-C
6炔基、C
3-C
8环烷基或-C
4-C
8环烯基;
R
2为-NS(O)(R
d)(R
e),所述R
d和R
e各自独立的为C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、6-10元芳基或5-10元杂芳基;
R
2为-NHC(O)-(C
1-C
6烷基)、-NHC(O)-NR
aR
b,所述R
a和R
b各自独立的为氢、-C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2为-NH-(CH
2)
k-NH-C(O)-R
aa,所述R
aa为C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基,且k为1或者2;
R
2为-NH-(CH
2)
i-R
f,所述i为0,1或者2且R
f为4-7元杂环烷基、杂芳基、C
1-C
6烷基磺酰基;
此外以上所述C
1-C
6烷基、C
1-C
6烷氧基、4-7元杂环烷基和杂芳基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-NO
2、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、4-7元杂环烷基、C
1-C
6烷氧基、C
1-C
6卤代烷基、C
1-C
6卤代烷氧基、C
1-C
6烷基磺酰基、苯基、苄基、杂芳基、-(CH
2)-杂芳基、-NHC(O)(C
1-C
6烷基)、C
3-C
8环烷氧基、苯氧基、杂芳基氧基或者-NR
aR
b的基团取代;所述R
a和R
b各自独立的选自氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2为-O-(CH
2)
z-苯基、-O-(CH
2)
z-(4-7元杂环烷基)、-O-(CH
2)
z-杂芳基,所述z为0,1或2,所述苯基、杂环烷基和杂芳基任选的被选自-OH、杂环烷基或者杂环烯基取代,且能被甲基或者氧代基取代;
或者R
2为
R
1为氢或-OR
A;
R
A为氢、C
3-C
10环烷基或3-10元杂环烷基;所述C
3-C
10环烷基和3-10元杂环烷基任选被1个或者多个相同或不同的R
a1和/或R
c1取代;
每个R
a1各自独立的为C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基各自独立的任选的被1个或者多个相同或不同的R
b1和/或R
c1取代;
每个R
b1各自独立的为-OR
c1、-NR
c1R
c1、卤素、-CN、-C(O)R
c1、-C(O)OR
c1、-C(O)NR
c1R
c1、-S(O)
2R
c1、-S(O)
2NR
c1R
c1、-NHC(O)R
c1、-N(C
1-C
4烷基)C(O)R
c1、氧代基所取代,且所述氧代基仅在非芳香环取代;
每个R
c1各自独立的为氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10杂芳基;
或者R
1选自C
3-C
10环烷基、C
3-C
10环烯基、C
6-C
10芳基、3-10元杂环烷基或5-10元杂芳基;所述C
3-C
10环烷基、C
3-C
10环烯基、C
6-C
10芳基、3-10元杂环烷基或5-10元杂芳基任选的被1个或多个R
a2和/或R
b2取代;
每个R
a2各自独立的选自C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
c2和/或R
b2取代;
每个R
b2各自独立的选自-OR
c2、-NR
c2R
c2、卤素、-CN、-C(O)R
c2、-C(O)OR
c2、-C(O)NR
c2R
c2、-OC(O)R
c2、-S(O)
2R
c2、-S(O)
2NR
c2R
c2、-NHC(O)R
c2、-N(C
1-C
4烷基)C(O)R
c2、-NHC(O)OR
c2、氧代基、=NH,且所述氧代基、=NH仅在非芳香环上取代;
每个R
c2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
d2和/或R
e2取代;
每个R
d2各自独立的为-OR
e2、-NR
e2R
e2、卤素、-CN、-C(O)R
e2、-C(O)OR
e2、-C(O)NR
e2R
e2、-S(O)
2R
e2、-S(O)
2NR
e2R
e2、-NHC(O)R
e2、-N(C
1-C
4烷基)C(O)R
e2、氧代基,所述氧代基仅在非芳香环上取代;
每个R
e2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
f2和/或R
g2取代;
每个R
f2各自独立的选自-OR
g2、-NR
g2R
g2、卤素、-CN、-C(O)R
g2、-C(O)OR
g2、-C(O)NR
g2R
g2、-S(O)
2R
g2、-S(O)
2NR
g2R
g2、-NHC(O)R
g2、-N(C
1-C
4烷基)C(O)R
g2、氧代基,所述氧代基仅在非芳香环上取代;
每个R
g2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;
或R
1选自C
2-C
4烷基、C
2-C
4烯基;所述C
2-C
4烷基和C
2-C
4烯基任选的R
b3取代;
R
b3选自-C(O)R
c3、-C(O)OR
c3、-C(O)NR
c3R
c3、-C(O)NHOR
c3或者-C(O)N(C
1-C
4烷基)OR
c3;
每个R
c3各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、 3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
d3和/或R
e3取代;
每个R
d3各自独立的选自-OR
e3、-NR
e3R
e3、卤素、-CN、-C(O)R
e3、-C(O)OR
e3、-C(O)NR
e3R
e3、-S(O)
2R
e3、-S(O)
2NR
e3R
e3、-NHC(O)R
e3、-N(C
1-C
4烷基)C(O)R
e3、氧代基,所述氧代基仅在非芳香环上取代;
每个R
e3各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;
R
3选自氢、C
1-C
4烷基、-O(C
1-C
4烷基)、-NH
2、-NH(C
1-C
4烷基)、-N(C
1-C
4烷基)
2或者卤素;
R
5选自氢、羟基或者-NHR’;
R’选自氢、C
1-C
3烷基和-C(O)C
1-C
3烷基;
R
4选自C
1-C
4烷基、羟基、氧代、氰基、C
1-C
4烷氧基、C
1-C
4卤代烷基、C
1-C
4羟基烷基、羟基-C
1-C
4卤代烷基、C
2-C
6烯基、-C
2-C
6炔基、C
3-C
6环烷氧基、C
3-C
6环烷基、3-6元杂环烷基、3-6元羟基杂环烷基、卤素或者-SO
2-C
1-C
4烷基;
R
6选自氢、C
1-C
4烷基或者卤素;
或者R
4、R
6与它们连接的碳原子一起形成任选取代(例如未取代的或者被氧代的)的C
5-C
6环烷基(例如形成
)和5-6元杂环烷基,所述5-6元杂环烷基中的杂原子选自包含1、2、3或4个独立选自-NH、-O-、-S-和N的杂原子或杂原子团;
R
7、R
8各自独立的为C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基或C
3-C
6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C
1-C
6烷氧基、C
3-C
6环烷基、C
3-C
6环烷氧基或卤素取代。
在一些实施方案中,所述S6中,当R
4、R
6与它们连接的碳原子一起形成任选取代的C
5-C
6环烷基和5-6元杂环烷基,所述取代是指被1、2、3或4个=O取代。
在一些实施方案中,所述S6中,R
1为氢或-OR
A,R
A为氢。
在一些实施方案中,所述S6中,R
1为氢。
在一些实施方案中,所述S6中,R
2为氢、C
1-C
4烷基、-O(C
1-C
4烷基)、-NH
2、-NH(C
1-C
4烷基)、-N(C
1-C
4烷基)
2或者卤素,所述C
1-C
4烷基和-O(C
1-C
4烷基)各自独立地任选被-O(C
1-C
4烷基)取代。
在一些实施方案中,所述S6中,R
2为氢、C
1-C
4烷基、-O(C
1-C
4烷基)、-NH
2、-NH(C
1-C
4烷基)、-N(C
1-C
4烷基)
2或者卤素。
在一些实施方案中,所述S6中,R
2为氢、C
1-C
4烷基或者-O(C
1-C
4烷基),所述-O(C
1-C
4烷基)任选的被-O(C
1-C
4烷基)取代。
在一些实施方案中,所述S6中,R
3为氢。
在一些实施方案中,所述S6中,R
5为氢或者-NHR’。
在一些实施方案中,所述S6中,R
7为C
1-C
6烷基。
在一些实施方案中,所述S6中,R
8为C
1-C
6烷基。
在一些实施方案中,所述S6中,R
1为氢或-OR
A;
R
A为氢;
R
2为氢、C
1-C
4烷基或者-O(C
1-C
4烷基)(例如甲氧基),所述-O(C
1-C
4烷基)任选的被-O(C
1-C
4烷基)(例如甲氧基)取代;
R
3为氢;
R
5为氢或者-NHR’;
R’选自氢、C
1-C
3烷基和-C(O)C
1-C
3烷基;
R
4为C
1-C
4卤代烷基;
R
6为氢或者卤素;
R
7为C
1-C
6烷基;
R
8为C
1-C
6烷基。
在一些实施方案中,所述S6中,当R
2为C
1-C
4烷基时,所述C
1-C
4烷基可为甲基。
在一些实施方案中,所述S6中,当R
2为-O(C
1-C
4烷基)时,所述-O(C
1-C
4烷基)可为-OCH
3。
在一些实施方案中,所述S6中,R
2为氢、甲基或-OCH
3。
在一些实施方案中,所述S6中,R
3为氢。
在一些实施方案中,所述S6中,当R’为C
1-C
3烷基时,所述C
1-C
3烷基可为乙基或异丙基。
在一些实施方案中,所述S6中,当R’为-C(O)C
1-C
3烷基时,所述的-C(O)C
1-C
3烷基可为-C(O)CH
3。
在一些实施方案中,所述S6中,R
5为氢或-NHR’,其中R’为氢、乙基、异丙基或-C(O)CH
3。
在一些优选的实施方案中,所述S6中,R
5为-NHR’,其中R’为氢。
在一些实施方案中,所述S6中,R
4为C
1-C
4卤代烷基;
R
6为氢或者卤素;
在一些实施方案中,所述S6中,当R
4为C
1-C
4卤代烷基时,所述的C
1-C
4卤代烷基可为C
1-C
4氟代烷基,例如三氟甲基。
在一些实施方案中,所述S6中,R
7为C
1-C
6烷基。
在一些实施方案中,所述S6中,当R
7为C
1-C
6烷基时,所述的C
1-C
6烷基可为甲基。
在一些实施方案中,所述S6中,R
8为C
1-C
6烷基。
在一些实施方案中,所述S6中,当R
8为C
1-C
6烷基时,所述的C
1-C
6烷基可为甲基。
优选的,本发明某些实施方式中,所述S6中R
8为甲基。
本发明某些实施方式中,所述S为S6':
其中所述S6'中,R
2、R
3、R
4、R
5、R
6、R
7如S6中所定义和描述。
本发明某些实施方式中,所述S为-X-S6',S6'的结构如上所述;X为O、NH或S,优选为O。
优选的,本发明某些实施方式中,所述S为S6a:
其中所述S6a中,R
1、R
2、R
3、R
4、R
5、R
6、R
7如S6中所定义和描述。
优选的,本发明某些实施方式中,所述S6或S6a中,R
1为氢;R
2选自-O(C
1-C
4烷基);R
3为氢;R
4为C
1-C
4卤代烷基;R
5选自为-NH
2;R
7选自C
1-C
4烷基或C
1-C
4卤代烷基。
优选的,本发明某些实施方式中,所述S为S6b:
其中所述S6b中,R
1、R
2、R
3、R
4、R
5、R
6和R
7如S6中所定义和描述。
优选的,本发明某些实施方式中,所述S为S6c:
其中所述S6c中,R
2、R
3、R
4、R
5、R
6和R
7如S6中所定义和描述。
本发明某些实施方式中,所述S为-X-S6c,S6c的结构和定义如上所述;其中,X为O、NH或者S,优选为O。
优选的,本发明某些实施方式中,所述S为S6d:
其中所述S6d中,X为O、NH或者S,优选为O;R
2、R
3、R
4、R
5、R
6和R
7如S6中所定义和描述。
优选的,本发明某些实施方式中,所述S6为WO2018115380A1(其全文通过引用的方式并入本文中)中I-1至I-383的具体化合物。优选的,本发明某些实施方式中,所述S为S6e:
其中所述S6e中,R
2、R
3和R
7如S6的任一方案中所定义和描述。
优选的,本发明某些实施方式中,所述S为-X-S6e,S6e的结构和定义如上所述;其中,X为O、NH或者S,优选为O。
优选的,本发明某些实施方式中,所述S6e中,R
2为-O(C
1-C
4烷基);R
3为氢;R
7为C
1-C
6烷基。
优选的,本发明某些实施方式中,所述S6e中,R
2为-OCH
3;R
3为氢;R
7为甲基。
本发明某些实施方式中,所述S6、S6'、S6a或S6c为如下任一结构:
本发明某些实施方式中,所述S为S6”:
其中所述S6”中,R
1、R
3、R
4、R
5、R
6、R
7和R
8如S6中所定义和描述。
本发明某些实施方式中,所述S为S6”':
其中所述S6”'中,R
3、R
4、R
5、R
6、R
7和R
8如S6中所定义和描述。
本发明某些实施方式中,所述S为-X-S6”',S6”'的结构如上所述;其中X为O、NH或S,优选为O。
优选的,本发明某些实施方式中,所述S为S6a”:
其中所述S6a”中,R
1、R
3、R
4、R
5、R
6、R
7如S6中所定义和描述。
优选的,本发明某些实施方式中,所述S为S6b”:
其中所述S6b”中,R
1、R
3、R
4、R
5、R
6和R
7如S6中所定义和描述。
优选的,本发明某些实施方式中,所述S为S6c”:
其中所述S6c”中,R
3、R
4、R
5、R
6和R
7如S6中所定义和描述。
优选的,本发明某些实施方式中,所述S为-X-S6c”,S6c”的结构和定义如上所述;其中,X为O、NH或者S,优选为O。
优选的,本发明某些实施方式中,所述S为S6d”:
其中所述S6d”中,X为O、NH或者S,优选为O;R
3、R
4、R
5、R
6和R
7如S6中所定义和描述。
优选的,本发明某些实施方式中,所述S为S6e”:
其中所述S6e”中,R
3和R
7如S6中所定义和描述。
优选的,本发明某些实施方式中,所述S为-X-S6e”,S6e”的结构和定义如上所述;其中,X为O、NH或者S,优选为O。
优选的,本发明某些实施方式中,所述S6e”中,R
3为氢;R
7为C
1-C
6烷基。
优选的,本发明某些实施方式中,所述S6e”中,R
3为氢;R
7为甲基。
优选的,本发明某些实施方式中,所述S为
更优选的,本发明某些实施方式中,所述S为
本发明某些实施方式中,所述S为S7:
其中所述S7中:
R
2选自氢、卤素、-OH、-CN、-NO
2、C
1-C
6烷基巯基或-NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2选自C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷氧基、C
3-C
6杂环烷氧基(例如
)、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、4-7元杂环烷基(例如
)、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、C
1-C
6卤代烷基、-COOH、-COOR
c;所述R
c为-C
1-C
6烷基、C
3-C
6烯基、C
3-C
6炔基、C
3-C
8环烷基或-C
4-C
8环烯基;
R
2为-NS(O)(R
d)(R
e),所述R
d和R
e各自独立的为C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、6-10元芳基或5-10元杂芳基;
R
2为-NHC(O)-(C
1-C
6烷基)、-NHC(O)-NR
aR
b,所述R
a和R
b各自独立的为氢、-C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2为-NH-(CH
2)
k-NH-C(O)-R
aa,所述R
aa为C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基,且k为1或者2;
R
2为-NH-(CH
2)
i-R
f,所述i为0,1或者2且R
f为4-7元杂环烷基、杂芳基、C
1-C
6烷基磺酰基;
此外以上所述C
1-C
6烷基、C
1-C
6烷氧基、4-7元杂环烷基和杂芳基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-NO
2、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、4-7元杂环烷基、C
1-C
6烷氧基、C
1-C
6卤代烷基、C
1-C
6卤代烷氧基、C
1-C
6烷基磺酰基、苯基、苄基、杂芳基、-(CH
2)-杂芳基、-NHC(O)(C
1-C
6烷基)、C
3-C
8环烷氧基、苯氧基、杂芳基氧基或者-NR
aR
b的基团取代;所述R
a和R
b各自独立的选自氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基;
R
2为-O-(CH
2)
z-苯基、-O-(CH
2)
z-(4-7元杂环烷基)、-O-(CH
2)
z-杂芳基,所述z为0,1或2,所述苯基、杂环烷基和杂芳基任选的被选自-OH、杂环烷基或者杂环烯基取代,且能被甲基或者氧代基取代;
或者R
2为
R
1为氢或-OR
A;
R
A为氢、C
3-C
10环烷基或3-10元杂环烷基;所述C
3-C
10环烷基和3-10元杂环烷基任选被1个或者多个相同或不同的R
a1和/或R
c1取代;
每个R
a1各自独立的为C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基各自独立的任选的被1个或者多个相同或不同的R
b1和/或R
c1取代;
每个R
b1各自独立的为-OR
c1、-NR
c1R
c1、卤素、-CN、-C(O)R
c1、-C(O)OR
c1、-C(O)NR
c1R
c1、-S(O)
2R
c1、-S(O)
2NR
c1R
c1、-NHC(O)R
c1、-N(C
1-C
4烷基)C(O)R
c1、氧代基所取代,且所述氧代基仅在非芳香环取代;
每个R
c1各自独立的为氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10杂芳基;
或者R
1选自C
3-C
10环烷基、C
3-C
10环烯基、C
6-C
10芳基、3-10元杂环烷基或5-10元杂芳基;所述C
3-C
10环烷基、C
3-C
10环烯基、C
6-C
10芳基、3-10元杂环烷基或5-10元杂芳基任选的被1个或多个R
a2和/或R
b2取代;
每个R
a2各自独立的选自C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
c2和/或R
b2取代;
每个R
b2各自独立的选自-OR
c2、-NR
c2R
c2、卤素、-CN、-C(O)R
c2、-C(O)OR
c2、-C(O)NR
c2R
c2、-OC(O)R
c2、-S(O)
2R
c2、-S(O)
2NR
c2R
c2、-NHC(O)R
c2、-N(C
1-C
4烷基)C(O)R
c2、-NHC(O)OR
c2、氧代基、=NH,且所述氧代基、=NH仅在非芳香环上取代;
每个R
c2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
d2和/或R
e2取代;
每个R
d2各自独立的为-OR
e2、-NR
e2R
e2、卤素、-CN、-C(O)R
e2、-C(O)OR
e2、-C(O)NR
e2R
e2、-S(O)
2R
e2、-S(O)
2NR
e2R
e2、-NHC(O)R
e2、-N(C
1-C
4烷基)C(O)R
e2、氧代基,所述氧代基仅在非芳香环上取代;
每个R
e2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
f2和/或R
g2取代;
每个R
f2各自独立的选自-OR
g2、-NR
g2R
g2、卤素、-CN、-C(O)R
g2、-C(O)OR
g2、-C(O)NR
g2R
g2、-S(O)
2R
g2、-S(O)
2NR
g2R
g2、-NHC(O)R
g2、-N(C
1-C
4烷基)C(O)R
g2、氧代基,所述氧代基仅在非芳香环上取代;
每个R
g2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;
或R
1选自C
2-C
4烷基、C
2-C
4烯基;所述C
2-C
4烷基和C
2-C
4烯基任选的R
b3取代;
R
b3选自-C(O)R
c3、-C(O)OR
c3、-C(O)NR
c3R
c3、-C(O)NHOR
c3或者-C(O)N(C
1-C
4烷基)OR
c3;
每个R
c3各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
d3和/或R
e3取代;
每个R
d3各自独立的选自-OR
e3、-NR
e3R
e3、卤素、-CN、-C(O)R
e3、-C(O)OR
e3、-C(O)NR
e3R
e3、-S(O)
2R
e3、-S(O)
2NR
e3R
e3、-NHC(O)R
e3、-N(C
1-C
4烷基)C(O)R
e3、氧代基,所述氧代基仅在非芳香环上取代;
每个R
e3各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;
R
4选自氢、C
1-C
4烷基、-O(C
1-C
4烷基)、-NH
2、-NH(C
1-C
4烷基)、-N(C
1-C
4烷基)
2或者卤素;
所述A
2(R
3)
Y为氢;
或者A
2为C
4-C
12环烷基、杂环烷基、芳基或杂芳基,且
R
3为氢、卤素、-OH、氧代、-CN、-NO
2、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、C
7-C
8环炔基、4-7元杂环烷基、5-10元杂环烯基、苯基、杂芳基、C
1-C
6卤代烷基;
所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-C
1-C
6烷基、-C
1-C
6烷氧基、-C
1-C
6卤代烷基、苯基、杂芳基或-C(O)NR
iR
j的取代基取代,所述R
i和R
j各自独立的为氢或者C
1-C
6烷基;
或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR
kR
l取代,所述R
k和R
l各自独立的为氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
1-C
6烷基磺酰基、苯基、杂芳基、-CH
2-C(O)-R
m、-C(O)R
p或4-7元杂环烷基,且所述烷基、炔基、烯基、环烷基、苯基、杂芳基和杂环烷基各自独立的任选的被1个、2个或3个选自C
1-C
6卤代烷基、-OH、氧代基、苯基、-CN、C
1-C
6烷氧基或杂芳基的取代基取代,且所述杂芳基任选被甲基取代;且所述R
m为双环杂芳基、C
1-C
6烷氧基或者-NR
nR
o,所述R
n和R
o各自独立的为氢、C
1-C
6烷基或者苯基,所述烷基任选被C
1-C
6烷氧基或者苯基取代,或者-NR
nR
o为4-7元氮杂环烷基,所述氮杂环烷基通过N原子连接分子其他部位,且还包含1个或者多个选自N或者O的杂原子;所述R
p选自C
1-C
6烷氧基、任选被1个、2个或者3个选自-OH或者C
1-C
6烷氧基取代的C
1-C
6烷基、单环或双环杂芳基、4-7元杂环烷基或者R
p为-CH
2-NR
qR
r,所述R
q和R
r各自独立的选自氢、苯基或者任选被F取代的C
1-C
6烷基;
或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR
sR
t取代,所述-NR
sR
t为通过氮原子连接至分子其他部位的4-7元氮杂环烷基或者通过氮原子连接至分子其他部位的6-10元氮螺杂环烷基,且进一步包括最多两个选自N或者O的杂原子,且任选的被1个、2个或者3个选自-OH、氧代基、C
1-C
6烷基、C
1-C
6羟基烷基、-C(O)OR
z的取代基取代,所述R
z为C
1-C
6烷基、卤素、-N(C
1-C
6烷基)
2、-CH
2N(C
1-C
6烷基)
2、-C(O)NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基(例如,所述R
a和R
b各自独立的为氢或C
1-C
6烷基);
或者R
3为C(O)R
v、-C(O)NH
2、-C(O)NHR
v、-C(O)NR
vR
w、-C(O)OR
v,所述R
v和R
w各自独立的为氢、C
1-C
4烷基、C
1-C
4卤代烷基、苯基或者-(CH
2)
2NR
xR
y,所述R
x和R
y各自独立的为氢、C
1-C
4烷基或者-(CH
2)
2N(CH
3)
2;
或者R
3为-NH
2、-NHR
z、-NR
zR
za、-NHC(O)R
z、-NHC(O)OR
z、-NHS(O)
2R
z、4-7元杂环烷基、杂芳基、螺杂环烷基、稠杂环烷基、桥杂环烷基,所述R
z和R
za各自独立的为C
1-C
4烷基、C
1-C
4卤代烷基或者苯基;
或者R
3为C
1-C
6烷氧基、C
1-C
6卤代烷氧基、-O(CH
2)
s-C
3-C
8环烷基、-O(CH
2)
s-苯基、-O(CH
2)
s-杂环烷基、-O(CH
2)
s-杂芳基,所述s为0、1、2或者3;
或者R
3为-S(O)
2R
z、-S(O)
2NH
2、-S(O)
2NHR
z、-S(O)
2NR
zR
za,所述R
z和R
za各自独立的为C
1-C
4烷基、C
1-C
4卤代烷基或者苯基;
Y为0、1、2、3、4或5;
L'为键、-(CH
2)
k-或者-O(CH
2)
k-,所述k为0、1、2或者3,或者L'为-CH=CH-(CH
2)
n,所述n为0、1或者2;
R
7、R
8各自独立的为C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基或C
3-C
6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C
1-C
6烷氧基、C
3-C
6环烷基、C
3-C
6环烷氧基或卤素取代。
优选的,本发明某些实施方式中,所述S为S7:
其中所述S7中:
R
1为氢或-OR
A;
R
A为氢、C
3-C
10环烷基或3-10元杂环烷基;所述C
3-C
10环烷基和3-10元杂环烷基任选被1个或者多个相同或不同的R
a1和/或R
c1取代;
每个R
a1各自独立的为C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基各自独立的任选的被1个或者多个相同或不同的R
b1和/或R
c1取代;
每个R
b1各自独立的为-OR
c1、-NR
c1R
c1、卤素、-CN、-C(O)R
c1、-C(O)OR
c1、-C(O)NR
c1R
c1、-S(O)
2R
c1、-S(O)
2NR
c1R
c1、-NHC(O)R
c1、-N(C
1-C
4烷基)C(O)R
c1、氧代基所取代,且所述氧代基仅在非芳香环取代;
每个R
c1各自独立的为氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10杂芳基;
或者R
1选自C
3-C
10环烷基、C
3-C
10环烯基、C
6-C
10芳基、3-10元杂环烷基或5-10元杂芳基;所述C
3-C
10环烷基、C
3-C
10环烯基、C
6-C
10芳基、3-10元杂环烷基或5-10元杂芳基任选的被1个或多个R
a2和/或R
b2取代;
每个R
a2各自独立的选自C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
c2和/或R
b2取代;
每个R
b2各自独立的选自-OR
c2、-NR
c2R
c2、卤素、-CN、-C(O)R
c2、-C(O)OR
c2、-C(O)NR
c2R
c2、-OC(O)R
c2、-S(O)
2R
c2、-S(O)
2NR
c2R
c2、-NHC(O)R
c2、-N(C
1-C
4烷基)C(O)R
c2、-NHC(O)OR
c2、氧代基、=NH,且所述氧代基、=NH仅在非芳香环上取代;
每个R
c2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
d2和/或R
e2取代;
每个R
d2各自独立的为-OR
e2、-NR
e2R
e2、卤素、-CN、-C(O)R
e2、-C(O)OR
e2、-C(O)NR
e2R
e2、-S(O)
2R
e2、-S(O)
2NR
e2R
e2、-NHC(O)R
e2、-N(C
1-C
4烷基)C(O)R
e2、氧代基,所述氧代基仅在非芳香环上取代;
每个R
e2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
f2和/或R
g2取代;
每个R
f2各自独立的选自-OR
g2、-NR
g2R
g2、卤素、-CN、-C(O)R
g2、-C(O)OR
g2、-C(O)NR
g2R
g2、-S(O)
2R
g2、-S(O)
2NR
g2R
g2、-NHC(O)R
g2、-N(C
1-C
4烷基)C(O)R
g2、氧代基,所述氧代基仅在非芳香环上取代;
每个R
g2各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;
或R
1选自C
2-C
4烷基、C
2-C
4烯基;所述C
2-C
4烷基和C
2-C
4烯基任选的R
b3取代;
R
b3选自-C(O)R
c3、-C(O)OR
c3、-C(O)NR
c3R
c3、-C(O)NHOR
c3或者-C(O)N(C
1-C
4烷基)OR
c3;
每个R
c3各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R
d3和/或R
e3取代;
每个R
d3各自独立的选自-OR
e3、-NR
e3R
e3、卤素、-CN、-C(O)R
e3、-C(O)OR
e3、-C(O)NR
e3R
e3、-S(O)
2R
e3、 -S(O)
2NR
e3R
e3、-NHC(O)R
e3、-N(C
1-C
4烷基)C(O)R
e3、氧代基,所述氧代基仅在非芳香环上取代;
每个R
e3各自独立的选自氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
10环烷基、C
6-C
10芳基、3-10元杂环烷基或者5-10元杂芳基;
R
2选自氢、C
1-C
4烷基、-O(C
1-C
4烷基)、-NH
2、-NH(C
1-C
4烷基)、-N(C
1-C
4烷基)
2或者卤素;
R
4选自氢、C
1-C
4烷基、-O(C
1-C
4烷基)、-NH
2、-NH(C
1-C
4烷基)、-N(C
1-C
4烷基)
2或者卤素;
所述A
2(R
3)
Y为氢;
或者A
2为C
4-C
12环烷基、杂环烷基、芳基或杂芳基,且
R
3为氢、卤素、-OH、氧代、-CN、-NO
2、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
4-C
8环烯基、C
7-C
8环炔基、4-7元杂环烷基、5-10元杂环烯基、苯基、杂芳基、C
1-C
6卤代烷基;
所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-C
1-C
6烷基、-C
1-C
6烷氧基、-C
1-C
6卤代烷基、苯基、杂芳基或-C(O)NR
iR
j的取代基取代,所述R
i和R
j各自独立的为氢或者C
1-C
6烷基;
或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR
kR
l取代,所述R
k和R
l各自独立的为氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
1-C
6烷基磺酰基、苯基、杂芳基、-CH
2-C(O)-R
m、-C(O)R
p或4-7元杂环烷基,且所述烷基、炔基、烯基、环烷基、苯基、杂芳基和杂环烷基各自独立的任选的被1个、2个或3个选自C
1-C
6卤代烷基、-OH、氧代基、苯基、-CN、C
1-C
6烷氧基或杂芳基的取代基取代,且所述杂芳基任选被甲基取代;且所述R
m为双环杂芳基、C
1-C
6烷氧基或者-NR
nR
o,所述R
n和R
o各自独立的为氢、C
1-C
6烷基或者苯基,所述烷基任选被C
1-C
6烷氧基或者苯基取代,或者-NR
nR
o为4-7元氮杂环烷基,所述氮杂环烷基通过N原子连接分子其他部位,且还包含1个或者多个选自N或者O的杂原子;所述R
p选自C
1-C
6烷氧基、任选被1个、2个或者3个选自-OH或者C
1-C
6烷氧基取代的C
1-C
6烷基、单环或双环杂芳基、4-7元杂环烷基或者R
p为-CH
2-NR
qR
r,所述R
q和R
r各自独立的选自氢、苯基或者任选被F取代的C
1-C
6烷基;
或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR
sR
t取代,所述-NR
sR
t为通过氮原子连接至分子其他部位的4-7元氮杂环烷基或者通过氮原子连接至分子其他部位的6-10元氮螺杂环烷基,且进一步包括最多两个选自N或者O的杂原子,且任选的被1个、2个或者3个选自-OH、氧代基、C
1-C
6烷基、C
1-C
6羟基烷基、-C(O)OR
z的取代基取代,所述R
z为C
1-C
6烷基、卤素、-N(C
1-C
6烷基)
2、-CH
2N(C
1-C
6烷基)
2、-C(O)NR
aR
b,所述R
a和R
b各自独立的为氢、C
1-C
6烷基、C
3-C
8杂环烷基或C
3-C
8环烷基(例如,所述R
a和R
b各自独立的为氢或C
1-C
6烷基);
或者R
3为C(O)R
v、-C(O)NH
2、-C(O)NHR
v、-C(O)NR
vR
w、-C(O)OR
v,所述R
v和R
w各自独立的为氢、C
1-C
4烷基、C
1-C
4卤代烷基、苯基或者-(CH
2)
2NR
xR
y,所述R
x和R
y各自独立的为氢、C
1-C
4烷基或者-(CH
2)
2N(CH
3)
2;
或者R
3为-NH
2、-NHR
z、-NR
zR
za、-NHC(O)R
z、-NHC(O)OR
z、-NHS(O)
2R
z、4-7元杂环烷基、杂芳基、螺杂环烷基、稠杂环烷基、桥杂环烷基,所述R
z和R
za各自独立的为C
1-C
4烷基、C
1-C
4卤代烷基或者苯基;
或者R
3为C
1-C
6烷氧基、C
1-C
6卤代烷氧基、-O(CH
2)
s-C
3-C
8环烷基、-O(CH
2)
s-苯基、-O(CH
2)
s-杂环烷基、-O(CH
2)
s-杂芳基,所述s为0、1、2或者3;
或者R
3为-S(O)
2R
z、-S(O)
2NH
2、-S(O)
2NHR
z、-S(O)
2NR
zR
za,所述R
z和R
za各自独立的为C
1-C
4烷基、C
1-C
4卤代烷基或者苯基;
Y为0、1、2、3、4或5;
L'为键、-(CH
2)
k-或者-O(CH
2)
k-,所述k为0、1、2或者3,或者L'为-CH=CH-(CH
2)
n,所述n为0、1或者2;
R
7、R
8各自独立的为C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基或C
3-C
6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C
1-C
6烷氧基、C
3-C
6环烷基、C
3-C
6环烷氧基或卤素取代。
本发明某些实施方式中,所述S7中,R
1为氢。
本发明某些实施方式中,所述S7中,R
2为氢、C
1-C
4烷基、-O(C
1-C
4烷基)、-NH
2、-NH(C
1-C
4烷基)、-N(C
1-C
4烷基)
2或者卤素,所述C
1-C
4烷基和-O(C
1-C
4烷基)各自独立地任选被-O(C
1-C
4烷基)取代。
本发明某些实施方式中,所述S7中,R
2为氢、C
1-C
4烷基、-O(C
1-C
4烷基)、-NH
2、-NH(C
1-C
4烷基)、-N(C
1-C
4烷基)
2或者卤素。
本发明某些实施方式中,所述S7中,R
2为氢、C
1-C
4烷基或者-O(C
1-C
4烷基),所述-O(C
1-C
4烷基)任选的被-O(C
1-C
4烷基)取代。
本发明某些实施方式中,所述S7中,R
2为-O(C
1-C
4烷基)。
本发明某些实施方式中,所述S7中,R
4为氢。
本发明某些实施方式中,所述S7中,R
3为氢、卤素或C
1-C
6烷基,所述烷基任选被-NR
kR
l取代;所述R
k和R
l各自独立的为氢或C
1-C
6烷基。
本发明某些实施方式中,所述S7中,A
2为芳基。
本发明某些实施方式中,所述S7中,Y为0、1、2或3。
本发明某些实施方式中,所述S7中,L'为键。
本发明某些实施方式中,所述S7中,R
7为C
1-C
6烷基。
本发明某些实施方式中,所述S7中,R
8为C
1-C
6烷基。
本发明某些实施方式中,所述S7中:
R
1为氢;
R
2为氢、C
1-C
4烷基或者-O(C
1-C
4烷基)(例如甲氧基),所述-O(C
1-C
4烷基)任选的被-O(C
1-C
4烷基)(例如甲氧基)取代;
R
4为氢;
R
3为氢、卤素或C
1-C
6烷基,所述烷基任选被-NR
kR
l取代;所述R
k和R
l各自独立的为氢或C
1-C
6烷基;
A
2为芳基;
Y为0、1、2或3;
L'为键;
R
7为C
1-C
6烷基;
R
8为C
1-C
6烷基。
本发明某些实施方式中,所述S7中,R
2为-O(C
1-C
4烷基),例如-OCH
3。
本发明某些实施方式中,所述S7中,R
3为氢、F、Cl、甲基或乙基,所述甲基和乙基被-NR
kR
l取代;所述R
k为甲基或乙基,R
l为氢、甲基或乙基。
本发明某些实施方式中,所述S7中,R
3为氢、Cl、-CH
2NHCH
3或-CH
2N(CH
3)
2。
本发明某些实施方式中,所述S7中,A
2为苯基。
本发明某些实施方式中,所述S7中,R
7为甲基。
优选的,本发明某些实施方式中,所述S7中,R
8为甲基。
优选的,本发明某些实施方式中,所述S为S7':
其中R
2、R
3、R
4、R
7、R
8、Y、A
2和L'如S7中所定义和描述。
本发明某些实施方式中,所述S为-O-S7',其中S7'的结构和定义如上所述。
优选的,本发明某些实施方式中,所述S为S7”:
其中R
2、R
3、R
4、R
7、Y、A
2和L'如S7中所定义和描述。
本发明某些实施方式中,所述S为-O-S7”,其中S7”的结构和定义如上所述。
优选的,本发明某些实施方式中,所述S为S7a:
其中R
1、R
2、R
3、R
4、R
7、R
8和Y如S7中所定义和描述。
优选的,本发明某些实施方式中,所述S为S7a':
其中R
2、R
3、R
4、R
7、R
8和Y如S7中所定义和描述。
本发明某些实施方式中,所述S为-O-S7a',其中S7a'的结构和定义如上所述。
优选的,本发明某些实施方式中,所述S为S7a”:
其中R
2、R
3、R
4、R
7和Y如S7中所定义和描述。
本发明某些实施方式中,所述S为-O-S7a”,其中S7a”的结构和定义如上所述。
本发明某些实施方式中,所述S7a、S7a'和S7a”中,
片段为
R
3a和R
3b的定义独立地如R
3中所述。本发明某些实施方式中,R
3b为C
1-C
6烷基,所述烷基被-NR
kR
l取代;所述R
k和R
l各自独立的为氢或C
1-C
6烷基。本发明某些实施方式中,R
3b为甲基或乙基,所述甲基和乙基被-NHR
l或-NR
kR
l取代;所述R
k和R
l各自独立的为甲基或乙基。本发明某些实施方式中,R
3b为-CH
2NHCH
3或-CH
2N(CH
3)
2。本发明某些实施方式中,R
3a为氢或卤素,例如H或Cl。
优选的,本发明某些实施方式中,所述S、S7、S7'、S7”、S7a、S7a'和S7a”为如下任一结构:
优选的,本发明某些实施方式中,所述S、S7、S7'、S7”、S7a、S7a'和S7a”为
优选的,本发明某些实施方式中,所述S、S7、S7'、S7”、S7a、S7a'和S7a”为如下结构:
优选的,本发明某些实施方式中,所述S、S7、S7'、S7”、S7a、S7a'和S7a”为如下结构:
本发明某些实施方式中,所述S为
本发明某些实施方式中,L为键。
本发明某些实施方式中,L为-(CH
2)
j-,所述-(CH
2)
j-中的1个或多个亚甲基任选的被选自-NR
3’-、-O-、 -S-、-S(O)-、-S(O)NR
3’-、-NR
3’S(O)-、-S(O)
2-、-S(O)
2NR
3’-、-NR
3’S(O)
2-、-NR
4’S(O)
2NR
3’-、-CR
1’R
2’-、-C(O)-、-C(O)O-、-OC(O)-、-NR
3’C(O)O-、-OC(O)NR
3’-、-C(O)NR
3’-、-NR
3’C(O)-、-NR
4’C(O)NR
3’-、-P(O)-、-P(O)O-、-OP(O)-、-OP(O)O-、亚乙烯基、亚乙炔基、3-12元亚环烷基、含有1个或多个选自N、O或S杂原子的3-12元亚杂环烷基、6-10元亚芳基或5-10元亚杂芳基的基团替代,所述亚乙烯基、亚环烷基、亚杂环烷基、亚芳基、亚杂芳基各自独立的任选的被1个或多个选自卤素、-OR
3’、-NR
3’R
4’、氧代、硝基、氰基、C1-C6烷基、-S(C1-C6烷基)、C3-C10环烷基、C3-C10杂环烷基、6-10芳基、5-10元杂芳基、-C(O)R
1’、-C(O)OR
3’、-OC(O)R
1’、-C(O)NR
3’、-NR
3’C(O)R
1’、-S(O)R
1’、-S(O)NR
3’、-S(O)
2R
1’、-S(O)
2NR
3’、-NR
3’S(O)
2R
1’、-NR
4’S(O)
2NR
3’、-OC(O)NR
3’、-NR
4’C(O)NR
3’的取代基取代,所述烷基、环烷基、杂环烷基、芳基、杂芳基各自独立的任选的被1个或多个选自卤素、-OH、-NR
3’R
4’、氧代、硝基、氰基、C
1-C
6烷基、C
3-C
10环烷基、C
3-C
10杂环烷基、6-10元芳基、5-10元杂芳基的取代基取代;R
1’、R
2’各自独立为卤素、-OH、-NR
3’R
4’、C
1-C
6烷基、氯代C
1-C
6烷基、羟基C
1-C
6烷基、-O(C
1-C
6烷基)、-NH(C
1-C
6烷基)、-NH(C
1-C
6烷基)2、C
3-C
10环烷基、-O(C
3-C
10环烷基)、-NH(C
3-C
10环烷基)、C
3-C
10杂环烷基、-O(C
3-C
10杂环烷基)、-NH(C
3-C
10杂环烷基)、6-10元芳基、-O(6-10元芳基)、-NH(6-10元芳基)、5-10元杂芳基、-O(5-10元杂芳基)、-NH(5-10元杂芳基),R
3’、R
4’各自独立的为氢、氘、C
1-C
6烷基、C
3-C
10环烷基、C
3-C
10杂环烷基、6-10元芳基、5-10元杂芳基;j为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25。
优选的,本发明某些实施方式中,L为-(CH
2)
j-,所述-(CH
2)
j-中的1个或多个亚甲基任选的被选自-NR
3’-、-O-、-CR
1’R
2’-、-C(O)-、-S(O)-、-S(O)
2-、-C(O)O-、-OC(O)-、-C(O)NR
3’-、-NR
3’C(O)-、-S(O)
2NR
3’-、-NR
3’S(O)
2-、亚乙烯基、亚乙炔基、苯基、8-10元双环亚芳基、3-7元饱和或部分不饱和的亚环烷基、5-11元的饱和或部分不饱和的亚螺环烷基、5-11元的饱和或部分不饱和的亚稠环烷基、8-10元双环饱和或部分不饱和的亚环烷基、具有1-2个独立地选自氮、氧或硫杂原子的4-7元饱和或部分不饱和的亚杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的5-11元饱和或部分不饱和的亚螺杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的5-11元饱和或部分不饱和的亚稠杂环烷基、具有1-2个独立地选自氮、氧或硫杂原子的8-10元双环饱和或部分不饱和的亚杂环烷基、具有1-4个独立地选自氮、氧或硫杂原子的5-6元亚杂芳基、或具有1-5个选自氮、氧或硫杂原子的8-10元双环杂芳基的基团替代,所述亚乙烯基、亚乙炔基、亚环烷基、亚杂环烷基、苯基、亚螺杂环烷基、亚稠杂环烷基、亚螺环烷基、亚稠环烷基、亚杂芳基各自独立的任选的被1个或多个选自卤素、氧代、-NR
3’R
4’、-OR
3’、硝基、-CN、C
1-C
6烷基、C
3-C
10环烷基、C
3-C
10杂环烷基的取代基取代,所述烷基、环烷基、杂环烷基任选被1个或多个选自卤素、-OH、-NH
2、-CN、C
1-C
4烷基、C
3-C
6环烷基的取代基取代,R
1’、R
2’各自独立为卤素、-OH、-NH
2、C
1-C
4烷基、C
1-C
4氯代烷基、C
1-C
4羟基烷基、-O(C
1-C
4烷基)、-NH(C
1-C
4烷基)、-NH(C
1-C
4烷基)、C
3-C
6环烷基、-O(C
3-C
6环烷基)、-NH(C
3-C
6环烷基)、C
3-C
6杂环烷基、-O(C
3-C
6杂环烷基)、-NH(C
3-C
6环烷基);R
3’、R
4’各自独立的为氢、氘、C
1-C
4烷基、C
3-C
6环烷基、C
3-C
6杂环烷基,j为2、3、4、5、6、7、8、9、10、11或12。
优选的,本发明某些实施方式中,L为-(CH
2)
j-,所述-(CH
2)
j-中的1个或多个亚甲基任选的被选自-NR
3’-、-O-、-CR
1’R
2’-、-C(O)-、-S(O)-、-S(O)
2-、-C(O)O-、-OC(O)-、-C(O)NR
3’-、-NR
3’C(O)-、-S(O)
2NR
3’-、-NR
3’S(O)
2-、亚乙烯基、亚乙炔基、苯基、8-10元双环亚芳基、3-7元饱和或部分不饱和的单环亚环烷基、5-11元的饱和或部分不饱和的亚螺环烷基、5-11元的饱和或部分不饱和的亚稠环烷基、8-10元双环饱和或部分不饱和的亚环烷基、具有1-2个独立地选自氮或氧杂原子的5-7元饱和或部分不饱和的亚杂环烷基、具有1-2个独立的选自氮或氧杂原子的5-11元饱和或部分不饱和的亚螺杂环烷基、具有1-2个独立的选自氮或氧杂原子的5-11元饱和或部分不饱和的亚稠杂环烷基、具有1-2个独立地选自氮或氧杂原子的8-10元双环饱和或部分不饱和的亚杂环烷基、具有1-4个独立地选自氮或氧杂原子的5-6元亚杂芳基、或具有1-5个选自氮或氧杂原子的8-10元双环杂芳基的基团替代,所述亚乙烯基、亚乙炔基、亚环烷基、亚杂环烷基、苯基、亚螺杂环烷基、亚稠杂环烷基、亚稠环烷基、亚螺环烷基、亚杂芳基各自独立的任选的被1个或多个选自卤素、氧代、-NR
3’R
4’、-OR
3’、硝基、-CN、C
1-C
6烷基、C
3-C
6环烷基、C
3-C
6杂环烷基的取代基取代,所述烷基、环烷基、杂环烷基任选被1个或多个选自卤素、-OH、-NH2、-CN、C1-C4烷基、C3-C6环烷基的取代基取代,R
1’、R
2’各自独立为卤素、-OH、-NH
2、C
1-C
4烷基、C
1-C
4氯代烷基、C
1-C
4羟基烷基、-O(C
1-C
4烷基)、-NH(C
1-C
4烷基)、-NH(C
1-C
4烷基)、C
3-C
6环烷基、-O(C
3-C
6环烷基)、-NH(C
3-C
6环烷基)、C
3-C
6 杂环烷基、-O(C
3-C
6杂环烷基)、-NH(C
3-C
6环烷基);R
3’、R
4’各自独立的为氢、氘、C
1-C
4烷基、C
3-C
6环烷基、C
3-C
6杂环烷基,j为2、3、4、5、6、7、8、9或10。
优选的,本发明某些实施方式中,L为-(CH
2)
j-,所述-(CH
2)
j-中的1个、2个、3个、4个或者5个亚甲基任选的被选自-NH-、-NCH
3-、-O-、-C(CH
3)
2-、-CHF-、-CHCF
3-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH
3-、-NHC(O)-、-NCH
3C(O)-、亚乙烯基、亚乙炔基、亚环丙基、亚环丁基、亚环戊基、亚环己基、亚氧杂环丙基、亚氧杂环丁基、亚氧杂环戊基、亚氧杂环己基、亚氮杂环丙基、亚氮杂环丁基、亚氮杂环戊基、亚哌啶基、亚哌嗪基、亚吗啉基、亚高吗啉基、亚苯基、亚吡咯基、亚噻吩基、亚呋喃基、亚咪唑基、亚吡唑基、亚三唑基、亚四唑基、亚噁唑基、亚异噁唑基、亚噻唑基、亚异噻唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、
的基团替代,且所述替代基团任选的被1个或多个选自卤素、氧代、-NR
3’R
4’、-OR
3’、C1-C4烷基的取代基取代,所述烷基任选被1个或多个选自卤素、-OH、-NH
2的取代基取代,R
3’、R
4’各自独立的为氢、氘、C1-C4烷基,j为2、3、4、5、6、7、8、9或者10。
优选的,本发明某些实施方式中,L为-(CH
2)
j-,所述-(CH
2)
j-中的1个、2个、3个、4个或者5个亚甲基任选的被选自-NH-、-NCH
3-、-O-、-C(CH
3)
2-、-CHF-、-CHCF
3-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH
3-、-NHC(O)-、-NCH
3C(O)-、亚环丙基、亚环丁基、亚环戊基、亚环己基、亚氧杂环丙基、亚氧杂环丁基、亚氧杂环戊基、亚氧杂环己基、亚氮杂环丙基、亚氮杂环丁基、亚氮杂环戊基、亚哌啶基、亚哌嗪基、亚吗啉基、亚高吗啉基、
的基团替代,且所述替代基团任选的被1个或多个选自F、Cl、氧代、-NR
3’R
4’、-OR
3’、C
1-C
4烷基的取代基取代,所述烷基任选被1个或多个选自卤素、-OH、-NH
2的取代基取代,R
3’、R
4’各自独立的为氢、氘、甲基、乙基、丙基,j为3、4、5、6、7、8、9或者10。
优选的,本发明某些实施方式中,L为-(CH
2)
j-,所述-(CH
2)
j-中的1个、2个、3个、4个或者5个亚甲基任选的被选自-O-、-NH-、-NCH
3-、-C(O)-、-C(O)NH-、-NHC(O)-、-NCH
3C(O)-、-C(O)NCH
3-、亚环己基、亚氮杂环丙基、亚氮杂环丁基、亚氮杂环戊基、亚哌啶基、亚哌嗪基、
的基团替代,j为4、5、6、7、8、9或者10。
优选的,本发明某些实施方式中,L选自-(CH
2)
j-1-C(O)-,所述-(CH
2)
j-1-C(O)-中的亚甲基如上述L中所定义,任选被1个或多个基团所替代,所述j如上述L中所定义。
优选的,本发明某些实施方式中,L选自
本发明某些实施方式中,所述L为如下任一结构:
优选的,本发明某些实施方式中,所述L为LA,
其中所述LA中:
环A为键、C
3-C
12亚环烷基(例如
其中a端与S连接,b端与X”'连接)或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基(例如
其中a端与S连接,b端与X”'连接),所述亚环烷基和亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6羟基烷基或-O-(C
1-C
6烷基)的取代基取代;
环B为键、C
3-C
12亚环烷基(例如,
其中c端与X”'连接,d端与L
3连接)或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基(例如
其中c端与X”'连接,d端与L
3连接),所述亚环烷基和亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6羟基烷基或-O-(C
1-C
6烷基)的取代基取代;
环C为C
3-C
12亚环烷基(例如
其中e端与L
3连接,f端与X”连接)或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基(例如
其中e端与L
3连接,f端与X”连接),所述亚环烷基和亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6羟基烷基或-O-(C
1-C
6烷基)的取代基取代;
X”为键、-NH-、-NCH
3-、-O-、-C(CH
3)
2-、-S-、-C=C-、-C≡C-、-CHF-、-CHCF
3-、-C(O)-、-S(O)-、-S(O)
2-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH
3-、-NHC(O)-、-NCH
3C(O)-或-C(O)CH
2O-;
L
3为-(CH
2)
k,所述L
3中的一个或两个亚甲基任选的被选自-O-、-NH-、-C≡C-、-N(C
1-C
6烷基)-、-N(C
1-C
6卤代烷基)-、-C(O)-、-N(C
1-C
6羟基烷基)-或-N(C
3-C
8环烷基)-替代,k为0、1、2、3、4、5、6或7;
X”'为键、-NH-、-NCH
3-、-O-、-C(CH
3)
2-、-S-、-C=C-、-C≡C-、-CHF-、-CHCF
3-、-C(O)-、-S(O)-、-S(O)
2-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH
3-、-CH
2NCH
3-、-NHC(O)-或-NCH
3C(O)-。
在一些实施方案中,所述LA中:
环A为C
3-C
12亚环烷基或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基,所述亚环烷基和亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6羟基烷基或-O-(C
1-C
6烷基)的取代基取代;
环B为C
3-C
12亚环烷基或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基,所述亚环烷基和 亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6羟基烷基或-O-(C
1-C
6烷基)的取代基取代;
环C为C
3-C
12亚环烷基或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基,所述亚环烷基和亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6羟基烷基或-O-(C
1-C
6烷基)的取代基取代;
X”为键、-NH-、-NCH
3-、-O-、-C(CH
3)
2-、-S-、-C=C-、-C≡C-、-CHF-、-CHCF
3-、-C(O)-、-S(O)-、-S(O)
2-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH
3-、-NHC(O)-或-NCH
3C(O)-;
L
3为-(CH
2)
k,所述L
3中的一个或两个亚甲基任选的被选自-O-、-NH-、-N(C
1-C
6烷基)-、-N(C
1-C
6卤代烷基)-、-N(C
1-C
6羟基烷基)-或-N(C
3-C
8环烷基)-替代,k为0、1、2、3或4;
X”'为键、-NH-、-NCH
3-、-O-、-C(CH
3)
2-、-S-、-C=C-、-C≡C-、-CHF-、-CHCF
3-、-C(O)-、-S(O)-、-S(O)
2-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH
3-、-NHC(O)-或-NCH
3C(O)-。
本发明某些实施方式中,所述LA中,L
3为-(CH
2)
k,所述L
3中的一个或两个亚甲基任选的被选自-O-、-NH-、-C≡C-、-N(C
1-C
6烷基)-、-N(C
1-C
6卤代烷基)-、-N(C
1-C
6羟基烷基)-或-N(C
3-C
8环烷基)-替代,k为0、1、2、3、4、5、6或7。
优选的,本发明某些实施方式中,所述LA中,环A为键。
优选的,本发明某些实施方式中,所述LA中,环A为3-7元饱和或部分不饱和的亚环烷基、4-11元的饱和或部分不饱和的亚螺环烷基、4-11元的饱和或部分不饱和的亚稠环烷基、8-10元双环饱和或部分不饱和的亚环烷基、具有1-2个独立地选自氮、氧或硫杂原子的4-7元饱和或部分不饱和的亚杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的4-11元饱和或部分不饱和的亚螺杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的4-11元饱和或部分不饱和的亚稠杂环烷基、具有1-2个独立地选自氮、氧或硫杂原子的8-10元双环饱和或部分不饱和的亚杂环烷基。
优选的,本发明某些实施方式中,所述LA中,环A为3-6元饱和的的亚环烷基或具有1个或2个独立地选自氮杂原子的4-7元饱和的单环亚杂环烷基。
优选的,本发明某些实施方式中,所述LA中,环A为亚环己基(例如环己-1,4-二基,例如反式的环己-1,4-二基)、亚哌啶基(例如哌啶-1,4-二基)或亚哌嗪基(例如哌嗪-1,4-二基)。
优选的,本发明某些实施方式中,所述LA中,环B为键。
优选的,本发明某些实施方式中,所述LA中,环B为3-7元饱和或部分不饱和的亚环烷基、4-11元的饱和或部分不饱和的亚螺环烷基、4-11元的饱和或部分不饱和的亚稠环烷基、8-10元双环饱和或部分不饱和的亚环烷基、具有1-2个独立地选自氮、氧或硫杂原子的4-7元饱和或部分不饱和的亚杂环烷基、具 有1-2个独立的选自氮、氧或硫杂原子的4-11元饱和或部分不饱和的亚螺杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的4-11元饱和或部分不饱和的亚稠杂环烷基、具有1-2个独立地选自氮、氧或硫杂原子的8-10元双环饱和或部分不饱和的亚杂环烷基。
优选的,本发明某些实施方式中,所述LA中,环B为含有1个或者2个氮杂原子的的4-7元饱和的单环亚杂环烷基、含有1个或者2个氮杂原子的的7-11元的亚螺杂环烷基或者亚稠杂环烷基。
优选的,本发明某些实施方式中,所述LA中,环B为亚哌啶基(例如哌啶-1,4-二基)或亚哌嗪基(例如哌嗪-1,4-二基)。
优选的,本发明某些实施方式中,所述LA中,环C为3-7元饱和或部分不饱和的亚环烷基、4-11元的饱和或部分不饱和的亚螺环烷基、4-11元的饱和或部分不饱和的亚稠环烷基、8-10元双环饱和或部分不饱和的亚环烷基、具有1-2个独立地选自氮、氧或硫杂原子的4-7元饱和或部分不饱和的亚杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的4-11元饱和或部分不饱和的亚螺杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的4-11元饱和或部分不饱和的亚稠杂环烷基、具有1-2个独立地选自氮、氧或硫杂原子的8-10元双环饱和或部分不饱和的亚杂环烷基。
优选的,本发明某些实施方式中,所述LA中,环C为含有1个或者2个氮杂原子的的4-7元饱和的单环亚杂环烷基、含有1个或者2个氮杂原子的的7-11元的亚螺杂环烷基或者亚稠杂环烷基。
优选的,本发明某些实施方式中,所述LA中,环C为亚哌啶基(例如哌啶-1,4-二基)、亚哌嗪基(例如哌嗪-1,4-二基)、
(例如
)、
(例如
)、
(例如
)、
(例如
)、
(例如
)、
(例如
)、
(例如
)或
(例如
)。
优选的,本发明某些实施方式中,所述LA中,X”为键或-C(O)-。
优选的,本发明某些实施方式中,所述LA中,X”为键。
优选的,本发明某些实施方式中,所述LA中,X”为-C(O)-。
优选的,本发明某些实施方式中,所述LA中,X”'为键或-C(O)-。
优选的,本发明某些实施方式中,所述LA中,X”'为键。
优选的,本发明某些实施方式中,所述LA中,X”'为-C(O)-。
优选的,本发明某些实施方式中,所述LA中,k为1、2、3、4或5。
优选的,本发明某些实施方式中,所述LA中,L
3为-(CH
2)
k,k为1、2、3、4或5。
优选的,本发明某些实施方式中,所述LA中,L
3为-(CH
2)
k,所述L
3中的一个或两个亚甲基任选的被-O-、-NH-、-C≡C-或-N(C
1-C
6烷基)-(例如-N(CH
3)-)替代,k为1、2、3、4或5。
优选的,本发明某些实施方式中,所述LA中,k为1、2、3或4。优选的,本发明某些实施方式中,所述LA中,L
3为-(CH
2)
k-,其中所述L
3中包含的一个或两个CH
2各自独立地任选的被-O-、-NH-或-N(C
1-C
6烷基)-(例如-N(CH
3)-)替代,或者所述L
3中包含的一个-CH
2CH
2-任选的被-C≡C-替代;k为1、2、3或4。
优选的,本发明某些实施方式中,所述LA中,L
3为-(CH
2)
k-,所述L
3中的一个亚甲基任选的被-O-、-NH-或-N(C
1-C
6烷基)-(例如-N(CH
3)-)的基团替代;k为1、2、3或4。
优选的,本发明某些实施方式中,所述LA中环A为3-6元饱和的的亚环烷基;环B含有1个或者2个氮杂原子的的4-7元饱和的单环亚杂环烷基;环C为含有1个或者2个氮杂原子的的4-7元饱和的单环亚杂环烷基、含有1个或者2个氮杂原子的的7-11元的亚螺杂环烷基或者亚稠杂环烷基;X”为键或-C(O)-;L
3为-(CH
2)
k,k为1、2、3、4或5(例如,k为1、2、3或4)。
优选的,本发明某些实施方式中,所述LA为LA-1:
其中所述环A、环B、环C、L
3、X”如LA中所定义和描述。
本发明某些实施方式中,所述LA为LA-2:
X”'为-C(O)-;
L
3为-(CH
2)
k-,其中所述L
3中包含的一个或两个CH
2各自独立地任选的被-O-、-NH-或-N(C
1-C
6烷基)-(例如-N(CH
3)-)替代;k为1、2、3或4;
X”为键或者-C(O)-。
优选的,本发明某些实施方式中,所述LA、LA-1和LA-2中,k为2、3或4。
优选的,本发明某些实施方式中,所述LA、LA-1和LA-2中,L
3为-(CH
2)
k-,其中所述L
3中包含的一个CH
2任选的被-O-替代;k为2、3或4。
本发明某些实施方式中,所述LA-2为如下任一结构:
本发明某些实施方式中,所述LA为LA-4:
X”'为键;
环B为键;
L
3为-(CH
2)
k-,其中所述L
3中包含的一个或两个CH
2各自独立地任选的被-O-、-NH-或-N(C
1-C
6烷基)-(例如-N(CH
3)-)替代;k为1、2、3或4;
X”为键。
本发明某些实施方式中,所述LA、LA-1和LA-2中,k为2、3或4。
本发明某些实施方式中,所述LA、LA-1和LA-2中,L
3为-(CH
2)
k-,其中所述L
3中包含的一个CH
2任选的被-O-替代;k为2、3或4。
本发明某些实施方式中,所述LA、LA-1和LA-2中,L
3可为-(CH
2)
2-或-(CH
2)
3-。
本发明某些实施方式中,所述LA-4为如下任一结构:
优选的,本发明某些实施方式中,所述LA为如下任一结构:
优选的,本发明某些实施方式中,所述式Ⅰ化合物为如下任一化合物:
在某些实施方案中,所述氘代化物是化合物结构(例如L,例如LA、LA-1、LA-2、LA-4中的环A、环B、L
3、环C)中的1、2、3、4、5、6、7、8、9或10个H被氘替代形成的结构。在某些实施方案中,氘代的LA结构为
本发明提供了一种式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐的制备方法。
本发明提供了一种药物组合物,包括治疗有效量的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,以及药学上可接受的载体、稀释剂或赋形剂。
本发明提供了一种降解SOS1蛋白的方法,包括使式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物与SOS1蛋白接触。
本发明提供了一种所述式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物用作治疗或预防SOS1介导的疾病或病症的药物使用。
本发明提供了一种所述式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物用作治疗或预防由SOS1与Ras(例如KRAS)或者SOS1与Rac(例如KRAS)相互作用所引起的疾病或病症(癌症)的药物的应用。
本发明提供了一种式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物在制备治疗或预防SOS1介导的疾病或病症的药物(例如癌症)中的应用。
本发明提供了式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物在制备治疗或预防由SOS1与Ras(例如KRAS)或者SOS1与Rac(例如KRAS)相互作用所引起的疾病或病症(例如癌症)的药物的应用。
本发明提供了一种式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物在制备治疗或预防癌症药物中的应用。
本发明提供了一种式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物在制备治疗或预防胰腺癌、肺癌、结肠直肠癌、胆管上皮癌、多发性骨髓瘤、黑色素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、子宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞性白血病、肝细胞癌、乳腺癌、卵巢癌、前列腺癌、成胶质细胞瘤、肾癌及肉瘤药物的应用。
本发明提供了一种式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物在制备治疗或预防1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多雀斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征和遗传性牙龈纤维瘤病药物的应用。
本发明提供一种治疗或预防由SOS1介导的疾病或病症的方法,包括向有需要的患者施用治疗有效量的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物。
本发明提供一种治疗或预防由SOS1与Ras(例如KRAS)或者SOS1与Rac(例如KRAS)相互作用调控的疾病或病症(例如癌症)的方法,包括向有需要的患者施用治疗有效量的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物。
本发明某些实施方案中,所述的癌症可选自:
心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、黏液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤组;
肺:支气管癌(鳞状细胞癌、未分化小细胞癌、未分化大细胞癌、腺癌)、肺泡癌(细支气管癌)、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤;
胃肠道食管(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌肿瘤、血管活性肠肽瘤)、小肠(腺癌、淋巴瘤、类癌肿瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛腺瘤、错构瘤、平滑肌瘤);
泌尿生殖系统:肾(腺癌、肾母细胞瘤、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎瘤、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤);
肝:肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤;
胆道:胆囊癌、壶腹癌、胆管癌;
骨:骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、软骨瘤(骨软骨外生骨病)、良性软骨瘤、成软骨瘤、软骨黏液纤维瘤、骨样骨瘤和巨细胞瘤;
神经系统:颅骨(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形骨炎)、脑膜(脑膜瘤、脑膜肉瘤、胶质瘤)、大脑(星形细胞瘤、髓母细胞瘤、胶质瘤、室管膜瘤、生发细胞瘤(松果体瘤)、多形胶质母细胞瘤、少突胶质母细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、胶质瘤、肉瘤);
妇科:子宫(子宫内膜癌(浆液性囊腺癌、粘液性囊腺癌、未分类癌)、颗粒-鞘膜细胞瘤、支持间质细胞瘤、无生殖细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑素瘤)、阴道(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎型横纹肌肉瘤)、输卵管(癌);
血液学:血液(髓系白血病(急性和慢性)、急性淋巴母细胞白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤);
皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、银屑病;
肾上腺:成神经细胞瘤。
本发明某些实施方案中,所述的癌症可选自胰腺癌、肺癌、结肠直肠癌、胆管上皮癌、多发性骨髓瘤、黑色素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、子宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞性白血病、肝细胞癌、乳腺癌、卵巢癌、前列腺癌、成胶质细胞瘤、肾癌及肉瘤。
本发明还提供了一种前述的式Ⅰ化合物,和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐或前述的药物组合物在制备用于治疗和/或预防KRAS介导的疾病或病症的药物中的应用。
本发明还提供了一种治疗和/或预防KRAS介导的疾病或病症的方法,包括向有需要的患者施用治疗有效量的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐,或其药物组合物。
本发明某些实施方案中,所述的KRAS可为突变型KRAS。所述突变型KRAS优选为KRAS G12C、 KRAS G12D、KRAS G13D和KRAS G12V中的一种或多种。
本发明提供了一种式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药或其药学上可接受的盐的制备方法:
INT-A与INT-B发生还原胺化反应得到目标化合物;其中所述还原胺化的还原试剂包括但不限于Pd/C、硼氢化钠、氰基硼氢化钠、硼烷、三乙酰氧基硼氢化钠。其中所述
指含有NH基团的环B;R
2、R
3、R
4、R
5、R
6、R
7如S6b中所定义和描述;
指含有醛基的L
3;、环A、环B、环C、X”如LA中所定义;E如本发明中所定义和描述,优选E为E7、E7a、E7b、E7c、E7d、E7e、E7a-1、E7a-2、E21、E21-1a、E21-1b、E21-1c、E21-1d、E21-1e、E21-1f、E21-1g、E21-1h、E21-1aa、E21-1bb、E21-1cc、E21-1dd、E21-1ee、E21-1ff、E21-1gg或E21-1hh。
INT-C与INT-D碱性条件下发生取代反应得到目标化合物;其中所述碱包括但不限于三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、碳酸氢钠。其中
指含有NH基团的环C;P
100为五氟苯基或者对硝基苯基;R
2、R
3、R
4、R
5、R
6、R
7如S6b中所定义和描述;环A、环B、环C、L
3如LA中所定义;E如本发明中所定义和描述,优选E为E7、E7a、E7b、E7c、E7d、E7e、E7a-1、E7a-2、E21、E21-1a、E21-1b、E21-1c、E21-1d、E21-1e、E21-1f、E21-1g、E21-1h、E21-1aa、E21-1bb、E21-1cc、E21-1dd、E21-1ee、E21-1ff、E21-1gg或E21-1hh。
INT-E与INT-D碱性条件下发生取代反应得到目标化合物;其中所述碱包括但不限于三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、碳酸氢钠。其中
指含有NH基团的环C;P
100为五氟苯基或者对硝基苯基;R
2、R
3、R
4、R
5、R
6、R
7如S6d中所定义和描述;环A、环B、环C、L
3如LA中所定义;E如本发明中所定义和描述,优选E为E7、E7a、E7b、E7c、E7d、E7e、E7a-1、E7a-2、E21、E21-1a、E21-1b、E21-1c、E21-1d、E21-1e、E21-1f、E21-1g、E21-1h、E21-1aa、E21-1bb、E21-1cc、E21-1dd、E21-1ee、E21-1ff、E21-1gg或E21-1hh、。
详细说明:除非有相反陈述、下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”是指饱和的脂肪族烃基团,包括直链或支链烷基;C
1-C
8烷基是指含有1-8个碳原子的烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1、1-二甲基丙基、1、2-二甲基丙基、2、2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1、1、2-三甲基丙基、1、1-二甲基丁基、1、2-二甲基丁基、2、2-二甲基丁基、1、3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2、3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2、3-二甲基戊基、2、4-二甲基戊基、2、2-二甲基戊基、3、3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2、3-二甲基己基、2、4-二甲基己基、2、5-二甲基己基、2、2-二甲基己基、3、3-二甲基己基、4、4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体;优选C
1-C
6烷基;更优选C
1-C
4烷基。所述烷基可以是取代的或未取代的。在一些实施方案中,所述烷基为C
1、C
2、C
3、C
4、C
5、C
6、C
7或C
8烷基。
“环烷基”指饱和或部分不饱和的单环或多环环状烃取代基;“C
3-C
11环烷基”指包括3至11个碳原子的环烷基;“C
3-C
8元环烷基”指包括3至8个碳原子的环烷基;“C
5-C
10元环烷基”指包括5至10个碳原子的环烷基;
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环丁基、环戊基、环己基;优选C
3-C
8元环烷基;更优选C
3-C
6元环烷基。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团,他们可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基,优选7-12元双螺环烷基。螺环烷基的非限制性实施例包含:
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选双环稠环烷基。稠环烷基的非限制性实施例包含:
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团,他们可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,根据组成环的数目可以分为双环、三环、四环或多环桥环烷基。桥环烷基的非限制性实施例包含:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。所述环烷基可以是任选取代的或未取代的。
在一些实施方案中,所述环烷基为C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11、C
12单环或多环(例如螺环、稠环或桥环)环烷基。
“杂环烷基”指饱和的或部分不饱和的单环或多环环状烃取代基,其中一个或多个(例如2、3、4或5)环原子选自氮、氧或S(O)
r(其中r是整数0、1或2),但不包含-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。“3-11元杂环烷基”指包含3至11个环原子的环基,“5-10元杂环烷基”指包含5至10个环原子的环基,“3-8元杂环烷基”指包含3至8个环原子的环基,优选含有1-2个选自N、O或S杂原子的“3-11元杂环烷基”,更优选含有1个或2个N原子的3-11元杂环烷基。
单环杂环烷基优选为含有1-2个N杂原子的3-8元单环杂环烷基;单环杂环烷基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等,优选哌啶基和哌嗪基。
多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“螺杂环烷基”指单环之间共用一个原子(称螺原子)的多环杂环烷基团,其中一个或多个环原子选自氮、氧或S(O)
r(其中r是整数0、1、2),其余环原子为碳。他们可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环烷基、双螺杂环烷基或多螺杂环烷基,优选含有1-2个选自N、O或S杂原子的饱和的“3-11元双螺杂环烷基”;更优选含有1个或2个N原子的饱和的“7-11元双螺杂环烷基”。螺杂环烷基的非限制性实施例包含:
“稠杂环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环烷基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子选自氮、 氧或S(O)
r(其中r是整数0、1、2),其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基,优选含有1-3个选自N、O或S杂原子的“3-11元双环稠杂环烷基”;更优选含有1个或2个N原子的饱和的“3-11元双环稠杂环烷基”。稠杂环烷基的非限制性实施例包含:
“桥杂环烷基”指任意两个环共用两个不直接连接的原子的多环杂环烷基团,他们可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子选自氮、氧或S(O)
r(其中r是整数0、1、2),其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,桥杂环烷基的非限制性实施例包含:
所述杂环烷基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环烷基,非限制性实施例包含:
在一些实施方案中,所述杂环烷基为3、4、5、6、7、8、9、10、11、12元单环或多环(例如螺环、稠环或桥环)杂环烷基,其中杂原子的个数可以为1、2、3、4或5个,每个杂原子独立地为氮、氧或S(O)
r(其中r是整数0、1或2)。
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)且具有共轭的π电子体系的多环基团,“6-10元芳基”指含有6-10个碳的全碳芳基,例如苯基和萘基;优选苯基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上,其中与母体结构连接在一起的环为芳基环,非限制性实施例包含:
“杂芳基”指包含1至4个杂原子的杂芳族体系,所述杂原子包括氮、氧或S(O)
r(其中r是整数0、1、 2),5-6元杂芳基指含有5-6个环原子的杂芳族体系,5-10元杂芳基指含有5-10个环原子的杂芳族体系,优选5-6元杂芳基;更优选含有1个或2个N原子的5-6元杂芳基;非限制实施例包括呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、吡唑、咪唑基、三唑基、四唑基等;优选吡啶基。所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包含:
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述所定义的烷基,“C
2-
8烯基”指含有2-8个碳的直链或支链烯基,包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3丁烯基等,优选“C
2-
6烯基”,更优选“C
2-
4烯基”。所述烯基可以是取代的或未取代的。在一些实施方案中,所述烯基为C
2、C
3、C
4、C
5、C
6、C
7、C
8烯基。
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基,“C
2-
8炔基”指含有2-8个碳的直链或支链炔基,包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基,优选“C
2-
6炔基”,更优选“C
2-
4炔基”。所述炔基可以是取代的或未取代的。在一些实施方案中,所述炔基为C
2、C
3、C
4、C
5、C
6、C
7、C
8炔基。
“亚基”指二价基团,如亚烷基指二价烷基,亚烯基指二价烯基,亚炔基指二价炔基,亚环烷基指二价环烷基,亚杂环烷基指二价杂环烷基,亚芳基指二价芳基,亚杂芳基指二价杂芳基,所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基如上所定义,所述亚基可以是任选取代的或未取代的。
“卤代烷基”指任选的被一个或多个氟、氯、溴或碘原子取代的烷基,其中所述烷基如上所定义,非限制性实施例包括二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“羟基烷基”指任选被一个或多个-OH取代的烷基,其中所述烷基如上所定义,非限制性实施例包括羟甲基、羟乙基、羟基丙基、羟基异丙基。
“烷氧基”指-O-烷基,其中所述烷基如上所定义,非限制性实施例包括甲氧基、乙氧基、异丙氧基、叔丁氧基等。
“环烷氧基”指-O-环烷基,其中所述环烷基如上所定义,非限制性实施例包括环丙烷氧基、环丁烷氧基、环戊烷氧基、环己烷氧基等。
“杂环烷氧基”指-O-杂环烷基,其中所述杂环烷基如上所定义,非限制性实施例包括氮杂环丁烷氧基、氮杂环戊烷氧基、哌啶基氧基、哌嗪基氧基、氧杂环戊基氧基、氧杂环己基氧基等。
“-C(O)C
1-C
3烷基”指-C(O)-CH
3、-C(O)-CH
2CH
3等。
“氰基”指-CN。
“羟基”指-OH。
“磺酰基”指-S(O)
2-。
“羧基”或“羧酸”指-COOH。
“氧代”指=O基团。
“卤素”指氟、氯、溴或碘。
“Pd(PPh
3)
2Cl
2”指(二氯二(三苯基磷)合钯)。
“TEA”指三乙胺。
“EA或EtOAc”指乙酸乙酯。
“THF”指四氢呋喃。
“NaBH
4”指硼氢化钠。
“DCM”指二氯甲烷。
“Tf
2O”指三氟甲基磺酸酐。
“(Bpin)
2”指双频哪醇联硼酸酯。
“Pd(dppf)
2Cl
2”指1,1'-双二苯基膦二茂铁二氯化钯。
“KOAc”指醋酸钾。
“DMF”指N,N-二甲基甲酰胺。
“NBS”指N-溴代琥珀酰亚胺。
“EtOH”指乙醇。
“MeOH”指甲醇。
“Pd/C”指钯/碳。
“Pd(OH)
2/C”指氢氧化钯/碳。
“DMSO”指二甲基亚砜。
“HATU”指2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
“TFA”指三氟醋酸。
“NMP”指N-甲基吡咯烷酮。
“IBX”指2-碘酰基苯甲酸。
“DIEA”指N,N-二异丙基乙胺。
“STAB”指三乙酰氧基硼氢化钠。
“T
3P”指2,4,6-三丙基-1,3,5,2,4,6-三氧三磷酸-2,4,6-三氧化物。
“NaOH”指氢氧化钠。
“DMAP”指4-二甲氨基吡啶。
“TPSCl”指2,4,6-三异丙基苯磺酰氯。
“DPBS”指杜氏磷酸缓冲液。
“Dess-Martin”指戴斯-马丁试剂。
“PBS”指磷酸缓冲盐溶液。
“SDS-PAGE”指十二烷基硫酸钠-聚丙烯酰胺凝胶电泳。
“PVDF”指聚偏二氟乙烯。
“PE”指石油醚。
“NaHCO
3”指碳酸氢钠。
“Na
2SO
4”指硫酸钠。
“NH
4Cl”指氯化铵。
“AcOH”指醋酸。
“HCl”指盐酸。
“DCC”指N,N'-二环己基碳二亚胺。
“Ti(OEt)
4”指钛酸四乙酯。
“L-Selectride”指三异丁基硼氢化锂。
“BOP”指六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷
“DBU”指1,8-二氮杂环[5,4,0]十一烯-7
“LiOH.H
2O”指一水合氢氧化锂
“EDCI”指1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
“NIS”N-碘代丁二酰亚胺。
“Ac
2O”指乙酸酐。
“HOAc”指乙酸。
“Hantzsch-ester”指1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸二乙酯.
“DMA”指二甲基乙酰胺。
“NiBr
2(dtbpy)”指4,4-二-叔丁基联吡啶二溴化镍.
“K
2CO
3”指碳酸钾。
“9-BBN”指9-硼双环[3.3.1]壬烷。
“MTBE”指甲基叔丁基醚。
“LiOH”指氢氧化锂。
“DCE”指二氯乙烷。
“NaBH
3CN”指氰基硼氢化钠。
“CBr
4”指四溴化碳。
“PPh
3”指三苯基膦。
“n-BuLi”指正丁基锂。
“NaH”指钠氢。
“i-PrOH”指异丙醇。
“ACN”指乙腈。
“NH
4HCO
3”指碳酸氢铵。
“m-CPBA”指间氯过氧苯甲酸。
“KI”指碘化钾。
“IPA”指间苯二甲酸
“N
2H
4-H
2O”指水合肼。
“NMI”指N-甲基咪唑。
“TCFH”指四甲基氯代脲六氟膦酸酯
“Ruphos Pd G2”指氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)。
“K
3PO
4”指磷酸钾。
“(Boc)
2O”指二碳酸二叔丁酯。
“Prep-HPLC”指制备高效液相色谱。
“sat.”指饱和溶液。
“aq”指水溶液。
本文的化学结构中,作为连接键的“-”表示单键,“=”表示双键(未限定构型的情况下,其可以为反式或顺式)。
“任选”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环烷基团”意味着烷基可以但不必须存在,该说明包括杂环烷基团被烷基取代的情形和杂环烷基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子、优选为最多5个、更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻、取代基仅处在它们的可能的化学位置、本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
除非另有说明,本文所用术语“任选取代的”可以是未取代的或者取代的;当被取代时,取代基可以是一个或多个(例如2、3、4、5或6个)独立选自烷基、烯基、炔基、羟基、羟基烷基、卤代烷基、烷氧基、氨基、氨基烷基、氰基、卤素、氧代、环烷基、杂环烷基、芳基和杂芳基,所述烷基、烯基、炔基、羟基、羟基烷基、卤代烷基、烷氧基、氨基、氨基烷基任选被一个或多个(例如2、3、4、5或6个)环烷基、杂环烷基、芳基和杂芳基取代;所述环烷基、杂环烷基、芳基和杂芳基任选被一个或多个选自烷基、烯基、炔基、羟基、羟基烷基、卤代烷基、烷氧基、氨基、氨基烷基、氰基、卤素、氧代的基团取代。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物、以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药、利于活性成分的吸收进而发挥生物活性。
本发明还提供式(I)化合物药学上可接受的盐。术语“药学上可接受的盐”是指相对无毒的本发明化合物的酸加成盐或碱加成盐。所述酸加成盐为本发明式(I)化合物与合适的无机酸或者有机酸形成的盐,这些盐 可在化合物最后的分离和提纯过程中制备,或者可用纯化的式(I)化合物以其游离碱形式与适宜的有机酸或无机酸进行反应来制备。代表性酸加成盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月硅酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、磷酸氢盐、碳酸盐、碳酸氢盐、甲苯甲酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、苯甲酸盐、甲磺酸盐、对甲苯磺酸盐、葡萄糖酸盐、乳糖酸盐和月桂基磺酸盐等。所述碱加成盐为式(I)化合物与合适的无机碱或者有机碱形成的盐,包括例如与碱金属、碱土金属、季铵阳离子形成的盐,例如钠盐、锂盐、钾盐、钙盐、镁盐、四甲基季铵盐、四乙基季铵盐等;胺盐包括与氨(NH
3)、伯胺、仲胺或叔胺形成的盐,如甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐、乙胺盐等。
本发明的化合物或其药学上可接受的盐可给药于哺乳动物包括人,可口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药(粉剂、软膏剂或滴剂)、或瘤内给药。
本发明化合物的给药剂量可以大约为0.05-300mg/kg体重/天,优选10-300mg/kg体重/天,更优选10-200mg/kg体重/天。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的固体剂型,包括但不限于胶囊剂、片剂、丸剂、散剂和颗粒剂等。在这些固体剂型中,本发明式(I)化合物作为活性成分与至少一种常规惰性赋形剂(或载体)混合,例如与柠檬酸钠或磷酸二钙,或与下述成分混合:(1)填料或增容剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等;(2)粘合剂,如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶等;(3)保湿剂,如甘油等;(4)崩解剂,如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠等;(5)缓溶剂,如石蜡等;(6)吸收加速剂,如季铵化合物等;(7)润湿剂如鲸蜡醇和单硬脂酸甘油酯等;(8)吸附剂,如高岭土等;和(9)润滑剂,如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠等,或其混合物。胶囊剂、片剂和丸剂中也可包含缓冲剂。
所述固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料例如肠溶衣和其他本领域公知的材料进行包衣或微囊化。它们可包含不透明剂,并且这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时、活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的液体剂型,包括但不限于药学上可接受的乳液、溶液、悬浮液、糖浆和酊剂等。除了作为活性成分的式(I)化合物或其药学上可接受的盐外,液体剂型可包含本领域中常规采用的惰性稀释剂如水和其他溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1、3-丁二醇、二甲基甲酰胺以及油类,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外,本发明液体剂型也可包含常规助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。
所述悬浮剂包括如乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇只、微晶纤维素、甲醇铝和琼脂等或这些物质的混合物。
本发明化合物或其药学上可接受的盐可以配制为用于肠胃外注射的剂型包括但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物或其药学上可接受的盐也可以配制为用于局部给药的剂型包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明式(I)化合物或其药学上可接受的盐在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明还提供药物组合物,它含有本发明式(I)化合物或其药学上可接受的盐作为活性成分,以及药学上可接受载体、赋形剂或稀释剂。在制备药物组合物时,通常是将本发明式(I)化合物或其药学上可接受的盐与药学上可接受载体、赋形剂或稀释剂混合。
可以按常规制备方法将所述本发明组合物配制为常规药物制剂。例如片剂、丸剂、胶囊剂、散剂、颗粒剂、乳液剂、混浮剂、分散液、溶液剂、糖浆剂、酏剂、软膏剂、滴剂、栓剂、吸入剂、喷射剂等。
本发明所述的化合物或其药学上可接受的盐可以单独给药,或者(如果需要)与其他药学上可接受的治疗剂联合给药,如与其他抗肿瘤药物。待组合的各成分可同时或顺序的给予,以单一制剂形式或以不同制剂的形式给予。所述组合不仅可包括本发明化合物和一种其他活性剂的组合,也可包括本发明化合物和两 种或更多种其他活性剂的组合。
本发明中,可与SOS1降解剂式(I)化合物一起或组合使用的其他药学上可接受的治疗剂可为:EGFR和/或其突变体抑制剂、ErbB2(Her2)和/或其突变体抑制剂、ALK和/或其突变体抑制剂、MEK和/或其突变体抑制剂、Kras和/或其突变体抑制剂、BCR-ABL和/或其突变体抑制剂、FGFR1/FGFR2/FGFR3和/或其突变体抑制剂、ROS1和/或其突变体抑制剂、c-MET和/或其突变体抑制剂、AXL和/或其突变体抑制剂、NTRK1和/或其突变体抑制剂、RET和/或其突变体抑制剂、紫杉烷、含铂化合物、抗代谢物、有丝分裂激酶抑制剂、免疫治疗剂、抗血管生成药物、拓扑异构酶抑制剂、A-Raf/B-Raf/C-RAf和/或其突变体抑制剂、ERK和/或其突变体抑制剂、细胞凋亡抑制剂、mTOR抑制剂、外遗传调控剂、IGF1/2和/或IGF1-R抑制剂、Ras GEF和/或其突变体抑制剂、PI3K和/或其突变体抑制剂。
本发明中,可与SOS1降解剂式(I)化合物一起或组合使用的其他药学上可接受的治疗剂可为:阿法替尼(afatinib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、拉帕替尼(lapatinib)、西妥昔单抗、帕尼单抗、奥希替尼、奥莫替尼(olmutinib)、EGF-816、、曲妥珠单抗(trastuzumab)、帕妥珠单抗(pertuzumab)、唑替尼(crizotinib)、阿雷替尼(alectinib)、恩曲替尼(entrectinib)、布吉替尼(brigatinib)、曲美替尼(trametinib)、考比替尼(cobimetinib)、贝美替尼(binimetinib)、司美替尼(selumetinib)、瑞法替尼(refametinib)、伊马替尼(imatinib)、达沙替尼(dasatinib)、尼罗替尼(nilotinib)、尼达尼布(nintedanib)、克唑替尼、劳拉替尼(lorlatinib)、色瑞替尼(ceritinib)、美乐替尼(merestinib)、紫杉醇(paclitaxel)、nab-紫杉醇、多西他赛(docetaxel)、顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、5-氟尿嘧啶、卡培他滨(capecitabine)、氟尿苷、阿糖胞苷(cytarabine)、吉西他滨(gemcitabine)、曲氟尿苷(trifluridine)及替比嘧啶(tipiracil)的组合(=TAS102)、帕博西尼(palbociclib)、瑞博西尼(ribociclib)、阿贝西尼(abemaciclib)、伊匹单抗(ipilimumab)、纳武单抗(nivolumab)、帕博利珠单抗(pembrolizumab)、阿替珠单抗(atezolizumab)、阿维鲁单抗(avelumab)、德瓦鲁单抗(durvalumab)、匹利珠单抗(pidilizumab)、PDR-001(=斯帕珠单抗(spartalizumab))、贝伐珠单抗(bevacizumab)、伊立替康(irinotecan)、脂质体伊立替康、托泊替康(topotecan)、乌利替尼(ulixertinib)、雷帕霉素、替西罗莫司(temsirolimus)、依维莫司(everolimus)、利达莫司(ridaforolimus)、JQ-1、GSK 525762、OTX 015(=MK8628)、CPI 0610、TEN-010(=RO6870810)、珍妥珠单抗(xentuzumab)(WO 2010/066868中的抗体60833)或MEDI-573(=杜昔妥单抗(dusigitumab))。
本发明通过SOS1激酶活性测试实验证明本发明所述式Ⅰ化合物能够有效的与SOS1靶蛋白结合或产生抑制效果,通过Western-Blot证明本发明所述式Ⅰ化合物能够有效的特异性的降解NCI-H358细胞中SOS1蛋白。本发明所述式Ⅰ化合物,和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐可有效的降解SOS1蛋白,从而达到预防或治疗与SOS1相关或与SOS1与Ras或者SOS1与Rac相互作用所引起的疾病或病症的效果。
下面将结合实施例对本发明做进一步详细、完整地说明,但决非限制本发明,本发明也并非仅局限于实施例的内容。本发明实施例中的起始原料是已知的并且可以在市场上买到、或者可以采用或按照本领域已知的方法来合成。在无特殊说明的情况下,本发明实施例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。
Ⅰ化合物制备实施例
中间体1:(R)-1-(3-硝基-5-(三氟甲基)苯基)乙基-1-胺盐酸盐的制备
步骤1:1-(3-硝基-5-(三氟甲基)苯基)乙基-1-酮的制备
氮气保护下,1-溴-3-硝基-5-(三氟甲基)苯(18g,66.7mmol),三丁基(1-乙氧基乙烯基)锡烷(31g,86.7 mmol),Pd(PPh
3)
2Cl
2(4.7g,6.67mmol)和TEA(13.5g,133mmol)在1,4-二氧六环(200mL)溶液中的反应混合物于80℃下搅拌反应过夜。反应液用氟化钾(饱和水溶液,300mL)淬灭,并用EA(200mL×3)萃取。收集有机层并减压浓缩。将浓缩物溶解在THF(180mL)中,加入盐酸(100mL,6M)后,在室温下搅拌3h。然后将混合物用水(300mL)淬灭,并用EA(200mL×3)萃取。收集有机层,并用无水硫酸钠干燥,过滤并减压浓缩。粗产
物经柱层析纯化得到目标产物1-(3-硝基-5-(三氟甲基)苯基)乙基-1-酮。
1H NMR(400MHz,CDCl
3)δ8.95(t,J=1.6Hz,1H),8.69(s,1H),8.54(d,J=0.5Hz,1H),2.76(s,3H).
步骤2:(R,E)-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)亚乙基)丙基-2-亚磺酰胺的制备
1-(3-硝基-5-(三氟甲基)苯基)乙基-1-酮(10.6g,45.5mmol),(R)-2-甲基丙基-2-亚磺酰胺(8.3g,68.2mmol)和钛酸四乙酯(25.9g,114mmol)在THF(200mL)溶液中的反应混合物于60℃下搅拌反应2h。用水(300mL)淬灭反应混合物,并用EA(200mL×3)萃取溶液。收集有机层并用无水硫酸钠干燥,过滤并在减压下浓缩。浓缩物经柱层析纯化得到目标产物(R,E)-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)亚乙基)丙基-2-亚磺酰胺。
1H NMR(400MHz,DMSO-d
6)δ8.87(s,1H),8.61(s,1H),8.43(s,1H),2.90(s,3H),1.37(s,9H).
步骤3:(R)-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)丙基-2-亚磺酰胺的制备
向(R,E)-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)亚乙基)丙基-2-亚磺酰胺(10g,30.7mmol)在THF(100mL)和水(20mL)溶液中的混合物中加入NaBH
4(1.28g,33.7mmol)。反应混合物在-10℃下搅拌反应1分钟后用水(300mL)淬灭反应混合物,并用EA(200mL×3)萃取溶液。收集有机层并用无水硫酸钠干燥,过滤并减压浓缩。浓缩物经柱柱层析纯化得到目标产物(R)-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)丙基-2-亚磺酰胺。
1H NMR(400MHz,CDCl
3)δ8.45–8.42(m,2H),7.96(s,1H),4.76–4.68(m,1H),3.56(d,J=4.2Hz,1H),1.62(d,J=6.7Hz,3H),1.26(s,9H).
步骤4:(R)-1-(3-硝基-5-(三氟甲基)苯基)乙基-1-胺盐酸盐的制备
将(R)-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)丙基-2-亚磺酰胺(5.5g,16.3mmol)置于盐酸(80mL,4M)二氧六环溶液中,并于25℃下搅拌反应2h。过滤粗产物,并用石油醚(100mL)洗涤,得到 目标产物(R)-1-(3-硝基-5-(三氟甲基)苯基)乙基-1-胺盐酸盐。
LC-MS:(ESI,m/z):[M+H]
+=235.2.
中间体2:4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)环己-3-烯-1-羧酸乙酯
步骤1:4-(((三氟甲基)磺酰基)氧基)环己-3-烯-1-羧酸乙酯的制备
在0℃下,向搅拌的4-氧代基环己烷-1-甲酸乙酯(5g,32.0mmol)和2,6-二甲基吡啶(4.6g,42.9mmol)在DCM(60mL)中的混合物中滴加Tf
2O(9g,32.0mmol)。反应混合物在0℃下搅拌反应1h。然后将反应混合物在25℃下搅拌反应15分钟,并加入Tf
2O(7g,25.6mmol)。然后将反应混合物在25℃下搅拌过夜。浓缩反应混合物,用水(300mL)淬灭反应,并用EA(200mL×3)萃取。收集有机层,并用无水硫酸钠干燥,过滤并减压浓缩。浓缩物经柱层析纯化得到4-(((三氟甲基)磺酰基)氧基)环己-3-烯-1-羧酸乙酯。
1H NMR(400MHz,DMSO-d
6)δ5.90(d,J=3.9Hz,1H),4.14–4.02(m,2H),2.68–2.60(m,1H),2.47–2.27(m,4H),2.08–1.98(m,1H),1.88–1.76(m,1H),1.19(t,J=7.1Hz,3H).
步骤2:4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)环己-3-烯-1-羧酸乙酯的制备
4-(((三氟甲基)磺酰基)氧基)环己-3-烯-1-羧酸乙酯(4.7g,16.8mmol),(Bpin)
2(6.4g,25.2mmol),Pd(dppf)
2Cl
2(1.2g,1.68mmol)和KOAc(4.9g,50.4mmol)在1,4-二氧六环(80mL)溶液中的混合物于90℃下搅拌反应过夜。用水(300mL)淬灭反应,并用EA(200mL×3)萃取。收集有机层,并用无水硫酸钠干燥,过滤并减压浓缩。浓缩物物经柱层析纯化得到4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)环己-3-烯-1-羧酸乙酯。
1H NMR(400MHz,DMSO-d
6)δ6.42(d,J=2.2Hz,1H),4.11-4.02(m,2H),2.33-1.95(m,4H),1.93-1.83(m,1H),1.53-1.38(m,1H),1.21-1.14(m,16H).
中间体3:((1R,4R)-4-(4-(((R)-1-(3-氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(哌嗪-1-基)甲酮
步骤1:2-氨基-5-溴-4-甲氧基苯甲酸的制备
0℃下,向搅拌的2-氨基-4-甲氧基苯甲酸(30g,179mmol)的DMF(600mL)溶液中加入NBS(35g,197mmol),反应混合物在25℃下搅拌反应1h。反应液用硫代硫酸钠(饱和水溶液,500mL)淬灭,并用EA(500mL×3)萃取。收集有机层,并用氯化钠(饱和水溶液,500mL×3)洗涤,无水硫酸钠干燥,过滤并浓缩,得到2-氨基-5-溴-4-甲氧基苯甲酸粗产物,粗产物无需进一步纯化即可直接用于下一步。
LC-MS:(ESI,m/z):[M+H]
+=246.0.
步骤2:6-溴-7-甲氧基-2-甲基喹唑啉-4(3H)-酮的制备
向搅拌的2-氨基-5-溴-4-甲氧基苯甲酸(17.0g,69.1mmol)的甲醇(170mL)溶液中加入乙酸铵(53.2g, 691mmol)和原乙酸三甲酯(83.0g,691mmol)。所得反应混合物在密闭容器中于120℃下搅拌反应24h。反应混合物倒入水(1L)中,并将固体产物过滤。用EA(1L)洗涤粗产物,得到目标产物6-溴-7-甲氧基-2-甲基喹唑啉-4(3H)-酮。粗产物无需纯化即可直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=268.9.
步骤3:6-溴-4-氯-7-甲氧基-2-甲基喹唑啉的制备
6-溴-7-甲氧基-2-甲基喹唑啉-4(3H)-酮(10g,37.2mmol)在三氯氧磷(200mL)溶液中的混合物在105℃下搅拌过夜。将反应混合物浓缩,用碳酸氢钠(饱和水溶液,500mL)淬灭,并用EA(300mL×3)萃取。收集有机层,并用无水硫酸钠干燥,过滤并浓缩。浓缩物经硅胶柱层析纯化,得到目标产物6-溴-4-氯-7-甲氧基-2-甲基喹唑啉。
LC-MS:(ESI,m/z):[M+H]
+=287.0.
步骤4:(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺的制备
向6-溴-4-氯-7-甲氧基-2-甲基喹唑啉(1.8g,6.27mmol)在EtOH(12mL)溶液中混合物中加入(R)-1-(3-硝基-5-(三氟甲基))苯基)乙基-1-胺盐酸盐(1.7g,7.52mmol)和DIEA(1.6g,12.5mmol)。将反应混合物在微波中于100℃搅拌反应5h。用水(300mL)淬灭反应,并用EA(300mL×3)萃取。收集有机层,并用经无水硫酸钠干燥,过滤并减压浓缩。浓缩物经柱层析纯化得到黄色油状(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺。
LC-MS:(ESI,m/z):[M+H]
+=484.9.
步骤5:4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己-3-烯-1-羧酸乙酯的制备
将(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺(2g,4.12mmol),4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)环己-3-烯-1-羧酸乙酯(2.31g,8.24mmol),碳酸钠(873mg,8.24mmol)和Pd(dppf)
2Cl
2(300mg,0.41mmol)在DMF(24mL)和水(3mL)中的反应混合物于110℃搅拌反应过夜。用水(300mL)淬灭反应。EA(300mL×3)萃取溶液,并用氯化钠(饱和的水溶液,500mL×3)洗涤,合并有机层。有机层经无水硫酸钠干燥,过滤并减压浓缩。浓缩物经柱层析纯化得到4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己-3-烯-1-羧酸乙酯。
LC-MS:(ESI,m/z):[M+H]
+=559.7.
步骤6:(R)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-1-羧酸 乙酯的制备
向4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己-3-烯-1-羧酸乙酯(1.7g,3.04mmol)在MeOH(60mL)溶液中的混合物中加入Pd/C(1.02g,0.6w/w)。反应混合物在氢气氛围下于50℃搅拌反应4天。将粗产物过滤,得到(R)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-1-羧酸乙酯。
LC-MS:(ESI,m/z):[M+H]
+=531.2.
步骤7:(1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7)甲氧基-2-甲基喹唑啉-6-基)环己烷-1-甲酸的制备
向(R)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸乙酯(1.5g,2.82mmol)在甲醇(8mL),THF(8mL)和水(16mL)中的混合物中加入氢氧化锂(203mg,8.46mmol)。将反应混合物于60℃搅拌反应过夜。粗产物通过制备型HPLC纯化,得到(1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7)甲氧基-2-甲基喹唑啉-6-基)环己烷-1-甲酸。
LC-MS:(ESI,m/z):[M+H]
+=503.2.
1H NMR(400MHz,DMSO-d
6)δ8.13(d,J=8.0Hz,1H),8.06(s,1H),6.99(s,1H),6.88(s,1H),6.86(s,1H),6.69(s,1H),5.56(dd,J=13.6,5.8Hz,3H),3.88(s,3H),2.92(t,J=11.7Hz,1H),2.35(s,3H),2.24(t,J=11.8Hz,1H),2.05(d,J=10.8Hz,2H),1.87(d,J=11.8Hz,2H),1.66–1.40(m,7H).
步骤8:4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7)甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-羧酸叔丁酯
向(1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-甲酸(220mg,0.44mmol)在EA(12mL)溶液中的混合物中加入哌嗪-1-甲酸叔丁基酯(163mg,0.88mmol),DIEA(169mg,1.31mmol)和T
3P(209mg,0.66mmol)。将反应混合物于0℃下搅拌3h。用水(100mL)淬灭反应,并用EA(100mL×3)萃取,收集有机层并用无水硫酸钠干燥,过滤并减压浓缩。浓缩物柱层析纯化,得到4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7)甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=671.3.
1H NMR(400MHz,DMSO-d
6)δ8.19–8.07(m,2H),6.99(s,1H),6.86(d,J=10.5Hz,2H),6.70(s,1H),5.56(dd,J=16.7,9.3Hz,3H),3.89(s,3H),3.47(m,4H),3.32(m,4H),2.95(s,1H),2.67(s,1H),2.36(s,3H),1.83(d,J=14.5Hz,4H),1.59(t,J=22.3Hz,7H),1.41(s,9H).
步骤9:((1R,4R)-4-(4-(((R)-1-(3-氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(哌嗪-1-基)甲酮的制备
将4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7)甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-羧酸叔丁酯(220mg,0.33mmol)在乙酸乙酯盐酸(3M,10mL)溶液中的混合物于25℃下搅拌反应2h。浓缩反应物,得到((1R,4R)-4-(4-(((R)-1-(3-氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(哌嗪-1-基)甲酮,粗产物无需进一步纯化即可用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=571.2.
中间体4:2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙醛
步骤1:2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮
向4-氟邻苯二甲酸(5.52g,0.03mol)的乙酸(50mL)溶液中加入3-氨基哌啶-2,6-二酮盐酸盐(5.0g,0.03mol)和乙酸钾(8.8g,0.09mol),反应混合物于120℃搅拌反应过夜,将反应混合物减压浓缩,浓缩物用水(100mL)稀释,在室温下搅拌30分钟,过滤,固体用水(50mL×2)洗涤。减压干燥得到产物。
LC-MS:(ESI,m/z):[M+H]
+=277.1
步骤2:2-(2,6-二氧代基哌啶-3-基)-5-(4-(2-羟乙基)哌啶-1-基)异吲哚啉-1,3-二酮的制备
2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(500mg,1.81mmol),2-(哌啶-4-基)乙基-1-醇(280mg,2.17mmol))和DIEA(701mg,5.43mmol)在NMP(5mL)中的混合物于140℃的微波反应器中反应5小时。用水(50mL)稀释反应混合物,并用乙酸乙酯(50mL×2)萃取。收集有机相并用水(100mL×2)和饱和食盐水(50mL)洗涤,经无水硫酸钠干燥后,过滤并浓缩。浓缩物经硅胶柱上纯化,得到产物。
LC-MS:(ESI,m/z):[M+H]
+=386.1.
步骤3:2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙醛的制备
2-(2,6-二氧代基哌啶-3-基)-5-(4-(2-羟乙基)哌啶-1-基)异吲哚啉-1,3-二酮(300mg,0.78mmol)和IBX(436mg,1.56mmol)在乙腈(6mL)中的混合物于80℃下搅拌反应2h。用水(30mL)稀释反应混合物,并用乙酸乙酯(30mL×2)萃取。收集有机相并用水(50mL×2)和饱和食盐水(30mL)洗涤,经无水硫酸钠干燥后,过滤并浓缩。浓缩物经通过硅胶柱层析纯化得到产物。
LC-MS:(ESI,m/z):[M+H]
+=384.1.
1H NMR(400MHz,DMSO-d
6)δ11.07(s,1H),9.69(t,J=1.6Hz,1H),7.65(d,J=8.6Hz,1H),7.31(d,J=2.0Hz,1H),7.23(dd,J=8.6,2.2Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.03(dd,J=10.3,2.9Hz,2H),3.04–2.82(m,3H),2.65–2.52(m,2H),2.41(dd,J=6.7,1.6Hz,2H),2.17–1.97(m,2H),1.73(d,J=11.1Hz,2H),1.2-1.18(m,2H).
中间体5:2-(3-(4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酰基)-3-氮杂螺[5.5]十一烷-9-基)乙醛
步骤1:4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸的制备
将3-氨基-4-氯苯甲酸(5.0g,2.93mmol)悬浮于丙烯酸(8.05mL,117mmol)中,并在100℃下搅拌反应3h,然后将反应液搅拌冷却至室温。加入乙酸(33ml),将搅拌的悬浮液在100℃加热10分钟,加入尿素(11.00g,183mmol),反应液在120℃搅拌反应过夜。将反应液加入到冰水和浓盐酸(37%)的混合液中,搅拌,将得到的悬浮液在5℃的冰箱中保存过夜,然后过滤,固体用水洗涤并干燥,得到固体。将固体在盐酸溶液(0.05M)中研磨,过滤,甲基叔丁基醚洗涤,40℃下减压干燥,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=269.0
步骤2:4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯的制备
4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸(2.0g,7.58mmol),2,3,4,5,6-五氟苯酚(1.67g,9.09mmol)和N,N'-二环己基碳酰亚胺(1.87g,9.09mmol)在N,N-二甲基甲酰胺(20mL)溶液中的混合物在室温下搅拌反应3h。将反应液倒入水(200mL)中并搅拌0.5h,溶液用乙酸乙酯(200mL×3)萃取。收集有机相,并用水(500mL×2)和饱和食盐水(300mL)洗涤,用无水硫酸钠干燥,过滤并浓缩。浓缩物经硅胶柱层析纯化,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=435.0
步骤3:2-(3-氮杂[5.5]十一烷-9-基)乙-1-醇的制备
向9-(2-羟乙基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯(1.0g,3mmol)在EA(10mL)溶液中的混合物中加如Pd(OH)
2/C(200mg),反应混合物在氢气氛围下于室温下搅拌反应16h。过滤混合物,浓缩滤液,得到目标产物。
步骤4:1-(2-氯-5-(9-(2-羟乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
向2-(3-氮杂螺[5.5]十一烷-9-基)乙-1-醇(500mg,2.5mmol)在DMSO(5mL)溶液中的混合物中加入4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸五氟苯基酯(1.0g,2.5mmol)和DIEA(0.5mL)。用水(30mL) 淬灭反应,并用EA(10mL×3)萃取。收集有机层并用水(10mL×2)和饱和食盐水(10mL)洗涤,用无水硫酸钠干燥,过滤并浓缩。浓缩物经柱层析纯化,得到目标化合物。
LC-MS:(ESI,m/z):[M+H]
+=448.1
步骤5:2-(3-(4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酰基)-3-氮杂螺[5.5]十一烷-9-基)乙醛的制备
向1-(2-氯-5-(9-(2-羟乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(700mg,1.56mmol)在THF(12mL)溶液中的混合物中加入IBX(873mg,3.1mmol)。反应混合物于80℃搅拌反应2h。用水(30mL)淬灭反应,并用EA(10mL×3)萃取溶液。收集有机层并用水(10mL×2)和饱和食盐盐水(10mL)洗涤,用无水硫酸钠干燥,过滤并浓缩。浓缩物经柱层析纯化,得到目标化合物。
LC-MS:(ESI,m/z):[M+H]
+=446.1
中间体6:2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)乙醛
步骤1:4-(2,2-二甲氧基乙基)哌嗪-1-羧酸叔丁酯的制备
向哌嗪-1-羧酸叔丁酯(2.0g,10.75mmol),碳酸钾(4.45g,32.26mmol)和碘化钾(892mg,5.38mmol)的丙酮(20mL)混合物中加入2-溴-1,1-二甲氧基乙烷(3.63g,21.51mmol)。并于80℃下搅拌反应过夜。反应液混合物减压下浓缩。将浓缩物溶解在乙酸乙酯(50mL)中,并用水(50mL×2)和饱和食盐水(50mL)洗涤。收集有机相,有机相经无水硫酸钠干燥,过滤并浓缩。浓缩物经硅胶柱层析纯化,得到所需产物。
LC-MS:(ESI,m/z):[M+H]
+=275.0.
步骤2:1-(2,2-二甲氧基乙基)哌嗪的制备
4-(2,2-二甲氧基乙基)哌嗪-1-羧酸叔丁酯(2.2g,8.03mmol)在盐酸/二氧六烷(4M,10mL)溶液中的混合物室温下搅拌过夜。减压浓缩得到目标产物(1.5g,粗品)。粗产物直接用于下一步。
步骤3:5-(4-(2,2-二甲氧基乙基)哌嗪-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮的制备
2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(1.48g,5.36mmol),1-(2,2-二甲氧基乙基)哌嗪(1.4g,8.05mmol)和DIEA(4.15g,36.16mmol)的NMP(10mL)溶液的混合物在微波反应器中140℃反应5h。用水(50mL)稀释混合物,并用乙酸乙酯(50mL×2)萃取。收集有机相并用水(100mL×2)和饱和食盐水(50mL)洗涤,经无水硫酸钠干燥,过滤并浓缩。浓缩物经硅胶柱层析纯化,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=431.1.
步骤4:2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)乙醛的制备
5-(4-(2,2-二甲氧基乙基)哌嗪-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮(1.8g,4.19mmol)在三氟乙酸/二氯甲烷(5mL/5mL)溶液中的混合物于室温下搅拌反应60h。减压浓缩混合物,加入水,并用碳酸氢钠(水溶液)将pH调节至8。混合物用乙酸乙酯(100mL×2)萃取。收集有机相,并用水(100mL×2)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤并浓缩。浓缩物经硅胶柱上纯化,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=285.0.
中间体7:2-(9-(4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酰基)-3,9-二氮杂螺[5.5]十一烷-3-基)乙醛
步骤1:9-(4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酰基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
在室温,氮气保护下,向3-(2,4-二氧代基四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酸(1.0g,3.78mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入HATU(1.66g,4.37mmol),3,9-二氮杂螺[5.5]十一烷基-3-羧酸叔丁酯(0.96g,3.78mmol)和N-甲基吗啡啉(0.8g,7.92mmol)。搅拌反应2h后,将反应混合物用水(50mL)淬灭,并用乙酸乙酯(50mL×3)萃取。收集有机层,并用饱和食盐水(50mL×3)洗涤,无水硫酸钠干燥,过滤并浓缩。浓缩物硅胶柱层析纯化,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=505.2
步骤2:1-(2-氯-5-(3,9-二氮杂螺[5.5]十一烷基-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
9-(4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酰基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1.56g,3.1mmol)在三氟乙酸/二氯甲烷(2.5mL/5mL)溶液中的反应液于室温搅拌反应4h。将反应液减压浓缩,得到目标化合物粗产物。粗产物直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=405.1
步骤3:1-(2-氯-5-(9-(2,2-二甲氧基乙基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
向1-(2-氯-5-(3,9-二氮杂螺[5.5]十一烷基-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(200mg,0.25mmol),碳酸钾(155mg,1.25mmol)和碘化钾(19mg,0.11mmol)在丙酮(4mL)溶液中的混合物中加入2-溴-1,1-二甲氧基乙烷(46mg,0.3mmol)。反应液在80℃下搅拌反应3h,随后减压浓缩。浓缩物硅胶柱层析纯化,得到目标化合物。
LC-MS:(ESI,m/z):[M+H]
+=493.3.
步骤4:2-(9-(4-氯-3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酰基)-3,9-二氮杂螺[5.5]十一烷-3-基)乙醛的制备
将1-(2-氯-5-(9-(2,2-二甲氧基乙基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(121mg,0.246mmol)在三氟乙酸/二氯甲烷(1mL/2mL)溶液中的混合物于室温搅拌反应4小时。减压浓缩反应液。浓缩物硅胶柱层析纯化,得到目标化合物。
LC-MS:(ESI,m/z):[M+H]
+=447.1.
中间体8:3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)丙醛
步骤1:2-(2,6-二氧代基哌啶-3-基)-5-(4-(3-羟丙基)哌啶-1-基)异吲哚啉-1,3-二酮的制备
2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(500mg,1.81mmol),3-(哌啶-4-基)丙基-1-醇(310mg,2.17mmol))和DIEA(701mg,5.43mmol)在NMP(5mL)中的混合物于140℃的微波反应器中反应5小时。用水(50mL)稀释反应混合物,并用乙酸乙酯(50mL×2)萃取。收集有机相并用水(100mL×2)和饱和食盐水(50mL)洗涤,经无水硫酸钠干燥后,过滤并浓缩。浓缩物经硅胶柱上纯化,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=400.2.
步骤2:3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)丙醛的制备
2-(2,6-二氧代基哌啶-3-基)-5-(4-(3-羟丙基)哌啶-1-基)异吲哚啉-1,3-二酮的(310mg,0.78mmol)和IBX(436mg,1.56mmol)在乙腈(6mL)中的混合物于80℃下搅拌反应2h。用水(30mL)稀释反应混合物,并用乙酸乙酯(30mL×2)萃取。收集有机相并用水(50mL×2)和饱和食盐水(30mL)洗涤,经无水硫酸钠干燥后,过滤并浓缩。浓缩物经硅胶柱层析纯化得到产物。
LC-MS:(ESI,m/z):[M+H]
+=398.2.
中间体9:(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(哌啶-4-基)喹唑啉-4-胺
步骤1:2-氨基-5-溴-4-甲氧基苯甲酸的制备
在0℃下,向搅拌的2-氨基-4-甲氧基苯甲酸(16.7g,100.0mmol)的DMF(300mL)溶液中加入NBS(19.6g,110.0mmol)。反应混合物于25℃下搅拌反应1h,并用水(300mL)淬灭反应,用EA(300mL×3)萃取,收集有机层,并用氯化钠(饱和的水溶液,300mL×3)洗涤,无水硫酸铵干燥并浓缩,得到目标粗产物。粗产物无需纯化直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=247.4.
步骤2:6-溴-7-甲氧基-2-甲基喹唑啉-4-醇的制备
向2-氨基-5-溴-4-甲氧基苯甲酸(19.5g,79.3mmol)在MeOH(195mL)溶液中的混合物中加入醋酸铵(61.0g,793mmol)和原乙酸三甲酯(95.1g,793mmol)。反应混合物在密闭容器中于120℃搅拌反应24小时。将反应混合物倒入水(500mL)中,并将固体产物过滤。粗产物用EA洗涤得到目标粗产物,粗产物无需纯化直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=271.0.
步骤3:4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的制备
向6-溴-7-甲氧基-2-甲基喹唑啉-4-醇(1.5g,3.09mmol)在DMF(30mL)和水(4mL)混合溶液中的混合物中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁基(1.73g,6.18mmol),碳酸钠(982mg,9.27mmol)和Pd(dppf)
2Cl
2(226mg,0.319mmol)。反应混合物在110℃下搅拌反应过夜。用水(300mL)淬灭反应混合物,并用EA(200mL×3)萃取,收集有机层,有机层经无水硫酸钠干燥并减压浓缩。浓缩物经柱层析纯化,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=372.2.
步骤4:4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-1-羧酸叔丁酯的制备
向4-(4-羟基-7-甲氧基喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(500mg,0.894mmol)的MeOH(20 mL)溶液中加入Pd/C(300mg)。反应混合物在50℃下H
2氛围下搅拌反应2天。反应液经硅藻土过滤,滤液减压浓缩得到目标产物4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-1-羧酸叔丁酯。粗品直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=374.2.
步骤5:4-(7-甲氧基-2-甲基-4-(((2,4,6-三异丙基苯基)磺酰基)氧基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯的制备
向4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)哌啶-1-羧酸叔丁酯(250.0mg,0.76mmol),TPSCl(295.0mg,1.0mmol),DMAP(13.0mg,0.1mmol)的DCM(5.0mL)溶液中加入TEA(0.3mL,2.4mmol)。反应混合物在室温下搅拌反应12h。反应液用DCM稀释,饱和NaHCO
3溶液洗。有机相用Na
2SO
4干燥,过滤,浓缩。所得粗品经柱层析(洗脱剂体系为EA/PE)纯化得到产物4-(7-甲氧基-2-甲基-4-(((2,4,6-三异丙基苯基)磺酰基)氧基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=640.0.
步骤6:(R)-4-(7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯的制备
向4-(7-甲氧基-2-甲基-4-(((2,4,6-三异丙基苯基)磺酰基)氧基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯(400mg,0.03mmol)的DMSO(8mL)溶液中加入(R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺盐酸盐(203mg,0.75mmol)和TEA(0.8mL)。反应混合物在90℃下搅拌反应过夜。反应用水淬灭,EA萃取。有机相用Na
2SO
4干燥,过滤,浓缩。所得粗品经正向柱纯化得到目标产物(R)-4-(7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=590.3.
步骤7:(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-基)喹唑啉-4-胺的制备
向(R)-4-(7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯(220mg,0.328mmol)的DCM溶液中加入TFA。反应混合物在25℃下搅拌反应2h。浓缩得到目标产物(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-基)喹唑啉-4-胺。所得粗品直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=490.2
步骤8:(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(哌啶-4-基)喹唑啉-4-胺的制备
向(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-基)喹唑啉-4-胺(124mg,0.25mmol)的EtOH/H
2O(3mL/1ml)溶液中加入NH
4Cl(135.6mg,2.5mmol)和Fe粉(141.5mg,2.5mmol)。反应混合物在70℃下N
2氛围下搅拌反应2h。反应液过滤,浓缩得到粗品。粗品经制备HPLC纯化得到目标产物(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(哌啶-4-基)喹唑啉-4-胺。
LC-MS:(ESI,m/z):[M+H]
+=460.2.
1H NMR(400MHz,DMSO-d
6)δ8.32(s,1H),8.09(s,1H),7.03(s,1H),6.88(d,J=11.1Hz,1H),6.70(s,1H),5.57(d,J=6.9Hz,1H),3.89(s,3H),3.39–3.25(m,2H),3.22–3.13(m,1H),3.07–2.95(m,2H),2.36(s,3H),2.03–1.85(m,4H),1.56(d,J=7.0Hz,3H).
中间体10:(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(哌啶-4-氧基)喹唑啉-4-胺
步骤1:4-((甲磺酰基)氧基)哌啶-1-羧酸叔丁酯
在0℃下,往4-羟基哌啶-1-羧酸叔丁酯(10.0g,49.7mmol)和TEA(15.0g,149.1mmol)在DCM(100mL)溶液中的混合物中滴加溶于DCM(20.0mL)溶液中的甲磺酰氯(7.4g,64.9mmol)。反应混合物于室温下搅拌反应过夜,然后加入水(200mL),用DCM(200mL×2)萃取,收集有机层,饱和食盐水洗涤,无水硫酸钠干燥并减压浓缩,浓缩物经柱层析纯化得目标产物。
LC-MS:(ESI,m/z):[M+H]
+=280.1.
步骤2:6,7-二甲氧基-2-甲基喹唑啉-4-醇的制备
向2-氨基-4,5-二甲氧基苯甲酸(20.0g,0.1mol)在2-甲氧基乙醇(120.0mL)溶液中的混合物中加入盐酸乙脒(19.0g,0.2mol)和醋酸钠(16.4g,0.2mol)。反应混合物于140℃搅拌反应过夜。将反应混合物倒入水(250mL)中,并在室温下搅拌10min。然后将混合物过滤,滤饼用水洗涤,并将固体真空干燥,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=221.2.
步骤3:7-甲氧基-2-甲基喹唑啉-4,6-二醇的制备
将6,7-二甲氧基-2-甲基喹唑啉-4-醇(9.1g,41.4mmol)和DL-蛋氨酸(10.5g,70.4mmol)在甲磺酸(50mL)中的反应混合物在80℃下搅拌反应过夜。用冰水淬灭反应,并用氢氧化钠(2N)溶液碱化。滤出沉淀物,得到目标粗产物。
LC-MS:(ESI,m/z):[M+H]
+=207.2.
步骤4:4-((4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)氧基)哌啶-1-羧酸叔丁酯的制备
将7-甲氧基-2-甲基喹唑啉-4,6-二醇(1.4g,6.8mmol),4-((甲磺酰基)氧基)哌啶-1-羧酸叔丁酯(2.2g,8.2mmol)和碳酸钾(1.8g,13.6mmol)在NMP(10.0mL)溶液中的反应混合物于100℃下搅拌反应过夜。然后加入水(50.0mL),并用EA(50mL×3)萃取,收集有机层,用饱和食盐水洗涤,无水硫酸钠干燥并减压浓缩,浓缩物经反相柱层析纯化(乙腈:水=0-100%)得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=390.2.
步骤5:4-((7-甲氧基-2-甲基-4-(((2,4,6-三异丙基苯基)磺酰基)氧基)喹唑啉-6-基)氧基)哌啶-1-羧酸叔丁酯的制备
将4-((4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)氧基)哌啶-1-羧酸叔丁酯(800.0mg,2.0mmol),2,4,6-三异丙基苯磺酰氯(748.0mg,2.4mmol),DMAP(125.0mg,0.4mmol)和TEA(623.0mg,6.0mmol)在DCM(10.0mL)溶液中的反应混合物于室温下搅拌反应过夜。浓缩反应混合物,浓缩物经柱层析纯化,得到目标产物。
LC-MS:(ESI,m/z):[M+Na]
+=678.1.
步骤6:(R)-4-((7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)哌啶-1-羧酸叔丁酯的制备
将4-((7-甲氧基-2-甲基-4-(((2,4,6-三异丙基苯基)磺酰基)氧基)喹唑啉-6-基)氧基)哌啶-1-羧酸叔丁酯(0.8g,1.2mmol),(R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺盐酸盐(0.43g,1.8mmol)和TEA(1.1g,10.8mmol)在DMSO(15.0mL)溶液中反应混合物于90℃下搅拌反应过夜。然后加入水(50.0mL),并用EA(50mL×3)萃取,收集有机层,并用饱和食盐水洗涤,无水硫酸钠干燥并浓缩,浓缩物经反相柱层析纯化(乙腈-水=0-100%)得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=606.0.
步骤7:(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-氧基)喹唑啉-4-胺的制备
将(R)-4-((7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)哌啶-1-羧酸叔丁酯(140mg,0.23mmol)在DCM(5.0mL)和TFA(1.0mL)溶液的混合物于室温下搅拌反应2.0h。减压浓缩反应物,得到(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-氧基)喹唑啉-4-胺。
LC-MS:(ESI,m/z):[M+H]
+=506.1.
步骤8:(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(哌啶-4-氧基)喹唑啉-4-胺的制备
将(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-氧基)喹唑啉-4-胺(100.0mg,0.19mmol)和Pd/C(20.0mg)在甲醇(5.0mL)溶液中的反应混合物于室温下在氢气氛围下搅拌反应过夜。将反应液过滤,浓缩滤液,浓缩物经制备型HPLC纯化,得到目标产物。
LC-MS:(ESI,m/z):[M+H]
+=476.3.
1H NMR(400MHz,DMSO-d
6)δ7.91(d,J=7.9Hz,1H),7.78(s,1H),7.04(s,1H),6.88(s,1H),6.85(s,1H),6.69(s,1H),5.66-5.46(m,3H),4.54-5.48(m,1H),3.87(s,3H),3.01-2.93(m,2H),2.64-2.53(m,2H),2.35(s,3H),1.93-1.89(m,2H),1.58-1.44(m,5H).
中间体11:4-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯
步骤1:4-((2-羧基乙基)氨基)苯甲酸的制备
将丙烯酸(23.62g,328.1mmol)加入4-氨基苯甲酸(15.0g,109.4mmol)的AcOH/H
2O(40ml/200mL)溶液中,110℃搅拌12小时,反应液冷却,过滤,得到目标产物4-((2-羧乙基)氨基)苯甲酸。
LC-MS:(ESI,m/z):[M+H]
+=210.0.
步骤2:4-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸的制备
将尿素(114.83g,1913.8mmol)加入到4-((2-羧乙基)氨基)苯甲酸(20.0g,95.69mmol)的AcOH(240mL)溶液中,110℃搅拌24h,反应液冷却后,加入HCl溶液,调节pH值至1-2,析出固体,过滤,得到目标产物4-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸。
LC-MS:(ESI,m/z):[M+H]
+=233.1.
步骤3:4-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯的制备
五氟苯酚(12.97g,70.51mmol)和DCC(14.52g,70.51mmol)加入到4-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸(15.0g,64.1mmol)的DMF(200mL)溶液中,室温搅拌过夜,用乙酸乙酯(100mL×3)萃取,饱和食盐水(300mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(EA:PE=3:7)纯化得 到目标产物4-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯。
1H NMR(400MHz,DMSO-d
6)δ10.59(s,1H),8.20(d,J=8.7Hz,2H),7.64(d,J=8.7Hz,2H),3.94(t,J=6.6Hz,2H),2.76(t,J=6.6Hz,2H).
中间体12:(R)-(3-(1-氨基乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯
步骤1:1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-酮的制备
将1-溴-3-硝基-5-(三氟甲基)苯(50.0g,185.1mmol),Pd(PPh
3)
2Cl
2(12.9g,18.5mmol),TEA(37.4g,370.2mmol)和三丁基(1-乙氧基乙烯基)锡烷(86.6g,240.6mmol)在二氧六环(300mL)中的反应液在80℃搅拌16h。反应液中加入水(900mL)淬灭反应,用EA(500mL×3),合并有机相并用饱和食盐水洗涤,经无水Na
2SO
4干燥,减压浓缩。残余物在6N HCl(200mL)和THF(200mL)的混合溶液中搅拌30min,然后加入水(500mL),EA(500mL×2),合并有机相,饱和食盐水洗涤经无水硫酸钠干燥,过滤,减压浓缩。粗品使用柱层析(EA:PE=0~1:9)纯化得到1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-酮。
1H NMR(400MHz,CDCl
3)δ8.95(s,1H),8.69(s,1H),8.53(s,1H),2.75(s,3H).
步骤2:1-(3-氨基-5-(三氟甲基)苯基)乙烷-1-酮的制备
将1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-酮(1.5g,6.4mmol)和Pd/C(400mg)在THF(30mL)中的混合物在60℃搅拌16h。反应液过滤,滤液减压浓缩得到1-(3-氨基-5-(三氟甲基)苯基)乙烷-1-酮。所得产物直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=203.0.
步骤3:(3-乙酰基-5-(三氟甲基)苯基)氨基甲酸叔丁酯的制备
将1-(3-氨基-5-(三氟甲基)苯基)乙烷-1-酮(1.1g,5.4mmol)和(Boc)
2O(5.9g,27.0mmol)在二氧六环(20mL)中的混合物在80℃搅拌16h。反应液直接减压浓缩,所得粗产物经层析柱(EA:PE=0~3:17)纯化得到(3-乙酰基-5-(三氟甲基)苯基)氨基甲酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=303.0.
1H NMR(400MHz,DMSO-d
6)δ8.26(s,1H),8.18(d,J=6.5Hz,1H),8.05(s,1H),2.67(d,J=11.4Hz,3H),1.41(d,J=11.7Hz,9H).
步骤4:(S,E)-(3-(1-((叔-丁基亚硫酰基)亚氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯的制备
将(3-乙酰基-5-(三氟甲基)苯基)氨基甲酸叔丁酯(1.0g,3.3mmol),Ti(OEt)
4(1.8g,6.6mmol),二乙烯二醇二甲基醚(2.3g,17.5mmol)和(S)-丙烷-2-亚磺酰胺(1.2g,9.9mmol)在THF(10mL)中的混合物在70℃搅拌12h。反应液中加水(50mL),用EA(30mL×3)萃取,合并有机相,饱和食盐水洗涤经无水硫酸钠干燥,过滤,减压浓缩。粗品使用柱层析(EA:PE=0~1:4)纯化得到(S,E)-(3-(1-((叔-丁基亚硫酰基)亚氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯.
LC-MS:(ESI,m/z):[M+H]
+=407.0.
步骤5:(3-((R)-1-(((S)-叔-丁基亚硫酰基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯的制备
-78℃时,向(S,E)-(3-(1-((叔-丁基亚硫酰基<亚磺酰>)亚氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯(1.0g,2.4mmol)的THF(20mL)溶液中加入L-Selectride(1.0mol/L/THF,3.6mL),反应液在-78℃搅拌50min。反应液中加入水(50mL)淬灭反应,然后用EA(50mL×2)萃取,合并有机相,饱和食盐水洗涤经无水硫酸钠干燥,过滤,减压浓缩。粗品使用柱层析(EA:PE=0~1:1)纯化得到(3-((R)-1-(((S)-叔-丁基亚硫酰基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=409.0.
1H NMR(400MHz,DMSO-d
6)δ9.71(s,1H),7.74(d,J=5.1Hz,2H),7.39(s,1H),4.15(q,J=6.7Hz,1H),1.48(s,15H),1.31(d,J=6.7Hz,3H),1.11(d,J=2.1Hz,3H).
步骤6:(R)-(3-(1-氨基乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯的制备
0℃下将(3-((R)-1-(((S)-叔-丁基亚硫酰基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯(1.0g,2.4mmol)在1N HCl/EtOAc(20mL)中搅拌3h。反应液经层析柱快速过滤,先用EtOAc冲洗,再用DCM/MeOH(5/1)混合溶剂冲洗,滤液用7N NH
3/MeOH碱化,有机相水洗,经无水Na
2SO
4干燥,过滤,浓缩得到(R)-(3-(1-氨基乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=305.1.
1H NMR(400MHz,DMSO-d
6)δ9.63(s,1H),7.71(s,1H),7.69(s,1H),7.35(s,1H),4.02–3.99(m,1H),1.48(s,9H),1.23(d,J=6.6Hz,3H).
中间体13:(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧基羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯
边搅拌边向(1R,4R)-4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(330mg,1.0mmol)的DMF(5mL)溶液中加入BOP(574mg,1.3mmol)和DBU(380mg,2.5mmol),搅拌15min后,再加入(R)-(3-(1-氨基乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯盐酸盐(396mg,1.3mmol),反应液在70℃继续搅拌12h。反应液中加水(10mL)淬灭反应,然后用EA(30mL×3)萃取。有机相用无水Na
2SO
4干燥,然后减压浓缩。所得粗品经层析柱(EA:PE=0~1)纯化得到(1R,4R)-4-(4-(((R)-1-(3-((叔-丁氧基羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=617.4.
1H NMR(400MHz,DMSO-d
6)δ9.69(s,1H),8.12(s,1H),7.77(d,J=25.2Hz,2H),7.41(s,1H),7.01(s,1H),5.71–5.55(m,1H),3.90(s,3H),3.62(s,3H),2.96(d,J=11.8Hz,1H),2.39(d,J=10.4Hz,4H),2.06(d,J=12.0Hz,2H),1.89(d,J=14.0Hz,2H),1.64–1.50(m,7H),1.46(s,9H).
中间体14:(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧基羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸
向(1R,4R)-4-(4-(((R)-1-(3-((叔-丁氧基羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(250mg,0.4mmol)的THF/H
2O(10mL/5mL)溶液中加入LiOH.H
2O(48mg,1.2mmol),反应液在40℃搅拌过夜。反应液用10%柠檬酸调节至pH为,然后用EtOAc(30mL×3)萃取,合并有机相,用饱和食盐水洗涤,减压浓缩得到(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧基羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=603.1.
1H NMR(400MHz,DMSO-d
6)δ9.67(s,1H),8.20(d,J=7.4Hz,1H),8.07(s,1H),7.77(d,J=24.0Hz,2H),7.41(s,1H),7.00(s,1H),5.68–5.52(m,1H),3.89(s,3H),2.95(d,J=11.3Hz,1H),2.40–2.23(m,4H),2.06(d,J=12.0Hz,2H),1.88(d,J=12.0Hz,2H),1.67–1.41(m,16H).
中间体15:(1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸
步骤1:(1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
边搅拌边向(1R,4R)-4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(500mg,1.52mmol)的DMF(10mL)溶液中加入BOP(871mg,1.97mmol)和DBU(577mg,3.80mmol),继续搅拌15min后,再加入(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺(461mg,1.97mmol)。然后反应液再70℃搅拌过夜。反应液中加水(50mL),用EA(50mL×3)萃取。合并有机相,用饱和食盐水(100mL)洗涤,无水Na
2SO
4干燥,过滤,减压浓缩。所得粗品经flash柱(EA:PE=0~1)纯化得到(1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=547.1.
1H NMR(400MHz,DMSO-d
6)δ8.62(s,1H),8.34(d,J=6.0Hz,3H),8.04(s,1H),7.01(s,1H),5.68(p,J=6.9Hz,1H),3.89(s,3H),3.64(s,3H),2.94(t,J=11.4Hz,1H),2.48–2.37(m,1H),2.34(s,3H),2.08(d,J=12.0Hz,2H),1.97–1.86(m,2H),1.69(d,J=7.1Hz,3H),1.65–1.47(m,4H).
步骤2:(1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸的制备
向(1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸甲酯(300mg,0.55mmol)的THF/H
2O(15mL,1:2)溶液中加入LiOH.H
2O(240mg,8.0mmol)。然后反 应液再50℃搅拌过夜。反应液中加入水(50mL)淬灭反应,用EA(50mL×3)萃取。合并有机相,用饱和食盐水(100mL)洗涤,无水Na
2SO
4干燥,过滤,减压浓缩得到(1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=533.3.
1H NMR(400MHz,DMSO-d
6)δ12.09(s,1H),8.89(s,1H),8.63(s,1H),8.36(d,J=10.6Hz,2H),8.14(s,1H),7.02(s,1H),5.89–5.64(m,1H),3.92(s,3H),2.95(t,J=11.6Hz,1H),2.41(s,3H),2.37–2.26(m,1H),2.08(d,J=10.7Hz,2H),1.96–1.85(m,2H),1.72(d,J=7.1Hz,3H),1.68–1.44(m,4H).
中间体16:(1R,4R)-4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸
步骤1:1-(1,3-二羰基异二氢吲哚-2-基)4-甲基(1R,4R)-环己烷-1,4-二羧酸酯的制备
向(1R,4R)-4-(甲氧羰基)环己烷-1-羧酸(20g,107.4mmol)和2-羟基异二氢吲哚-1,3-二酮(20g,107.4mmol)的DCM(300mL)溶液中加入EDCI(34.7g,118.2mmol)和DMAP(1.3g,10.7mmol)。然后反应液在室温搅拌2h。反应液中加入食盐水和DCM。分离有机层,用无水Na
2SO
4干燥,过滤,减压浓缩。粗品经层析柱(DCM)纯化得到1-(1,3-二羰基异二氢吲哚-2-基)4-甲基(1R,4R)-环己烷-1,4-二羧酸酯。
LC-MS:(ESI,m/z):[M+Na]
+=354.1.
步骤2:2-氨基-5-碘-4-甲氧基苯甲腈的制备
向2-氨基-4-甲氧基苯甲腈(86.3g,582mmol)的DMF(1000mL)溶液中加入NIS(133g,613mmol)。然后反应液在室温搅拌2h。反应液中加入食盐水和DCM。分离有机层,经无水Na
2SO
4干燥过滤,减压浓缩得到2-氨基-5-碘-4-甲氧基苯甲腈。
LC-MS:(ESI,m/z):[M+Na]
+=296.9.
步骤3:N-(2-氰基-4-碘-5-甲氧苯基)乙酰胺的制备
向2-氨基-5-碘-4-甲氧基苯甲腈(160g,580mmol)的HOAc(1600mL)溶液中加入Ac
2O(71.3g,700mmol)。然后反应液在室温搅拌过夜。反应液过滤然后浓缩得到N-(2-氰基-4-碘-5-甲氧苯基)乙酰胺。
LC-MS:(ESI,m/z):[M+H]
+=317.0.
步骤4:(1R,4R)-4-(4-乙酰氨基-5-氰基-2-甲氧苯基)环己烷-1-羧酸甲酯的制备
向N-(2-氰基-4-碘-5-甲氧苯基)乙酰胺(15.0g,47.45mmol),1-(1,3-二羰基异二氢吲哚-2-基)4-甲基(1R,4R)-环己烷-1,4-二羧酸酯(31.40g,94.90mmol)和Hantzsch-ester(24.00g,94.90mmol)的DMA(237mL,0.2M)溶液中加NiBr
2(dtbpy)(2.31g,4.75mmol)。反应液用N
2吹5分钟并两个Kessil PR160-purple LED lamps(30W High Luminous DEX 2100LED,λmax=390nm)照射16h。反应温度控制在30-40℃。反应结束后,反应液倒入水(1L)中,然后用EtOAc(150mLx3)萃取。合并有机相并用饱和食盐水(400mLx3)洗涤,经无水Na
2SO
4干燥,减压浓缩。所得粗品经层析柱(MeOH:DCM=1:99)纯化。收集含有产物的洗脱液浓缩值80mL,过滤,滤液浓缩得到顺反比列为1:1的混合物,滤饼为顺反比列为15:1的混合物。将顺反比列为15:1的混合物溶解在DMA(85mL)中,然后加入0.5M K
2CO
3水溶液(200mL),所得混合物室温搅拌2小时,过滤得到顺反比列为20:1的混合物,将此混合物用乙腈(180mL)进行重结晶得到目标产物(顺反比例为97:2)
LC-MS:(ESI,m/z):[M+H]
+=331.1.
1H NMR(400MHz,CDCl
3)δ8.04(s,1H),7.55(s,1H),7.29(s,1H),3.89(s,3H),3.69(s,3H),2.90-2.84(m,1H),2.35-2.26(m,1H),2.25(s,3H),2.11-2.08(m,2H),1.92-1.89(m,2H),1.63-1.56(m,2H),1.39-1.33(m,2H).
步骤5:(1R,4R)-4-(7-甲氧基-2-甲基-4-羰基-3,4-二氢喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
将(1R,4R)-4-(4-乙酰氨基-5-氰基-2-甲氧苯基)环己烷-1-羧酸甲酯(3g,9.08mmol)加到i-PrOH(80mL)中,,然后室温下通HCl气体1h。将反应液过滤,干燥得到(1R,4R)-4-(7-甲氧基-2-甲基-4-羰基-3,4-二氢喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=331.1.
1H NMR(400MHz,DMSO-d
6)δ7.87(s,1H),7.23(s,1H),3.95(s,3H),3.61(s,3H),2.98-2.87(m,1H),2.58(s,3H),2.47-2.39(m,1H),2.06-1.98(m,2H),1.88-1.80(m,2H),1.59-1.42(m,4H).
步骤6:(R,Z)-N-(1-(4-溴噻吩-2-基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的制备
将1-(4-溴噻吩-2-基)乙烷-1-酮(10.0g,48.80mmol),(R)-2-甲基丙烷-2-亚磺酰胺(8.90g,73.20mmol)和Ti(OEt)
4(27.8g,122.00mmol)在THF(70mL)中的反应液在80℃搅拌3h。反应液中加水(200mL)淬灭,然后用EA(100mLx3)萃取。合并有机相,经无水Na
2SO
4干燥,过滤,减压浓缩。所得粗品经层析柱(DCM:MeOH=100:1)纯化得到(R,Z)-N-(1-(4-溴噻吩-2-基)亚乙基)-2-甲基丙烷-2-亚磺酰胺。
1H NMR(400MHz,DMSO-d
6)δ7.96(d,J=1.2Hz,1H),7.85(d,J=1.2Hz,1H),2.68(s,3H),1.19(s,9H).
步骤7:(R)-N-((R)-1-(4-溴噻吩-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备
向(R,Z)-N-(1-(4-溴噻吩-2-基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(7.0g,22.7mmol)的THF(10mL)溶液中加9-BBN/THF(0.5M,200mL)。反应液在25℃搅拌0.5h。反应液中加MeOH(10mL)淬灭反应,然后加入水(100mL),再用EA(100mLx3)萃取。合并有机相用无水Na
2SO
4干燥,过滤,减压浓缩。所得粗品经层析柱(DCM:MeOH=100:1)纯化得到(R)-N-((R)-1-(4-溴噻吩-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺。
1H NMR(400MHz,DMSO-d
6)δ7.54(d,J=1.2Hz,1H),7.08(s,1H),5.93(d,J=7.2Hz,1H),4.64-4.58(m,1H),1.48(d,J=6.8Hz,3H),1.12(s,9H).
步骤8:(R)-1-(4-溴噻吩-2-基)乙烷-1-胺盐酸盐的制备
向(R)-N-((R)-1-(4-溴噻吩-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(6.0g,19.34mmol)的1,4-二氧六环(60mL)溶液中加HCl(12M,454mmol)。然后反应液在25℃搅拌2h。反应液直接浓缩。所得粗品在MTBE(100mL)溶液中搅拌,过滤,干燥得到(R)-1-(4-溴噻吩-2-基)乙烷-1-胺盐酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.62(s,3H),7.71(s,1H),7.32(s,1H),4.71-4.67(m,1H),1.57(d,J=6.8Hz,3H).
步骤9:(1R,4R)-4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
室温时向(1R,4R)-4-(7-甲氧基-2-甲基-4-羰基-3,4-二氢喹唑啉-6-基)环己烷-1-羧酸甲酯(3.00g,9.07mmol)和BOP(5.21g,11.79mmol)的DMF(35mL)溶液中加DBU(3.45g,22.67mmol),搅拌15分钟后,滴加(R)-1-(4-溴噻吩-2-基)乙烷-1-胺盐酸盐(2.86g,11.79mmol)的DMF(35mL)溶液,然后反应液先在室温搅拌20分钟,再升温至70℃搅拌8小时。反应液经反相柱纯化得到(1R,4R)-4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=518.0,520.0.
步骤10:(1R,4R)-4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸的制备
向(1R,4R)-4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(2.00g,3.86mmol)的THF/H
2O(20.0mL/20.0mL)溶液中加LiOH(0.81g,19.30mmol)。反应液在25℃搅拌16h。反应液用2N HCl溶液酸化,有沉淀生成。过滤,滤饼真空干燥得到(1R,4R)-4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=504.0,506.0.
中间体17:4-(2,6-二氧代基哌啶-3-基)苯甲酸五氟苯酯
步骤1:4-(4-氰基-1-甲氧基-1-氧丁烷-2-基)苯甲酸甲酯的制备
将苄基三甲基氢氧化铵(6.03g,36.057mmol)和丙烯腈(5.727g,79.32mmol)加入4-(2-甲氧基-2-氧乙 烷)苯甲酸甲酯(15.0g,72.12mmol)的甲苯溶液(200mL)中,30℃搅拌16h,用乙酸乙酯(100mL×5)提取,饱和食盐水(500mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(EA:PE=3:7)纯化得到目标产物4-(4-氰基-1-甲氧基-1-氧丁烷-2-基)苯甲酸甲酯。
1H NMR(400MHz,DMSO-d
6)δ7.95(d,J=4.0Hz,2H),7.46(d,J=6.0Hz,2H),3.90-3.80(m,4H),3.62(s,3H),2.48-2.38(m,2H),2.36-2.26(m,1H),2.10-1.96(m,1H).
步骤2:4-(2,6-二氧哌啶-3-基)苯甲酸的制备
将4-(4-氰基-1-甲氧基-1-氧丁烷-2-基)苯甲酸甲酯(8.5g,32.56mmol)溶解在乙酸(30mL)中,加入硫酸(15mL),110℃搅拌12h,用二氯甲烷/甲醇(10/1,150ml×3)提取,饱和食盐水(500mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:10)纯化得到4-(2,6-二氧哌啶-3-基)。
1H NMR(400MHz,DMSO-d
6)δ12.89(s,1H),10.89(s,1H),7.91(d,J=4.0Hz,2H),7.36(d,J=4.0Hz,2H),4.02-3.92(m,1H),2.72-2.63(m,1H),2.56-2.45(m,1H),2.30-2.20(m,1H),2.10-2.00(m,1H).
步骤3:4-(2,6-二氧代基哌啶-3-基)苯甲酸五氟苯酯的制备
将4-(2,6-二氧哌啶-3-基)苯甲酸(1.3g,5.579mmol)用DMF(100mL)溶解,加入五氟苯酚(1.129g,6.14mmol)和DCC(1.265g,6.14mmol),室温搅拌过夜,用乙酸乙酯(100mL×3)提取,饱和食盐水(150mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(EA:PE=3:7)纯化得到4-(2,6-二氧代基哌啶-3-基)苯甲酸五氟苯酯。
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),8.17(d,J=4.0Hz,2H),7.56(d,J=4.0Hz,2H),4.14-4.08(m,1H),2.79-2.69(m,1H),2.66-2.55(m,1H),2.30-2.23(m,1H),2.15-2.05(m,1H).
中间体18:3-(2,4-二氧代基四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酸五氟苯酯
步骤1:3-(2,4-二氧代基四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酸的制备
将3-氨基-4-甲氧基苯甲酸(5.0g,2.93mmol)悬浮于丙烯酸(8.05mL,117mmol)中,并在100℃下搅拌反应3h,然后将反应液搅拌冷却至室温。加入乙酸(33ml),将搅拌的悬浮液在100℃加热10分钟,加入尿素(11.00g,183mmol),反应液在120℃搅拌过夜。将反应液加入到冰水和浓盐酸(37%)的混合液中,搅拌,将得到的悬浮液在5℃的冰箱中保存过夜,然后过滤,固体用水洗涤并干燥,得到固体。将固体在盐酸溶液(0.05M)中研磨,过滤,甲基叔丁基醚洗涤,40℃下减压干燥,得到目标产物。
1H NMR(400MHz,DMSO-d
6)δ12.70(s,1H),10.34(s,1H),7.92(dd,J=8.6,2.2Hz,1H),7.83(d,J=2.2Hz,1H),7.21(d,J=8.8Hz,1H),3.94-3.82(m,3H),3.60(t,J=6.7Hz,2H),2.69(s,2H).
步骤2:3-(2,4-二氧代基四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酸五氟苯酯的制备
3-(2,4-二氧代基四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酸(2.0g,7.58mmol),2,3,4,5,6-五氟苯酚(1.67g,9.09mmol)和N,N'-二环己基碳酰亚胺(1.87g,9.09mmol)在N,N-二甲基甲酰胺(20mL)溶液中的混合物在室温下搅拌反应3h。将反应液倒入水(200mL)中并搅拌0.5h,溶液用乙酸乙酯(200mL×3)萃取。收集有机相,并用水(500mL×2)和饱和食盐水(300mL)洗涤,用无水硫酸钠干燥,过滤并浓缩。浓缩物经柱层析纯化,得到目标产物3-(2,4-二氧代基四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酸五氟苯酯。
LC-MS:(ESI,m/z):[M+H]
+=431.1.
中间体19:3-(2,4-二氧代基四氢嘧啶-1(2H)-基)-4-氟苯甲酸五氟苯酯
参照中间体18的方法制备。
LC-MS:(ESI,m/z):[M+H]
+=419.0.
中间体20:3-(2,4-二氧代基四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯
参照中间体18的方法制备。
LC-MS:(ESI,m/z):[M+H]
+=401.0.
中间体21:(1R,4R)-4-(4-(((R)-1-(4-(2-((二甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯
步骤1:(1R,4R)-4-(4-(((R)-1-(4-(2-甲酰基苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
向(1R,4R)-4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(250mg,0.48mmol)的1,4-二氧六环/H
2O(1.5mL/0.5mL)溶液中加K
3PO
4(255mg,1.2mmol),(PPh
3)
2PdCl
2(34mg,0.048mmol)和(2-甲酰基苯基)硼酸(87mg,0.58mmol)。反应液在100℃搅拌过夜。反应液浓缩,然后经层析柱(PE/EA=2/1to 1/2)纯化得到(1R,4R)-4-(4-(((R)-1-(4-(2-甲酰基苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=544.1.
步骤2:(1R,4R)-4-(4-(((R)-1-(4-(2-((二甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
向(1R,4R)-4-(4-(((R)-1-(4-(2-甲酰基苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(200mg,0.36mmol)和二甲基胺盐酸(60mg,0.74mmol)混合物中加MeOH(3mL),DCE(3mL)和AcOH(5滴)。上述溶液在室温搅拌1h后,加入NaBH
3CN(46mg,0.74mmol)然后反应液在室温继续搅拌3h。反应液中加入DCM和水,分离有机相,经无水Na
2SO
4干燥,过滤,减压浓缩。所得粗品经Prep-HPLC纯化得到(1R,4R)-4-(4-(((R)-1-(4-(2-((二甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=573.3
1H NMR(400MHz,CDCl
3)δ7.44-7.34(m,3H),7.33-7.28(m,4H),7.12(s,1H),6.11-6.02(m,1H),5.69-5.60(m,1H),3.92(s,3H),3.69(s,3H),3.38(s,2H),3.04-2.98(m,1H),2.63(s,3H),2.44-2.33(m,1H),2.24-2.18(m,6H),2.16-2.07(m,2H),2.05-1.95(m,2H),1.82-1.79(d,J=6.8Hz,3H),1.67-1.60(m,4H).
中间体22:4-(3-溴丙-1-炔-1-基)哌啶-1-羧酸叔丁酯
步骤1:4-(2,2-二溴乙烯基)哌啶-1-羧酸叔丁酯的制备
0℃时搅拌下,向CBr
4(14.0g,42.24mmol)的DCM(200mL)溶液中加入PPh
3(22.13g,84.48mmol),并在0℃时继续搅拌30min,然后加入4-醛基哌啶-1-羧酸叔丁酯(6.0g,28.16mmol),反应液在室温搅拌过夜。反应液用EA(200mL)稀释,然后过滤。滤液减压浓缩。所得粗品经flash柱(EA:PE=0~3:7)得到4-(2,2-二溴乙烯基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M-tBu]
+=313.9.
步骤2:4-(3-羟基丙-1-炔-1-基)哌啶-1-羧酸叔丁酯的制备
-78℃下,向4-(2,2-二溴乙烯基)哌啶-1-羧酸叔丁酯(4.0g,10.86mmol)的THF(60mL)溶液中加入n-BuLi(13.6mL,1.6M/正己烷)。混合液在-78℃搅拌1h后,加入多聚甲醛(977mg,32.60mmol)。反应液在室温搅拌过夜。反应液中加入NH
4Cl(100mL)淬灭反应,并用EA(100mL×3)萃取,合并有机相并用饱和食盐水(300mL)洗涤,无水Na
2SO
4干燥,过滤并浓缩。所得粗品经flash柱(EA:PE=0~4:1)纯化得到4-(3-羟基丙-1-炔-1-基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M-Boc]
+=140.2.
1H NMR(400MHz,DMSO-d
6)δ5.04(t,J=5.9Hz,1H),4.04(dd,J=5.8,2.0Hz,2H),3.65–3.55(m,2H),3.04(t,J=10.1Hz,2H),2.60(ddd,J=8.8,7.0,3.5Hz,1H),1.77–1.64(m,2H),1.43–1.31(m,11H).
步骤3:4-(3-溴丙-1-炔-1-基)哌啶-1-羧酸叔丁酯的制备
0℃时,边搅拌边向4-(3-羟基丙-1-炔-1-基)哌啶-1-羧酸叔丁酯(700mg,2.92mmol)和PPh
3(1.94g,5.83mmol)的DCM(10mL)溶液中加入CBr
4(1.94g,5.83mmol)。反应液在室温搅拌过夜。反应液中加入EA(10mL)稀释,然后过滤。滤液减压浓缩。所得粗品经flash柱(EA:PE=0~3:7)纯化得到4-(3-溴丙-1-炔-1-基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M-tBu]
+=246.0.
1H NMR(400MHz,DMSO-d
6)δ4.24(d,J=2.0Hz,2H),3.64–3.54(m,2H),3.13–3.00(m,2H),2.75–2.65(m,1H),1.78–1.68(m,2H),1.44–1.33(m,11H).
中间体23:4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯
步骤1:4-(2-(吡啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯的制备
0℃时,向4-(2-羟基乙基)哌啶-1-羧酸叔丁酯(1.0g,4.36mmol)的THF(20mL)溶液中加入NaH(60%,1.2g,30.58mmol),并在0℃搅拌20分钟,升至室温后,加入4-(溴甲基)吡啶溴化氢(1.3g,5.13mmol),然后反应混合物于室温下搅拌反应过夜。反应液中加入水(30mL),EA(30mL×3)萃取,合并有机相并用食盐水洗(30mL),Na
2SO
4干燥,减压浓缩。浓缩物经flash柱纯化(EA:PE=0~4:1)得到目标产物4-(2-(吡啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=321.1.
1H NMR(400MHz,CDCl
3)δ8.57(d,J=5.9Hz,2H),7.24(d,J=5.7Hz,2H),4.51(s,2H),4.09(d,J=15.9Hz,2H),3.55(t,J=6.1Hz,2H),2.70(t,J=12.2Hz,2H),1.66(d,J=13.9Hz,2H),1.58(m,2H),1.45(s,9H),1.26(m,1H),1.13(d,J=8.4Hz,2H).
步骤2:4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯的制备
将4-(2-(吡啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯(1.9g,5.9mmol)和Pd/C(570mg)在i-PrOH/H
2O(30mL/35mL)中的混合液在75℃下搅拌过夜。反应液经硅藻土过滤,滤液浓缩得到目标产物4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯。所得产物无需纯化,直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=327.2.
中间体24:2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)乙醛
步骤1:2-(2,6-二氧代基哌啶-3-基)-4-(4-(2-羟基乙基)哌啶-1-基)异吲哚啉-1,3-二酮的制备
向2-(2,6-二氧代基哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(1.0g,3.6mmol)的DMF(10mL)溶液中加2-(哌啶-4-基)乙烷-1-醇(467mg,3.6mmol)和DIEA(1.4g,10.8mmol)。反应液在100℃搅拌过夜。反应液中加水(100mL)淬灭反应。然后用EA(20mL×3)萃取。合并有机相用饱和食盐水(60mL)洗涤,无水Na
2SO
4干燥,过滤,减压浓缩。所得粗品经flash柱(EA:PE=0~1:1)纯化得到2-(2,6-二氧代基哌啶-3-基)-4-(4-(2-羟基乙基)哌啶-1-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=386.1.
步骤2:2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)乙醛的制备
边搅拌边向2-(2,6-二氧代基哌啶-3-基)-4-(4-(2-羟基乙基)哌啶-1-基)异吲哚啉-1,3-二酮(1.1g,3.0mmol)的ACN(20mL)溶液中加IBX(1.7g,6.0mmol)。反应液在80℃搅拌2h。反应液过滤,滤液浓缩。所得粗品经flash柱(EA:PE=0~1:1)纯化得到2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)乙醛。
LC-MS:(ESI,m/z):[M+H]
+=384.0.
1H NMR(400MHz,DMSO-d
6)δ11.08(s,1H),9.72(s,1H),7.77–7.58(m,1H),7.34(dd,J=7.7,4.9Hz,2H),5.09(dd,J=12.9,5.4Hz,1H),3.68(d,J=11.8Hz,2H),2.97-2.82(m,3H),2.64–2.53(m,2H),2.45(d,J=6.6Hz,2H),2.13–1.99(m,3H),1.82-1.72(m,2H),1.50-1.30(m,2H).
中间体25:3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)丙醛
步骤1:3-(哌啶-4-基)丙烷-1-醇的制备
向4-(3-羟基丙基)哌啶-1-羧酸叔丁酯(930.0mg,3,8mmol)的DCM(8.00mL)中加TFA(4.0mL)。反应液室温搅拌过夜。反应液直接浓缩得到3-(哌啶-4-基)丙烷-1-醇。所得粗品直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=144.2.
步骤2:2-(2,6-二氧代基哌啶-3-基)-4-(4-(3-羟基丙基)哌啶-1-基)异吲哚啉-1,3-二酮的制备
边搅拌边向3-(哌啶-4-基)丙烷-1-醇(730mg,TFAsalt,3.8mmol)的DMF(10mL)溶液中加2-(2,6-二氧代基哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(1.0g,3.8mmol)和DIEA(1.5g,11.4mmol)。反应液在100℃搅拌过夜。反应液中加水(100mL)淬灭反应。然后用EA(20mL×3)萃取。有机相用饱和食盐水(60mL)洗涤,无水Na
2SO
4干燥,过滤,浓缩。所得粗品经flash柱(EA:PE=0~1:1)纯化得到2-(2,6-二氧代基哌啶-3-基)-4-(4-(3-羟基丙基)哌啶-1-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=400.0.
步骤3:3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)丙醛的制备
边搅拌边向2-(2,6-二氧代基哌啶-3-基)-4-(4-(3-羟基丙基)哌啶-1-基)异吲哚啉-1,3-二酮(700mg,1.7mmol)的ACN(20mL)溶液中加IBX(982mg,3.5mmol)。反应液在80℃搅拌2h。反应液过滤,滤液浓缩。所得粗品经flash柱(EA:PE=0~1:1)纯化得到3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)丙醛。
LC-MS:(ESI,m/z):[M+H]
+=398.0.
1H NMR(400MHz,DMSO-d
6)δ11.08(s,1H),9.71(t,J=1.4Hz,1H),7.74–7.60(m,1H),7.33(dd,J=7.7,3.4Hz,2H),5.09(dd,J=12.9,5.4Hz,1H),3.69(d,J=11.9Hz,2H),2.93-2.79(m,3H),2.64–2.46(m,4H),2.07–2.00(m,1H),1.80-1.72(m,2H),1.54(dd,J=14.0,7.1Hz,2H),1.40-1.27(m,3H)
中间体26:9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯
步骤1:9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将9-醛基-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1.0g,3.56mmol)和(9H-芴-9-基)甲基哌嗪-1-羧酸酯(1.35g,3.91mmol)溶于THF(20mL)中,加入STAB(2.26g,10.68mmol),室温搅拌过夜,加水(100mL),用乙酸乙酯(100mLx3)提取,饱和食盐水(150mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(EA/PE=3:2)纯化得到9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=574.2.
步骤2:(9H-芴-9-基)甲基4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸酯的制备
将9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1.1g,1.92mmol)溶解在DCM(10mL)中,加入TFA(2mL),室温搅拌1h,减压浓缩,得到(9H-芴-9-基)甲基4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸酯,直接用于下一步。
LC-MS:(ESI,m/z):[M+H]
+=474.1.
步骤3:9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯的制备
将(9H-芴-9-基)甲基4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸酯(1.1g,2.33mmol)溶于ACN(20mL)中,加入NaHCO
3饱和溶液(20mL),搅拌下加入CbzCl(0.60g,3.50mmol),室温下反应过夜。减压浓缩除去乙腈,加水(50mL),用乙酸乙酯(100mLx3)提取,饱和食盐水(150mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(EA/PE=11:9)纯化得到9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=608.1.
步骤4:9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯的制备
将9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯(0.97g,1.60mmol)溶于CAN(10Ml)中,加入哌啶(2mL),室温搅拌3h。减压浓缩除去溶剂,加水(50mL),用乙酸乙酯(100mLx3)提取,饱和食盐水(150mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层柱(MeOH/DCM=3:17)纯化得到9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=386.1.
中间体27:4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯
步骤1:4-(((三氟甲氧基)磺酰基)氧)环己-3-烯-1-羧酸甲酯的制备
将2,6-二甲基-1λ
2-哌嗪(51.4g,480.37mmol)和Tf
2O(90.38g,320.50mmol)加入到4-氧代环己烷-1-羧酸甲酯(50.0g,320.51mmol)的二氯甲烷(500ml)中,0℃搅拌1h,再补加Tf
2O(72.3g,256.38mmol),常 温下搅拌过夜,用水洗,无水硫酸钠干燥,减压浓缩,粗品用柱层析(PE:EA=5:1)得到4-(((三氟甲氧基)磺酰基)氧)环己-3-烯-1-羧酸甲酯。
1H NMR(400MHz,DMSO-d
6)δ5.90(s,1H),3.63(s,3H),2.70–2.60(m,1H),2.47–2.28(m,4H),2.11–1.98(m,1H),1.81(tt,J=8.9,6.0Hz,1H).
步骤2:4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)环己-3-烯-1-羧酸甲酯的制备
将(Bpin)
2(39.1g,153.94mmol),Pd(dppf)
2Cl
2(7.5g,10.24mmol)和醋酸钾(30.4g,310.2mmol)加入到4-(((三氟甲氧基)磺酰基)氧)环己-3-烯-1-羧酸甲酯(30.0g,104.17mmol)的二氧六环(500ml)中,90℃搅拌过夜,反应液用水(2L)稀释,乙酸乙酯(500mL×3)萃取,饱和食盐水洗(500mL),无水硫酸钠干燥,减压浓缩,粗品使用柱层析纯化(PE:EA=0:100)得到4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)环己-3-烯-1-羧酸甲酯。
1H NMR(400MHz,CDCl
3)δ6.53(s,1H),3.71–3.64(m,3H),2.61–2.46(m,1H),2.42–1.95(m,6H),1.28–1.19(m,12H).
步骤3:4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯的制备
将4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)环己-3-烯-1-羧酸甲酯(25.0g,93.98mmol),Pd(dppf)
2Cl
2(5.3g,7.24mmol)和Na
2CO
3(15.3g,144.34mmol)加入到6-溴-7-甲氧基-2-甲基喹唑啉-4-醇(19.4g,72.12mmol)的DMF/H
2O(300ml/30ml)中,110℃搅拌过夜,反应液用水(1L)稀释,乙酸乙酯(500mL×3)萃取,饱和食盐水(500mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(PE:EA=0:100)纯化得到粗产品4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=329.0.
中间体28:(1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸甲酯
将(1R,4R)-4-(4-(((R)-1-(4-(2-醛基苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(180mg,0.33mmol)和甲胺溶液(0.33ml,0.66mmol,2M in THF)加到MeOH/DCE(2mL/2mL)中,再滴加几滴AcOH(4drops)。混合溶液在室温搅拌1h后,加入NaBH
3CN(42mg,0.66mmol)并继续搅拌反应3h。反应液中加入DCM和水,分离有机相,用无水Na
2SO
4干燥,过滤,减压浓缩。粗品经Prep-HPLC纯化得到(1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=559.4.
1H NMR(400MHz,CDCl
3)δ7.42-7.39(m,1H),7.35-7.26(m,5H),7.24-7.20(m,1H),7.10(s,1H),6.08-6.01(m,1H),5.65-5.60(m,1H),3.92(s,3H),3.73-3.69(m,5H),3.04-2.98(m,1H),2.63(s,3H),2.44-2.36(m,4H),2.14-1.99(m,4H),1.80(d,J=6.8Hz,3H),1.70-1.53(m,4H).
实施例1:5-(4-(2-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮
((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(哌嗪-1-基)甲酮(50mg,0.09mmol),2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙醛(40mg,0.09mmol)和STAB(55mg,0.27mmol)在THF(3mL)溶液中的反应混合物于25℃搅拌反应1小时。用水(50mL)淬灭反应,并用EA(50mL×3)萃取。收集有机层并用经无水硫酸钠干燥,过滤并减压浓缩。浓缩物通过制备型HPLC(乙腈/0.08%碳酸氢铵水溶液中,5%至95%)纯化,得到5-(4-(2-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=938.3.
1H NMR(400MHz,DMSO-d
6)δ11.08(s,1H),8.11(d,J=7.7Hz,1H),8.07(s,1H),7.65(d,J=8.6Hz,1H),7.31(s,1H),7.23(d,J=8.1Hz,1H),7.00(s,1H),6.88(s,1H),6.86(s,1H),6.70(s,1H),5.66–5.47(m,3H),5.12–5.01(m,1H),4.11–3.96(m,2H),3.89(s,3H),3.57–3.40(m,4H),3.04–2.80(m,4H),2.72–2.57(m,3H),2.45–2.25(m,9H),2.07–1.95(m,1H),1.93–1.73(m,6H),1.71–1.49(m,8H),1.45–1.35(m,2H),1.27–1.11(m,2H).
实施例2:5-(4-(2-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)哌嗪-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮
参照实施例1的方法制备。
LC-MS:(ESI,m/z):[M+H]
+=939.6.
1H NMR(400MHz,DMSO-d
6)δ11.08(s,1H),8.11(d,J=9.0Hz,1H),8.07(s,1H),7.68(d,J=8.4Hz,1H),7.34(s,1H),7.26(d,J=8.4Hz,1H),7.00(s,1H),6.88(s,1H),(s,1H),6.70(s,1H),5.63–5.49(m,3H),5.15–5.01(m,1H),3.89(s,3H),3.55–3.38(m,8H),3.01–2.83(m,2H),2.72–2.53(m,6H),2.47–2.27(m,11H),2.07–1.97(m,1H),1.91–1.77(m,4H),1.73–1.48(m,8H).
实施例3:5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮
参照实施例1的方法制备。
LC-MS:(ESI,m/z):[M+H]
+=952.5
1H NMR(400MHz,DMSO-d
6)δ11.07(s,1H),8.16–8.01(m,2H),7.65(d,J=8.6Hz,1H),7.30(d,J=2.0Hz,1H),7.22(dd,J=8.7,2.1Hz,1H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.62-5.48(m,3H),5.06(dd,J=12.9,5.4Hz,1H),4.04(d,J=13.0Hz,2H),3.88(s,3H),3.55-4.32(m,4H),3.25-3.22(m,1H),2.98-2.82(m,4H),2.68-2.53(m,2H),2.38-2.25(m,9H),2.03-1.97(m,1H),1.92-1.42(m,16H),1.26–1.12(m,4H).
实施例4:5-(4-(2-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧)哌啶-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮
将(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(哌啶-4-氧基)喹唑啉-4-胺(50mg,0.105mmol),2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙醛(48mg,0.126mmol),STAB(31mg,0.24mmol)在THF(5mL)溶液中的混合物于室温下搅拌过夜。反应液浓缩,浓缩物经制备HPLC纯化得目标产物5-(4-(2-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧)哌啶-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=843.3.
1H NMR(400MHz,DMSO-d
6)δ11.06(s,1H),7.92–7.88(m,1H),7.78(s,1H),7.65(d,J=8.6Hz,1H),7.33–7.18(m,2H),7.04(s,1H),6.87(s,1H),6.84(s,1H),6.69(s,1H),5.61–5.46(m,3H),5.10–5.02(m,1H),4.51–4.45(m,1H),4.08–4.01(m,2H),3.87(s,3H),2.99–2.81(m,3H),2.78–2.65(m,2H),2.63–2.55(m,2H),2.42–2.32(m,5H),2.28–2.18(m,2H),2.05–1.92(m,3H),1.81–1.65(m,4H),1.62–1.52(m,4H),1.45–1.36(m,2H),1.25–1.13(m,2H).
实施例5:5-(4-(3-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧代)哌啶-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮
将(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(哌啶-4-氧基)喹唑啉-4-胺(50mg,0.105mmol),3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)丙醛(50mg,0.12mmol),STAB(67mg,0.31mmol)在THF(5mL)溶液中的混合物于室温下搅拌过夜。反应液浓缩,浓缩物经制备HPLC纯化,得到目标产物5-(4-(3-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧代)哌啶-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=857.3.
1H NMR(400MHz,DMSO-d
6)δ11.07(s,1H),7.93–7.89(m,1H),7.78(s,1H),7.65(d,J=8.6Hz,1H),7.33–7.18(m,2H),7.05(s,1H),6.88(s,1H),6.84(s,1H),6.70(s,1H),5.61–5.46(m,3H),5.10–5.02(m,1H),4.51–4.45(m,1H),4.08–4.01(m,2H),3.87(s,3H),2.99–2.81(m,2H),2.78–2.65(m,2H),2.63–2.55(m,2H),2.43–2.30(m,7H),2.28–2.18(m,2H),2.05–1.92(m,4H),1.81–1.52(m,7H),1.45–1.36(m,2H),1.25 –1.13(m,2H).
实施例6:4-(4-(2-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧代)哌啶-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮
将(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(哌啶-4-氧基)喹唑啉-4-胺(50mg,0.10mmol),2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)乙醛(48mg,0.12mmol),STAB(65mg,0.30mmol)在THF(5mL)溶液中的混合物于室温下搅拌反应过夜。反应液浓缩,浓缩物经制备HPLC(乙腈/0.08%NH
4HCO
3水溶液,5%至95%)纯化,得到目标产物4-(4-(2-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧代)哌啶-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=843.3.
1H NMR(400MHz,DMSO-d
6)δ11.08(s,1H),7.91(d,J=7.7Hz,1H),7.79(s,1H),7.71–7.64(m,1H),7.36–7.29(m,2H),7.05(s,1H),6.87(s,1H),6.84(s,1H),6.69(s,1H),5.62–5.47(m,3H),5.15-5.05(m,1H),4.55-4.45(m,1H),3.87(s,3H),3.68(d,J=10.9Hz,2H),2.91–2.82(m,3H),2.79–2.68(m,2H),2.65-2.55(m,2H),2.45-2.20(m,6H),2.09–1.89(m,4H),1.85-1.66(m,4H),1.55(d,J=7.0Hz,3H),1.50-1.31(m,5H).
实施例7:4-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮
将((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(哌嗪-1-基)甲酮(80mg,0.14mmol),3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)丙醛(56mg,0.14mmol),STAB(89mg,0.42mmol)在THF(5mL)溶液中的混合物于25℃下搅拌1h。反应液中加水(50mL)淬灭,用EA(50mL×3)萃取,有机相用Na
2SO
4干燥,过滤,浓缩。粗品经制备HPLC(乙腈/0.08%NH
4HCO
3水溶液,5%至95%)纯化,得到目标产物4-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=952.4.
1H NMR(400MHz,DMSO-d
6)δ8.11(d,J=7.6Hz,1H),8.06(s,1H),7.71–7.64(m,1H),7.32(dd,J=7.6,5.2Hz,2H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.66–5.46(m,3H),5.12–5.03(m,1H),3.89(s,3H),3.69(d,J=11.4Hz,2H),3.55–3.40(m,4H),3.00–2.79(m,4H),2.70–2.54(m,3H),2.42–2.26(m,9H),2.07–1.98(m,1H),1.92–1.73(m,6H),1.72–1.61(m,2H),1.61–1.40(m,8H),1.38–1.23(m,4H).
实施例8:5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮
步骤1:4-(2-((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶 -1-羧酸叔丁酯的制备
将4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯(500mg,1.533mmol)溶解在DMF(3mL)中,然后加入2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(846mg,3.066mmol)和DIEA(593mg,4.599mmol),110℃下搅拌过夜。用水(20mL)稀释,EA(20mL×2)萃取。有机相经无水Na
2SO
4干燥,过滤,减压浓缩。用柱层析(MeOH:DCM=3:97)纯化得到4-(2-((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=583.2.
步骤2:2-(2,6-二氧代基哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)异吲哚啉-1,3-二酮的制备
将4-(2-((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯(500mg,1.533mmol)溶解在DCM(3mL)中,然后加入TFA(1mL),室温搅拌2h。反应液直接减压浓缩得到2-(2,6-二氧代基哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=483.3.
步骤3:(3-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯的制备
将(1R,4R)-4-(4-(((R)-1-(3-(叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(200mg,0.331mmol)溶解在DMF(3mL)中,然后加入DIEA(128.4mg,0.993mmol)和HATU(164.0mg,0.431mmol),搅拌20分钟后再加入2-(2,6-二氧代基哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)异吲哚啉-1,3-二酮(192mg,0.397mmol)。反应液室温搅拌3h。反应液中加入水(20mL),用DCM(30mL×2)萃取,有机相用无水Na
2SO
4干燥,过滤,减压浓缩。粗品经层析柱(MeOH:DCM=0~1:9)纯化得到(3-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1067.6.
步骤4:5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮的制备
将(3-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯(200mg,0.331mmol)溶解在DCM(3mL)中,然后加入TFA(3mL)。反应液室温搅拌2h。反应液减压浓缩。粗品经Prep-HPLC(乙腈/0.05%NH
4HCO
3水溶液,5%~95%)纯化得到5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=967.5.
1H NMR(400MHz,DMSO-d
6)δ11.07(s,1H),8.37-8.07(m,2H),7.64(d,J=8.5Hz,1H),7.30(s,1H),7.22(d,J=8.7Hz,1H),6.99(s,1H),6.86(d,J=10.3Hz,2H),6.70(s,1H),5.65–5.48(m,3H),5.06(dd,J=12.8,5.5Hz,1H),4.39(d,J=11.9Hz,1H),4.05(d,J=12.8Hz,2H),3.95-3.83(m,4H),3.41(t,J=6.3Hz,2H),3.23(d,J=6.2Hz,2H),3.09–2.80(m,6H),2.70-2.60(m,2H),2.35(s,3H),2.04-1.96(m,1H),1.87–1.50(m,18H),1.50–1.41(m,2H),1.25–1.15(m,2H).
实施例9:1-(5-(9-(2-(4-((1S,4S)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:(R)-4-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-羧酸叔丁酯的制备
将(R)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(220mg,0.44mmol)用乙酸乙酯(12mL)溶解并冷却到0℃,N-Boc哌嗪(163mg,0.88mmol),DIEA(169mg,1.31mmol)和T
3P(209mg,0.66mmol)分别加入,反应液在0℃搅拌3小时,用水(30mL)淬灭,乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(20mL)洗一次,无水硫酸钠干燥,过滤并减压浓缩,粗产品经柱层析(PE:EA=10:1)纯化得到(R)-4-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=671.3.
步骤2:(R)-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(哌嗪-1-基)甲酮的制备
将(R)-4-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基) 哌嗪-1-羧酸叔丁酯(220mg,0.33mmol)加入到氯化氢的乙酸乙酯溶液中(3M/EA,10mL),反应液室温搅拌2小时,直接减压浓缩得到(R)-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(哌嗪-1-基)甲酮,无需纯化直接用于下一步。
步骤3:1-(5-(9-(2-(4-((1S,4S)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(R)-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(哌嗪-1-基)甲酮(115mg,0.165mmol)用四氢呋喃(5mL)溶解,2-(3-(4-氯-3-(2,4-氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)acetaldehyde(39mg,0.09mmol)和三乙酰氧基硼氢化钠(55mg,0.27mmol)依次加入,反应液室温搅拌2小时,用水(10mL)淬灭,二氯甲烷(30mL×3)萃取,无水硫酸钠干燥,过滤并减压浓缩,粗产品使用反相制备(先甲酸体系纯化,后用碳酸氢铵体系纯化)得到1-(5-(9-(2-(4-((1S,4S)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1000.1.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.31(d,J=7.9Hz,1H),7.95(s,1H),7.63(d,J=8.2Hz,1H),7.54(d,J=1.9Hz,1H),7.38(dd,J=8.2,1.8Hz,1H),6.98(s,1H),6.88(s,1H),6.84(s,1H),6.69(s,1H),5.66–5.42(m,3H),3.87(s,3H),3.75-3.50(m,5H),3.50-3.40(m,5H),3.00-2.70(m,5H),2.39-2.23(m,7H),2.00-1.84(m,4H),1.75-1.63(m,6H),1.59-1.18(m,13H),1.13-0.96(m,4H).
实施例10:1-(2-氯-5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-(乙氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
向1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮(70mg,0.071mmol)的THF(3ml)溶液中加入乙醛(40%水溶液,16mg,0.142mmol),混合液在室温搅拌30分钟后,加入三乙酰氧基硼氢化钠(75mg,0.355mmol)并室温搅拌过夜。反应液用水(15mL)稀释,DCM(20×3ml)萃取,无水Na
2SO
4干燥,过滤并减压浓缩,所得粗品经prep-HPLC纯化得到1-(2-氯-5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-(乙氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1014.3.
1H NMR(400MHz,DMSO-d
6)δ10.52(s,1H),8.13(s,1H),8.07(s,1H),7.64(d,J=8.3Hz,1H),7.55(s,1H),7.39(d,J=8.0Hz,1H),7.00(s,1H),6.90(d,J=6.5Hz,2H),6.64(s,1H),6.05(s,1H),5.60(t,J=6.4Hz,1H),3.89(s,3H),3.75-3.40(m,8H),3.11–3.00(m,2H),3.00-2.90(m,1H),2.87-2.70(m,2H),2.70-2.60(m,1H),2.40-2.25(m,7H),2.18-2.07(m,2H),1.90-1.75(m,4H),1.75-1.20(m,18H),1.18-0.96(m,7H).
实施例11:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-甲氧基苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:5-氨基-2-氯吡啶-4-甲酰胺的制备
将5-氨基-2-氯吡啶-4-羧酸(14.0g,81.13mmol)用DCM(200mL)溶解,HOBt(13.2g,97.67mmol)和EDCI(18.7g,97.67mmol)加入,常温搅拌1h,加入NH
3H
2O(200mL)搅拌2h,过滤,减压浓缩,得到粗品5-氨基-2-氯吡啶-4-甲酰胺。
LC-MS:(ESI,m/z):[M+H]
+=172.0.
步骤2:4-(5-氨基-4-氨基甲酰吡啶-2-基)环己-3-烯-1-羧酸甲酯的制备
将5-氨基-2-氯吡啶-4-甲酰胺(5.0g,29.24mmol)用Dioxane/H
2O(200mL/20ml)解,Cs
2CO
3(47.51g,146.18mmol),Pd(dppf)Cl
2(2.67g,3.65mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)环己-3-烯-1-羧酸甲酯(10.1g,38.1mmol)分别加入,反应液在氮气保护下升温至100℃搅拌过夜,加水(500ml)稀释,用乙酸乙酯(600ml)萃取,无水硫酸钠干燥,减压浓缩,粗产品用柱层析(PE:EA=1:3)纯化得到4-(5-氨基-4-氨基甲酰吡啶-2-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=276.0.
步骤3:4-(4-羟基-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己-3-烯-1-羧酸甲酯的制备
将4-(5-氨基-4-氨基甲酰吡啶-2-基)环己-3-烯-1-羧酸甲酯(4.0g,14.55mmol)加入到原乙酸三甲酯(17.46g,145.5mmol)的甲醇(100ml)溶液中,使用闷罐120℃搅拌过夜,冷却后减压浓缩,得到粗产品4-(4-羟基-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=300.0.
步骤4:(1R,4R)-4-(4-羟基-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯的制备
将4-(4-羟基-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己-3-烯-1-羧酸甲酯(800mg,3.33mmol)和Pd(OH)
2(320mg)加入到甲醇(50mL)溶液中,反应液用氢气置换3次,升温至70℃搅拌过夜,过滤,减压浓缩,粗品用甲醇(40mL)溶解,甲醇钠(1mL,5.4mmol/L)加入,70℃搅拌过夜,H
2SO
4调节pH至3-4,50℃搅拌过夜,减压浓缩,通过反相制备纯化得到(1R,4R)-4-(4-羟基-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=302.1.
步骤5:(1R,4R)-4-(2-甲基-4-(((2,4,6-三异丙基苯基)磺酰基)氧)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯的制备
将2,4,6-三异丙基苯基磺酰氯(1.0g,3.3mmol)和DMAP(20.3mg,0.165mmol),TEA(503mg,4.98mmol)加入到(1R,4R)-4-(4-羟基-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯(500mg,1.66mmol)的二氯甲烷(30ml)溶液中,常温搅拌过夜,用水(50ml)和饱和食盐水(40mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,通过柱层析(PE:EA=1:3)纯化得到(1R,4R)-4-(2-甲基-4-(((2,4,6-三异丙基苯基)磺酰基)氧)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=568.2.
步骤6:(1R,4R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯的制备
将(1R,4R)-4-(2-甲基-4-(((2,4,6-三异丙基苯基)磺酰基)氧)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯(800mg,1.41mmol)和TEA(546.1mg,4.23mmol)加入到1-(3-硝基-5-(三氟甲基)苯基)乙基-1-胺(462mg,1.97mmol)的DMSO(20mL)溶液中,室温搅拌过夜,粗品使用反相柱层析(ACN/H
2O=2/1)纯化得到(1R,4R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=518.4.
步骤7:(1R,4R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸的制备
将(1R,4R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸甲酯(400mg,0.774mmol)溶解在THF/H
2O(40ml/10ml)溶液中,加入LiOH(93mg,3.87mmol),反应液升温至50℃搅拌过夜,用HCl(1M)调节pH至中性,加水(50ml)溶解,用乙酸乙酯(100ml)萃取,减压浓缩,得到粗品(1R,4R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=504.2.
步骤8:1-(2-甲氧基-5-(4-((2-(1-((1R,4R)-4-(2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(1R,4R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧酸(180mg,0.357mmol),HATU(203.5mg,0.536mmol)和DIEA(138.2mg,1.07mmol)加入到1-(2-甲氧基-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的DMF(6ml)溶液中,室温搅拌过夜,加水(50ml)溶解,用二氯甲烷(30ml×3)萃取,减压浓缩,粗品使用反相柱层析(ACN/H
2O=1/2)纯化得到1-(2-甲氧基-5-(4-((2-(1-((1R,4R)-4-(2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=958.5.
步骤9:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-甲氧基苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1-(2-甲氧基-5-(4-((2-(1-((1R,4R)-4-(2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(300mg,0.313mmol)溶于乙醇(20ml),Raney-Ni(aq.,1mL),水合肼(0.5mL)加入,反应液室温搅拌1小时,过滤,减压浓缩,粗品使用反相制备纯化得到1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-甲氧基苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=928.5.
1H NMR(400MHz,DMSO-d
6)δ10.33(s,1H),8.91(s,1H),8.58(d,J=7.9Hz,1H),8.10(s,1H),7.36(dd,J=8.4,1.9Hz,1H),7.32(d,J=1.9Hz,1H),7.15(d,J=8.5Hz,1H),6.89(s,1H),6.85(s,1H),6.71(s,1H),5.57–5.51(m,3H),4.45-4.33(m,1H),4.00-3.90(m,1H),3.84(s,3H),3.59(t,J=6.6Hz,2H),3.41(t,J=6.2Hz,2H),3.24(d,J=6.2Hz,2H),3.05-2.95(m,2H),2.83-2.70(m,2H),2.70-2.65(m,3H),2.43(s,3H),2.05-1.96(m,2H),1.88-1.40(m,20H),1.23-0.89(m,4H).
实施例12:1-(5-(2-(4-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)哌啶-1-基)-2-氧代乙氧基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(哌啶-4-基甲基)哌嗪-1-羧酸叔丁酯的制备
将4-((1-((苄氧基)羰基)哌啶-4-基)甲基)哌嗪-1-羧酸叔丁酯(500mg,1.20mmol)和Pd/C(100mg)在MeOH(10mL)中的混合物在室温H
2氛围下搅拌2.0h。反应液过滤,减压浓缩得到4-(哌啶-4-基甲基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=284.1.
步骤2:4-((1-(2-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯氧基)乙酰基)哌啶-4-基)甲基)哌嗪-1-羧酸叔丁酯的制备
将2-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯氧基)乙酸(240mg,0.805mmol),4-(哌啶-4-基甲基)哌嗪-1-羧酸叔丁酯(251mg,0.886mmol),HATU(612mg,1.61mmol)和DIEA(312mg,2.42mmol)在DMF(5mL)中的混合物在室温搅拌3h。反应加水(20mL)淬灭,DCM(20mL×2)萃取,分离有机相,用无水Na
2SO
4干燥,过滤,减压浓缩。粗品经层析柱(MeOH:DCM=0-1:24))纯化得到4-((1-(2-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯氧基)乙酰基)哌啶-4-基)甲基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=564.2.
步骤3:1-(2-氯-5-(2-氧代-2-(4-(哌嗪-1-基甲基)哌啶-1-基)乙氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-((1-(2-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯氧基)乙酰基)哌啶-4-基)甲基)哌嗪-1-羧酸叔丁酯(350mg,0.622mmol)的TFA/DCM(10mL/3mL)混合物在室温搅拌2h。反应液直接浓缩得到1-(2-氯-5-(2-氧代-2-(4-(哌嗪-1-基甲基)哌啶-1-基)乙氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=464.2.
步骤4:(3-((R)-1-((6-((1R,4R)-4-(4-((1-(2-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯氧基)乙酰基)哌啶-4-基)甲基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
向1-(2-氯-5-(2-氧代-2-(4-(哌嗪-1-基甲基)哌啶-1-基)乙氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(260mg,0.562mmol),HATU(426mg,1.12mmol)和DIEA(217mg,3.36mmol)的DMF(3mL)溶液中加入(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(405.6mg,0.674mmol)。然后反应液在室温搅拌1h。反应液中加水(20mL)淬灭反应,DCM(20mL×2)萃取,有机相经无水Na
2SO
4干燥,过滤,减压浓缩。粗品经柱层析(MeOH:DCM=0-2:23))纯化得到(3-((R)-1-((6-((1R,4R)-4-(4-((1-(2-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯氧基)乙酰基)哌啶-4-基)甲基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1048.6.
步骤5:1-(5-(2-(4-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)哌啶-1-基)-2-氧代乙氧基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((R)-1-((6-((1R,4R)-4-(4-((1-(2-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯氧基)乙酰基)哌啶-4-基)甲基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(140mg,0.13mmol)的DCM/TFA(3mL/1mL)溶液在室温下搅拌2h。反应液直接减压浓缩,所得粗品经Prep-HPLC(乙腈/0.05%NH
4HCO
3水溶液,5%~95%)纯化得到1-(5-(2-(4-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)哌啶-1-基)-2-氧代乙氧基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=948.4.
1H NMR(400MHz,DMSO-d
6)δ10.47(s,1H),8.24-7.87(m,2H),7.45(d,J=8.9Hz,1H),7.11(d,J=2.9Hz,1H),6.99(s,1H),6.93(dd,J=9.0,3.0Hz,1H),6.86(d,J=10.9Hz,2H),6.70(s,1H),5.67-5.40(m,3H),4.93–4.63(m,2H),4.40-4.24(m,1H),3.89(s,3H),3.82-3.65(m,2H),3.63-3.42(m,4H),3.09-2.89(m,2H),2.77-2.55(m,5H),2.41-2.25(m,7H),2.12(d,J=6.5Hz,2H),1.9-1.48(m,14H),1.15-0.88(m,2H).
实施例13:(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯
步骤1:1-(2-氯-5-(羟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(2.0g,4.61mmol)溶解于无水四氢呋喃中(40mL),氮气保护下降温至-60℃,边搅拌边向上述溶液中滴加氢化铝锂的四氢呋喃溶液(9.22mL,1.0mmol/L)。加完后-60℃下搅拌1小时后,向反应液中滴加饱和氯化铵水溶液(20mL),过滤,母液用乙酸乙酯(30mLx3)提取。有机相用饱和食盐水(100mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩。粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到1-(2-氯-5-(羟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=255.0
步骤2:4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲醛的制备
1-(2-氯-5-(羟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(450mg,1.76mmol)用乙腈(20mL)溶解,加入IBX(988mg,3.53mmol)并升温至80℃搅拌1小时。反应液过滤,滤饼用甲醇(20mLx3)洗涤,滤液减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲醛。
LC-MS:(ESI,m/z):[M+H]
+=253.0.
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),10.01(s,1H),8.06(d,J=1.8Hz,1H),7.93(dd,J=8.2,1.9Hz,1H),7.84(d,J=8.2Hz,1H),3.80(dd,J=16.6,9.3Hz,1H),3.64(dt,J=12.1,6.1Hz,1H),2.77(dd,J=12.5,6.4Hz,2H).
步骤3:4-(3-氧代丙基)哌啶-1-羧酸叔丁酯的制备
将4-(3-羟丙基)哌啶-1-羧酸叔丁酯(500mg,2.05mmol)溶解于乙腈(20mL)中,加入IBX(1.15g,4.11mmol)并升温至70℃搅拌1小时。反应液过滤,滤饼用甲醇(20mLx3)洗涤,滤液减压浓缩,粗品使用柱层析(乙酸乙酯:石油醚=1:1)纯化得到4-(3-氧代丙基)哌啶-1-羧酸叔丁酯。
1H NMR(400MHz,DMSO-d
6)δ9.68(t,J=1.5Hz,1H),3.91(d,J=12.0Hz,2H),2.65(m,2H),2.46(td,J=7.5,1.5Hz,2H),1.61(d,J=13.0Hz,2H),1.46(2H),1.42–1.33(m,10H),0.94(2H).
步骤4:4-((3-(1-(叔丁氧羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯的制备
4-(3-氧代丙基)哌啶-1-羧酸叔丁酯(300mg,1.2mmol)和4-(甲氨基)哌啶-1-羧酸苄酯(308mg,1.2mmol)用四氢呋喃(20mL)溶解,搅拌下加入三乙酰氧基硼氢化钠(1.2g,6.0mmol)。室温下搅拌2小时后,加水(50mL),用二氯甲烷(30mLx3)提取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到4-((3-(1-(叔丁氧羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=474.3.
步骤5:4-(3-(甲基(哌啶-4-基)氨基)丙基)哌啶-1-羧酸叔丁酯的制备
4-((3-(1-(叔丁氧羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯(400mg,0.84mmol)溶于EA(20mL)中,加入Pd(OH)
2/C(200mg,0.28mmol),在氢气氛围下升温至70℃并搅拌过夜。反应液冷却至室温,过滤,滤液减压浓缩得到4-(3-(甲基(哌啶-4-基)氨基)丙基)哌啶-1-羧酸叔丁酯。粗品无需纯化直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=340.3.
步骤6:4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羧酸叔丁酯的制备
4-(3-(甲基(哌啶-4-基)氨基)丙基)哌啶-1-羧酸叔丁酯(280mg,0.82mmol)和4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲醛(311mg,1.23mmol)用四氢呋喃(20mL)溶解,加入三乙酰氧基硼氢化钠(869mg,4.1mmol)。反应液升温至50℃并搅拌2小时,加水(50mL)稀释,用二氯甲烷(30mLx3)提取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=576.2.
步骤7:1-(2-氯-5-((4-(甲基(3-(哌啶-4-基)丙基)氨基)-1-基)甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羧酸叔丁酯(180mg,0.31mmol)用二氯甲烷(5mL)溶解,三氟乙酸(2mL)加入并室温搅拌2小时,直接减压浓缩得到1-(2-氯-5-((4-(甲基(3-(哌啶-4-基)丙基)氨基)-1-基)甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮,无需纯化直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=476.3.
步骤8:(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
1-(2-氯-5-((4-(甲基(3-(哌啶-4-基)丙基)氨基)-1-基)甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(180mg,0.31mmol)溶于DMF(10mL)中,加入(1R,4R)-4-(4-(((R)-1-(3-(叔丁氧羰基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(150mg,0.24mmol),HATU(118mg,0.31mmol)和N,N-二异丙基乙胺(93mg,0.72mmol),室温下搅拌2h,加水(100mL),用乙酸乙酯(30mLx3)提取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1060.5.
步骤9:1-(5-((4-((3-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-基)甲基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(200mg,0.19mmol)用二氯甲烷(5mL)溶解,加入三氟乙酸(2mL),室温搅拌2小时后,反应液减压浓缩,所得油状物用10%甲醇/二氯甲烷混合溶液(20mL)溶解,加入5%碳酸氢钠水溶液(20mL)并搅拌1小时,分离所得有机相经无水硫酸钠干燥,过滤,减压浓缩得到粗品,粗品经Pre-HPLC(CH
3CN/0.08%NH
4HCO
3水溶液,5%~95%)纯化得到1-(5-((4-((3-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-基)甲基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=960.5.
1H NMR(400MHz,DMSO-d
6)δ10.45(s,1H),8.16–8.02(m,2H),7.50(d,J=8.2Hz,1H),7.38(s,1H),7.29(d,J=8.3Hz,1H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.64–5.47(m,3H),4.45-4.35(m, 1H),3.96-3.85(m,4H),3.76–3.54(m,2H),3.47-3.40(m,2H),3.08-2.90(m,2H),2.89-2.77(m,2H),2.77-2.60(m,3H),2.35(s,6H),2.15(s,3H),1.98-1.40(m,23H),1.24-1.18(m,2H),1.08-0.82(m,2H).
实施例14:5-(4-((2-(1-((1S,4S)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮步骤1:2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羧酸的制备
将1,3-二氧代-1,3-二氢异苯并呋喃-5-羧酸(1.0g,5.21mmol)用AcOH(10ml)溶解,乙酸钾(945mg,5.73mmol)和3-氨基哌啶-2,6-二酮盐酸盐(945mg,5.73mmol)加入,反应液加热到90℃搅拌过夜,减压浓缩,水(20mL)加入到粗品中,搅拌10分钟,过滤,滤饼用水洗涤(10mL×3),真空干燥得到粗品2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=303.0.
步骤2:2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羧酸五氟苯酯的制备
将2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羧酸(1.4g,4.64mmol)用DMF(20ml)溶解,DCC(1.43g,6.96mmol)和2,3,4,5,6-五氟苯酚(1.30g,6.96mmol)加入,反应液室温下搅拌过夜,用水(150mL)稀释,乙酸乙酯(100ml×3)萃取,无水硫酸钠干燥,减压浓缩,粗产品通过柱层析(PE:EA=1:1)纯化得到2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羧酸五氟苯酯。
1H NMR(400MHz,DMSO-d
6)δ11.16(s,1H),8.41(dd,J=7.8,1.3Hz,1H),8.28(s,1H),8.06(d,J=7.8Hz,1H),5.20(dd,J=12.8,5.4Hz,1H),2.66–2.47(m,5H).
步骤3:4-(2-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯的制备
将2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羧酸五氟苯酯(480mg,1.02mmol)加入到4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯(400mg,1.22mmol)的DMSO(10mL)中,室温下搅拌过夜,用水(50mL)稀释,乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥,减压浓缩,粗产品通过柱层析(PE:EA=1:10)纯化得到4-(2-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=611.3.
步骤4:2-(2,6-二氧代哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)异吲哚啉-1,3-二酮的制备
将4-(2-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯(250mg,0.41mmol)用DCM(5mL)溶解,三氟乙酸(1mL)加入,反应液室温搅拌过夜,减压浓缩得到粗品2-(2,6-二氧代哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=511.3.
步骤5:(3-((1R)-1-((6-((1S,4S)-4-(4-(2-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
将2-(2,6-二氧代哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)异吲哚啉-1,3-二酮(200mg,0.40mmol),HATU(130mg,0.35mmol)和DIEA(89mg,0.69mmol)加入到(1S,4S)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(140mg,0.23mmol)的DMF(10mL)中,反应液室温搅拌2小时,用水(50mL)稀释,搅拌10分钟,过滤,固体用水洗涤(5mL×2),得到粗产品(3-((1R)-1-((6-((1S,4S)-4-(4-(2-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1095.5.
步骤6:5-(4-((2-(1-((1S,4S)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮的制备
(3-((1R)-1-((6-((1S,4S)-4-(4-(2-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(250mg,0.23mmol)用DCM(5mL)溶解,三氟乙酸(1mL)加入,反应液室温搅拌过夜,减压浓缩,粗品使用反相制备纯化得到5-(4-((2-(1-((1S,4S)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=995.4.
1H NMR(400MHz,DMSO-d
6)δ11.13(s,1H),8.15(s,1H),8.11(d,J=8.1Hz,1H),8.06(s,1H),7.98(d,J=7.6Hz,1H),7.88–7.82(m,2H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.59–5.50(m,3H),5.18(dd,J=12.8,5.4Hz,1H),4.47-4.39(m,2H),3.95-3.85(m,4H),3.41(t,J=6.4Hz,2H),3.24(d,J=5.3Hz,2H),3.12-2.77(m,5H),2.70-2.55(m,4H),2.36(s,3H),2.09-1.40(m,21H),1.22-0.90(m,4H).
实施例15:1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:1-苯基哌啶-2,2,6,6-d
4-4-醇的制备
将三氟乙酸(2.34g,20.5mmol)滴入苄胺(2.19g,20.5mmol)中,加入CD
2O的D
2O溶液(20%,1.5g CD
2O溶于6mL D
2O中),超声10分钟后,20℃搅拌1h至溶液澄清,烯丙基三甲基硅烷(2.56g,22.5mmol)加入,升温至40℃搅拌过夜,用水(10mL)稀释,用碳酸钾固体调节至pH大于9,加水(50mL),乙酸乙酯(50mLx3)提取,饱和食盐水(100mL)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9,洗脱剂中添加1%氨水)纯化得到1-苯基哌啶-2,2,6,6-d
4-4-醇。
LC-MS:(ESI,m/z):[M+H]
+=196.3.
步骤2:哌啶-2,2,6,6-d
4-4-醇的制备
将1-苯基哌啶-2,2,6,6-d
4-4-醇(470mg,2.4mmol)溶解在甲醇(30mL)中,加入Pd/C(100mg)和Pd(OH)
2/C(100mg),氢气环境中70℃搅拌过夜,过滤,减压浓缩,得到哌啶-2,2,6,6-d
4-4-醇。
LC-MS:(ESI,m/z):[M+H]
+=106.4.
步骤3:4-羟基哌啶-1-羧酸-2,2,6,6-d
4叔丁酯的制备
哌啶-2,2,6,6-d
4-4-醇(215mg,2.05mmol)用DCM(10mL)溶解,(Boc)
2O(491mg,2.26mmol),TEA(620mg,6.15mmol)和DMAP(25mg,0.21mmol)加入,室温下搅拌过夜。反应液用水(50mL)稀释,二氯甲烷(50mLx3)提取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(EA:PE=1:1)纯化得到4-羟基哌啶-1-羧酸-2,2,6,6-d
4叔丁酯。
LC-MS:(ESI,m/z):[M+Na]
+=228.
步骤4:4-(吡啶-4-基甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯的制备
将4-羟基哌啶-1-羧酸-2,2,6,6-d
4叔丁酯(200mg,0.98mmol)用THF(20mL)溶解,在0℃下加入NaH(60%,235mg,5.88mmol),搅拌2小时,溴甲基吡啶氢溴酸盐(296mg,1.18mmol)加入,反应液加热到70℃搅拌过夜。用水(50mL)稀释,乙酸乙酯(50mLx3)提取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:19)纯化得到4-(吡啶-4-基甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=297.2.
步骤5:4-(哌啶-4-基甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯的制备
将4-(吡啶-4-基甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯(150mg,0.51mmol)用异丙醇(6mL)和水(7mL)的混合溶液溶解,Pd(OH)
2/C(45mg)加入,氢气环境中70℃搅拌过夜。过滤,减压浓缩,得到4-(哌啶-4-基甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=303.2.
步骤6:4-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯的制备
将4-(哌啶-4-基甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯(130mg,0.43mmol)用DMSO(5mL)溶解,加入DIEA(133mg,1.04mmol)和4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)benzoate苯甲酸五氟苯酯(150mg,0.35mmol),反应液室温搅拌2h,加水(30mL)并搅拌5分钟,用乙酸乙酯(30mLx3)提取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到4-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯。
LC-MS:(ESI,m/z):[M+Na]
+=575.3.
步骤7:1-(2-氯-5-(4-(((哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)哌啶-1-羧酸-2,2,6,6-d
4叔丁酯(130mg,0.24mmol)用DCM(5mL)溶解,三氟乙酸(1mL)加入,室温搅拌2小时,减压浓缩得到1-(2-氯-5-(4-(((哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮,直接用于下一步。
LC-MS:(ESI,m/z):[M+H]
+=453.2.
步骤8:(3-((R)-1-((6-((1R,4R)-4-(4-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)哌啶-1-羰基-2,2,6,6-d
4)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
将1-(2-氯-5-(4-(((哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(130mg,0.29mmol)用DMSO(5mL)溶解,加入(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(130mg,0.22mmol),HATU(110mg,0.29mmol)和DIEA(142mg,1.10mmol),室温搅拌2小时,加水(30mL)并搅拌5分钟,用乙酸乙酯(30mLx3)提取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到(3-((R)-1-((6-((1R,4R)-4-(4-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)哌啶-1-羰基-2,2,6,6-d
4)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1037.5.
步骤9:1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((R)-1-((6-((1R,4R)-4-(4-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)哌啶-1-羰基-2,2,6,6-d
4)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(130mg,0.13mmol)溶于DCM(5mL),TFA(1mL)加入,室温搅拌2小时,减压浓缩,粗品用DCM(20mL)溶解,用饱和碳酸氢钠水溶液(20mL)调节pH至中性,搅拌10分钟,用MeOH/DCM(v:v=1:9,20mL×3)提取,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相制备纯化得到1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=937.4.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.14-8.02(m,2H),7.64(d,J=8.2Hz,1H),7.54(d,J=1.9Hz,1H),7.38(dd,J=8.2,1.9Hz,1H),6.99(s,1H),6.86(d,J=10.5Hz,2H),6.70(s,1H),5.64-5.46(m,3H),4.51-4.39(m,1H),3.88(s,3H),3.75-3.42(m,4H),3.12–3.01(m,1H),2.95(t,J=11.2Hz,1H),2.83–2.57(m,5H),2.35(s,3H),1.95-1.50(m,17H),1.45-1.27(m,2H),1.25-1.07(m,2H).
实施例16:5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-基)-2-(2,4-二氧代环己基)异吲哚啉-1,3-二酮
步骤1:4-(2-((1-(2-(2,4-二氧代环己基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯的制备
向4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯(430mg,1.3mmol)和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(718mg,2.6mmol)的DMF(3mL)溶液中加入DIEA(675mg,3.9mmol),反应混合物加热到110℃并搅拌过夜。反应液倒入水中,用EA(30ml×2),有机相用无水Na
2SO
4干燥,减压浓缩,所得粗品经自动过主机(EA/PE)纯化得到4-(2-((1-(2-(2,4-二氧代环己基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=583.4.
步骤2:2-(2,6-二氧代哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)异吲哚啉-1,3-二酮的制备
将4-(2-((1-(2-(2,4-二氧代环己基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯(210mg,0.36mmol)的HCI/1,4-二氧六环(4M,5mL)溶液在室温搅拌1h。反应液直接浓缩得到2-(2,6-二氧代哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M+H]
+=483.3.
步骤3:5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-基)-2-(2,4-二氧代环己基)异吲哚啉-1,3-二酮的制备
向(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(100mg,0.17mmol和2-(2,6-二氧代哌啶-3-基)-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)异吲哚啉-1,3-二酮(87mg,0.17mmol)的DMF(5mL)溶液中加入HATU(77mg,0.20mmol)和DIEA(65mg,0.51mmol)。反应液在室温搅拌2h。反应液倒入水中,并用EA(20mL×3)萃取,无水Na
2SO
4干燥,减压浓缩,所得粗品经prep-HPLC纯化得到5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-基)-2-(2,4-二氧代环己基)异吲哚啉-1,3-二酮。
LC-MS:(ESI,m/z):[M-H]
-=1057.4.
1H NMR(400MHz,DMSO-d
6)δ11.07(s,1H),8.31(d,J=8.1Hz,1H),8.05(s,1H),7.64(d,J=8.5Hz,1H),7.49–7.38(m,2H),7.36–7.29(m,2H),7.23(dd,J=9.8,1.7Hz,2H),7.02(s,1H),6.96(s,1H),6.03–5.87(m,1H),5.10-5.00(m,1H),4.42-4.31(m,1H),4.10-4.00(m,2H),3.97-3.85(m,4H),3.41(t,J=6.3Hz,2H),3.23(d,J=6.2Hz,2H),3.18–3.07(m,2H),3.05–2.81(m,5H),2.71–2.52(m,3H),2.42(s,3H),2.01(s,6H),1.89- 1.44(m,20H),1.26-0.86(m,4H).
实施例17:(R)-1-(5-(9-(((3-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)氨基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:(3-羟基丙基)(甲基)羧酸苄酯的制备
将3-(甲基氨基)丙烷-1-醇(5.0g,56.17mmol)和氯甲酸苄酯(10.5g,61.79mmol)溶于1,4-二氧六环(40mL)中,再加入氢氧化钠溶液(2mol/L,48mL)在50℃下搅拌0.5小时,直接减压浓缩得到粗品(3-羟基丙基)(甲基)羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=224.3.
步骤2:(3-溴丙基)(甲基)羧酸苄酯的制备
将(3-羟基丙基)(甲基)羧酸苄酯(4.6g,20mmol)溶于四氢呋喃(40mL),三苯基磷(7.8g,30mmol)和四溴化碳(10g,30mmol)分别加入,反应液室温下搅拌2小时,用水(200mL)稀释,乙酸乙酯(200mL×3)萃取,无水硫酸钠干燥,减压浓缩,粗品使用柱层析(PE:EA=1:1)纯化得到(3-溴丙基)(甲基)羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=288.1.
步骤3:(3-(4-溴-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯的制备
将4-溴吡啶-2(1H)-酮(790mg,4.5mmol)用无水DMF(5mL)溶解并降至0℃,NaH(218mg,5.5mmol)加入,反应液搅拌0.5小时,然后在室温下加入(3-溴丙基)(甲基)羧酸苄酯(1.3g,4.5mmol)并搅拌12小时,用水(100mL)稀释,乙酸乙酯(150mL×4)萃取,有机相用饱和食盐水洗(100mL),无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(PE:EA=1:2)纯化得到(3-(4-溴-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯。
LC-MS:(ESI,m/z):(ESI,m/z):[M+H]
+=379.0.
步骤4:甲基(3-(2-氧代-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-1(2H)-基)丙基)羧酸苄酯的制备
将(3-(4-溴-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯(1.2g,3.2mmol)和4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧硼戊烷)(979mg,3.8mmol)用无水1,4-二氧六环溶解,加入Pd(dppf)Cl
2(120mg)和碳酸钾(880mg,6.47mmol)然后在氮气保护下100℃搅拌过夜,用水(100mL)稀释,乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水洗(100mL),无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(乙酸乙酯:石油醚=1:1)纯化得到产品甲基(3-(2-氧代-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-1(2H)-基)丙基)羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=427.4.
步骤5:(3-(4-(4-羟基-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯的制备
将6-溴-2,7-二甲基喹唑啉-4-醇(450mg,1.77mmol)和甲基(3-(2-氧代-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-1(2H)-基)丙基)羧酸苄酯(980mg,2.3mmol)溶于DMF/水溶液中(10/1,4mL)中,加入碳酸钾(480mg,3.5mmol)和Pd(dppf)Cl
2(90mg),氮气置换,在氮气保护下加热到100℃搅拌2小时,用水(50mL)稀释,乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水洗(100mL),无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(DCM:MEOH=10:1)纯化得到产品(3-(4-(4-羟基-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯。
LC-MS:(ESI,m/z):(ESI,m/z):[M+H]
+=473.3.
步骤6:(R)-(3-(4-(4-((1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯的制备
将(3-(4-(4-羟基-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯(480mg,1.02mmol)用DMF(4mL)溶解,加入DBU(388mg,2.55mmol)和BOP(583mg,1.32mmol),在室温下搅拌0.5小时,加入(R)-(3-(1-氨乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(403mg,1.32mmol),反应液加热到70℃搅拌过夜,加水(50mL)稀释,乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(乙酸乙酯:石油醚=1:1)纯化得到产品(R)-(3-(4-(4-((1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=759.4.
步骤7:(R)-(3-(1-((2,7-二甲基-6-(1-(3-(甲基氨基)丙基)-2-氧代-1,2-二氢吡啶-4-基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
将(R)-(3-(4-(4-((1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)羧酸苄酯(300mg,0.4mmol)用乙酸乙酯(4mL)溶解,Pd/C(60mg)加入,置换氢气,在氢气氛围下室温搅拌2小时,过滤浓缩得到粗品(R)-(3-(1-((2,7-二甲基-6-(1-(3-(甲基氨基)丙基)-2-氧代-1,2-二氢吡啶-4-基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=625.5.
步骤8:(R)-9-(((3-(4-(4-((1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)甲基)氨基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将(R)-(3-(1-((2,7-二甲基-6-(1-(3-(甲基氨基)丙基)-2-氧代-1,2-二氢吡啶-4-基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(130mg,0.21mmol)和9-醛基-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(59mg,0.21mmol)用THF(4mL)溶解,三乙酰氧基硼氢化钠(131mg,0.63mmol)加入,在室温下搅拌2小时,用水(50mL)稀释,乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(二氯甲烷:甲醇=10:1)纯化得到产品(R)-9-(((3-(4-(4-((1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)甲基)氨基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=890.5.
步骤9:(R)-1-(3-(((3-氮杂螺[5.5]十一烷-9-基)甲基)(甲基)氨基)丙基)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)吡啶-2(1H)-酮的制备
将(R)-9-(((3-(4-(4-((1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)甲基)氨基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(100mg,0.11mmol),加入到氯化氢的1,4-二氧六环溶液(4M,3mL)在室温下反应2小时,直接减压浓缩得到粗产品(R)-1-(3-(((3-氮杂螺[5.5]十一烷-9-基)甲基)(甲基)氨基)丙基)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)吡啶-2(1H)-酮。
LC-MS:(ESI,m/z):[M+H]
+=690.5.
步骤10:(R)-1-(5-(9-(((3-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)氨基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(R)-1-(3-(((3-氮杂螺[5.5]十一烷-9-基)甲基)(甲基)氨基)丙基)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)吡啶-2(1H)-酮(80mg,0.12mmol)和perfluorophenyl 4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(51mg,0.12mmol)溶于DMSO(3mL),DIEA(60mg,0.48mmol)加入,反应液室温下搅拌2小时,用水(30mL)稀释,乙酸乙酯(30mL*3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品使用Prep-HPLC纯化得到产品(R)-1-(5-(9-(((3-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)-2-氧代吡啶-1(2H)-基)丙基)(甲基)氨基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M-H]
-=940.5.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.36(d,J=8.2Hz,1H),8.29(s,1H),7.73(d,J=6.6Hz,1H),7.63(d,J=8.2Hz,1H),7.54(s,1H),7.50(s,1H),7.38(d,J=8.3Hz,1H),6.88(s,1H),6.84(s,1H),6.69(s,1H),6.42(s,1H),6.36(d,J=7.0Hz,1H),5.60-5.48(m,3H),4.00-3.90(m,2H),3.80-3.50(m,5H),3.29-3.20(m,3H),2.77-2.70(m,2H),2.44-2.26(m,7H),2.20-2.06(m,4H),1.87-1.78(m,2H),1.74-1.65(m,2H),1.62-1.20(m,10H),1.16-0.92(m,4H).
实施例18:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶- 2,4(1H,3H)-二酮
步骤1:4-(2-甲氧基乙氧基)-2-硝基苯甲酸甲酯的制备
在三口瓶中加入2-甲氧基乙烷-1-醇(365mg,4.8mmol),用THF(10mL)溶解,置换三次氮气,在0℃条件下加入t-BuOK(1M/THF,4.2mL,4.2mmol),0℃反应1h后滴加4-氟-2-硝基苯甲酸甲酯(600mg,3.0mmol)的THF(10mL)溶液,继续在0℃反应2h后,加水(50mL),用乙酸乙酯(50mLx3)萃取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(EA:PE=2:3)纯化得到4-(2-甲氧基乙氧基)-2-硝基苯甲酸甲酯。
1H NMR(400MHz,DMSO-d
6)δ7.87(d,J=8.7Hz,1H),7.57(d,J=2.5Hz,1H),7.34(dd,J=8.7,2.5Hz,1H),4.29–4.24(m,2H),3.81(s,3H),3.70–3.66(m,2H),3.31(s,3H).
步骤2:2-氨基-4-(2-甲氧基乙氧基)苯甲酸甲酯的制备
将4-(2-甲氧基乙氧基)-2-硝基苯甲酸甲酯(850mg,3.3mmol),溶于EtOH(20mL),加入Raney-Ni(1mL),在H
2氛围中室温搅拌2h,过滤,减压浓缩,得到2-氨基-4-(2-甲氧基乙氧基)苯甲酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=226.1.
步骤3:2-氨基-5-溴-4-(2-甲氧基乙氧基)苯甲酸甲酯的制备
将2-氨基-4-(2-甲氧基乙氧基)苯甲酸甲酯(680mg,3.0mmol)用DMF(10mL)溶解,0℃加入NBS(484mg,2.7mmol),0℃反应1h,加水(100mL)并搅拌5分钟,用乙酸乙酯(100mLx3)萃取,饱和食盐水(200mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(EA:PE=2:3)纯化得到2-氨基-5-溴-4-(2-甲氧基乙氧基)苯甲酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=304.0.
步骤4:2-氨基-5-溴-4-(2-甲氧基乙氧基)苯甲酸的制备
将2-氨基-5-溴-4-(2-甲氧基乙氧基)苯甲酸甲酯(710mg,2.3mmol)溶于THF/H
2O(15mL,2:1)中,加入LiOH(570mg,23.0mmol),50℃搅拌过夜,加水(20mL),用1M盐酸调节pH至6,用MeOH/DCM混合溶液(1/10,30mL x3)萃取,经无水硫酸钠干燥,过滤,减压浓缩,得到2-氨基-5-溴-4-(2-甲氧基乙氧基)苯甲酸。
LC-MS:(ESI,m/z):[M+3]
+=292.0.
步骤5:6-溴-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-醇的制备
在闷罐中加入2-氨基-5-溴-4-(2-甲氧基乙氧基)苯甲酸(665mg,2.3mmol),用MeOH(20mL)溶解,加入乙酸铵(2.66g,34.5mmol)和原乙酸三甲酯(4.14g,34.5mmol),120℃反应过夜,减压浓缩除去甲醇,加水(50mL),用乙酸乙酯(50mLx3)萃取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:4)纯化得到6-溴-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-醇。
LC-MS:(ESI,m/z):[M+H]
+=312.9.
步骤6:4-(4-羟基-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯的制备
将6-溴-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-醇(210mg,0.67mmol)用DMF/H
2O混合溶液(11mL,10:1)溶解,加入methyl 4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)环己-3-烯-1-羧酸甲酯(233mg,0.88mmol),Na
2CO
3(143mg,1.34mmol)和Pd(dppf)Cl
2(25mg,0.03mmol),在氮气保护下110℃反应过夜,加水(100mL)并搅拌5分钟,用乙酸乙酯(50mLx3)萃取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到4-(4-羟基-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=373.1.
步骤7:(1R,4R)-4-(4-羟基-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
在高压釜中,加入4-(4-羟基-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯(500mg,1.3mmol),用MeOH(30mL)溶解后,加入Pd(OH)
2/C(150mg,20%),在氢气环境中(2MPa)于70℃反应48小时,过滤,减压浓缩,粗品使用反相制备分离得到(1R,4R)-4-(4-羟基-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=375.2.
步骤8:(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
将(1R,4R)-4-(4-羟基-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(80mg,0.21mmol)溶于DMF(5mL),加入BOP(123mg,0.28mmol)和DBU(81mg,0.53mmol),室温搅拌0.5h后,加入(R)- (3-(1-氨基乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(70mg,0.23mmol),并移至70℃油浴中反应过夜,加水(50mL)并搅拌5分钟,用乙酸乙酯(30mLx3)提取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相纯化得到(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=661.2.
步骤9:(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸的制备
将(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(66mg,0.10mmol)溶于THF/H
2O混合溶液(15mL,2:1)中,加入LiOH(48mg,2.0mmol),50℃搅拌过夜,加水(20mL),用浓盐酸调节pH至6,用MeOH/DCM(10%,30mLx3)萃取,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相纯化得到(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=647.4.
步骤10:(3-((R)-1-((6-((1R,4R)-4-(4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
将(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羧酸(50mg,0.08mmol)溶于DMF(5mL),加入1-(2-氯-5-(9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(48mg,0.10mmol),DIEA(52mg,0.40mmol)和pyBOP(50mg,0.10mmol),室温反应1h,加水(50mL)并搅拌5分钟,用乙酸乙酯(30mLx3)萃取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相制备纯化得到(3-((R)-1-((6-((1R,4R)-4-(4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1130.4.
步骤11:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((R)-1-((6-((1R,4R)-4-(4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸 叔丁酯(80mg,0.07mmol)溶于DCM(5mL)中,加入TFA(1mL),室温搅拌1小时,减压浓缩后,加入MeOH/DCM(1:9,20mL)溶解,再加入饱和碳酸氢钠水溶液(20mL)调节pH至中性,搅拌10分钟后,用MeOH/DCM(1:9,20mL×3)萃取,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相制备纯化得到1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-(2-甲氧基乙氧基)-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1030.5.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.12(d,J=7.7Hz,1H),8.05(s,1H),7.63(d,J=8.2Hz,1H),7.55(d,J=1.8Hz,1H),7.39(d,J=8.2Hz,1H),6.98(s,1H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.61–5.48(m,3H),4.22-4.17(m,2H),3.75(d,J=4.6Hz,3H),3.65–3.52(m,3H),3.51-3.41(m,4H),3.36(s,3H),3.02-2.88(m,1H),2.79-2.71(m,2H),2.68-2.60(m,1H),2.29-2.38(m,5H),2.28-2.21(m,2H),2.16-2.06(m,2H),1.95-1.85(m,2H),1.84-1.80(m,2H),1.76-1.19(m,18H),1.17-0.95(m,4H).
实施例19:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-氟苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸苄酯的制备
(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(100mg,0.17mmol)溶解于DMF(8mL)中,4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸苄酯(72mg,0.2mmol),HATU(90mg,0.23mmol)与DIEA(64mg,0.5mmol)分别加入。反应液室温搅拌5小时后,向反应液中加入水(50mL),用乙酸乙酯(30mLx3)萃取,有机相用饱和食盐水(50mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩。粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=945.5.
步骤2:(3-((R)-1-((7-甲氧基-2-甲基-6-((1R,4R)-4-(4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羰基)环己基)喹啉唑-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸苄酯(100mg,0.11mmol)用乙酸乙酯(8mL)溶解,加入Pd(OH)
2/C(50mg,0.14mmol),在氢气氛围下升温至70℃搅拌过夜。反应液冷却至室温,过滤,滤液减压浓缩得到(3-((R)-1-((7-甲氧基-2-甲基-6-((1R,4R)-4-(4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羰基)环己基)喹啉唑-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=811.5.
步骤3:(3-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-氟苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
(3-((R)-1-((7-甲氧基-2-甲基-6-((1R,4R)-4-(4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羰基)环己基)喹啉唑-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(80mg,0.098mmol)用DMSO(8mL)溶解,加入1-(2-氟-5-(五氟苯甲酰)苯基)二氢嘧啶-2,4(1H,3H)-二酮(40mg,0.098mmol)和DIEA(40mg,0.28mmol),室温下搅拌2小时。反应液加入水(100mL),用乙酸乙酯(30mLx3)萃取,有机相用饱和食盐水(50mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到(3-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-氟苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1045.3.
步骤4:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-氟苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
(3-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-氟苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(50mg,0.047mmol)用二氯甲烷(5mL)溶解,加入三氟乙酸(2mL),室温下搅拌2小时。反应液直接减压浓缩,粗品经Prep-HPLC纯化得到1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-氟苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=945.4.
1H NMR(400MHz,MeOD)δ10.52(s,1H),8.19–7.99(m,2H),7.49(d,J=7.9Hz,1H),7.37(d,J=8.3Hz,2H),6.99(s,1H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.65–5.47(m,3H),4.50-4.33(m,2H),3.96-3.85(m,4H),3.74(t,J=6.7Hz,2H),3.41(t,J=6.4Hz,2H),3.23(d,J=6.2Hz,2H),3.08–2.89(m,3H),2.72(t,J=6.7Hz,2H),2.69-2.60(m,1H),2.40-2.30(m,4H),1.99-1.37(m,22H),1.16-0.94(m,4H).
实施例20:1-(5-(4-((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)哌啶-1-羰基-2,2,6,6-d
4)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-((1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)哌啶-1-羧酸叔丁酯-2,2,6,6-d
4的制备
将4-(哌啶-4-基甲氧基)哌啶-1-羧酸叔丁酯-2,2,6,6-d
4(150mg,0.50mmol)用DMF(5mL)溶解,加入(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(150mg,0.25mmol),HATU(123mg,0.32mmol)和DIEA(161mg,1.25mmol),室温搅拌2小时, 加水(50mL)并搅拌5分钟,用乙酸乙酯(30mLx3)提取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到4-((1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)哌啶-1-羧酸叔丁酯-2,2,6,6-d
4。
LC-MS:(ESI,m/z):[M+H]
+=887.4.
步骤2:((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(((哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-基)甲酮的制备
将4-((1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)哌啶-1-羧酸叔丁酯-2,2,6,6-d
4(200mg,0.23mmol)溶于DCM(5mL)中,加入TFA(1mL),室温搅拌2小时,减压浓缩得到((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(((哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-基)甲酮,直接用于下一步。
LC-MS:(ESI,m/z):[M+H]
+=687.4.
步骤3:1-(5-(4-((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)哌啶-1-羰基-2,2,6,6-d
4)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(((哌啶-4-基-2,2,6,6-d
4)氧)甲基)哌啶-1-基)甲酮(200mg,0.29mmol)溶于DMSO(5mL),加入DIEA(149mg,1.15mmol)和4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(100mg,0.23mmol),室温搅拌2h,加水(50mL)并搅拌5分钟,用乙酸乙酯(30mLx3)提取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相制备纯化得到1-(5-(4-((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)哌啶-1-羰基-2,2,6,6-d
4)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):(ESI,m/z):[M+H]
+=937.5.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.13(s,1H),8.09(s,1H),7.63(d,J=8.2Hz,1H),7.57(d,J=1.9Hz,1H),7.40(dd,J=8.2,2.0Hz,1H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.62–5.50(m,3H),4.42(d,J=11.5Hz,1H),4.0–3.92(m,4H),3.74(s,1H),3.67–3.47(m,2H),3.29(d,J=4.5Hz,2H),3.09–2.87(m,2H),2.76-2.73(m,2H),2.67-2.63(m,1H),2.36(s,3H),1.94–1.50(m,17H),1.50–1.38(m,2H),1.16–0.91(m,2H).
实施例21:3-(2-氯-5-(4-((2-(1-(4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)哌啶-2,6-二酮
步骤1:4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-yl)环己-3-烯-1-羧酸甲酯的制备
将(R)-1-(4-溴-2-基)乙烷-1-胺(607mg,3mmol)溶于DMF(5mL),加入BOP(574.6mg,1.3mmol)和DBU(456.0mg,3.0mmol),反应液在室温下搅拌0.5小时,接着向反应液中加入4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯(328mg,1mmol)并升温至70℃反应16小时。反应液用水(50mL)稀释,乙酸乙酯萃取(30mL×3),合并上层有机相并用饱和食盐水洗,无水Na
2SO
4干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-yl)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=516.1.
步骤2:4-(4-(((R)-1-(4-(2-氯-6-苯甲醛)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯的制备
将3-氯-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)苯甲醛(206mg,0.77mmol)和4-(4-(((R)-1-(4-溴噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-yl)环己-3-烯-1-羧酸甲酯(400mg,0.77mmol)溶于DMF/H
2O(3mL/0.3mL),加入Pd(dppf)Cl
2(100mg)和K
2CO
3(214mg,1.55mmol),置换氮气,在氮气保护下100℃搅拌2小时。反应结束后反应液用水(50mL)稀释,乙酸乙酯萃取(30mL×3),合并有机相并用饱和食盐水洗,无水Na
2SO
4干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到4-(4-(((R)-1-(4-(2-氯-6-苯甲醛)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=576.3.
步骤3:4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯的制备
将4-(4-(((R)-1-(4-(2-氯-6-苯甲醛)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯(130mg,0.22mmol)溶于1,2-二氯乙烷(5mL),加入三乙酰氧基硼氢化钠(143mg,0.68mmol),反应液80℃搅拌1小时。反应液用水(50ml)稀释,二氯甲烷萃取(30mL×3),合并有机相,无水Na
2SO
4干燥,减压浓缩,粗品使用柱层析(MeOH:DCM=1:19)纯化得到4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=605.3.
步骤4:4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸的制备
将4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯(170mg,0.28mmol)用MeOH/H
2O(2mL/0.2mL)溶解,加入LiOH(52mg,1.3mmol),反应液加热至60℃搅拌1小时。冷却,用稀盐酸(1.0mol/L)调节pH至3-4,再加入NaHCO
3饱和溶液调节pH至7-8,乙酸乙酯萃取(30mL×3),合并有机相,用无水Na
2SO
4干燥,过滤,减压浓缩得到4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=591.3.
步骤5:3-(2-氯-5-(4-((2-(1-(4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)哌啶-2,6-二酮的制备
将4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸(125mg,0.22mmol)和3-(2-氯-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)哌啶-2,6-二酮(108mg,0.22mmol)用DMF(3mL)溶解,加入HATU(96mg,0.25mmol)和DIEA(82mg,0.64mmol),室温下搅拌1小时。反应液用水(50mL)稀释,乙酸乙酯萃取(30mL×3),有机相用饱和食盐水洗,无水Na
2SO
4干燥,过滤,减压浓缩,粗品使用Prep-HPLC纯化得到产品3-(2-氯-5-(4-((2-(1-(4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)哌啶-2,6-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1049.3.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.41(s,1H),8.05(s,1H),7.63(d,J=8.2Hz,1H),7.54(s,1H),7.48–7.30(m,4H),7.24(s,1H),7.02(s,1H),6.96(s,1H),6.01–5.89(m,1H),5.83(s,1H),4.47-4.37(m,1H),3.99-3.91(m,1H),3.86(s,3H),3.74(s,1H),3.68-3.52(m,2H),3.44-3.37(m,2H),3.26-3.18(m,3H),3.18-2.96(m,3H),2.90-2.82(m,1H),2.81-2.70(m,2H),2.43(s,3H),2.39-2.29(m,2H),2.25-2.16(m,1H),2.03(s,6H),1.89-1.55(m,10H),1.49-1.40(m,2H),1.30-1.20(m,2H),1.20–0.95(m,4H).
实施例22:(1R,4R)-N-(3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-N-甲基环己烷-1-甲酰胺
步骤1:4-(3-羟基丙基)哌啶-1-羧酸苄酯的制备
于0℃下向3-(哌啶-4-基)丙-1-醇(5.00g,34.91mmol)的THF(20mL)溶液中加入CbzCl(5.40ml,38.40 mmol),反应1小时反应完成后,反应液用饱和NaHCO
3水溶液(50mL)淬灭,并用乙酸乙酯(100mLx3)萃取。合并有机相并用盐水(100mL)洗涤,经硫酸钠干燥,过滤,滤液浓缩。粗品通过硅胶柱层析纯化(MeOH:DCM=1:100~1:10),得浅黄色油状的4-(3-羟丙基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=278.2.
步骤2:4-(3-氧代丙基)哌啶-1-羧酸苄酯的制备
于0℃下向4-(3-羟丙基)哌啶-1-甲酸苄酯(3.00g,10.8mmol)的DCM(60mL)溶液中加入Dess-Martin(5.50g,13.0mmol),反应1小时。反应完成后,反应液用饱和Na
2S
2O
3(50mL)和饱和NaHCO
3(50mL)淬灭,并用DCM(80mLx3)萃取。合并有机相并用盐水(100mL)洗涤,经硫酸钠干燥,过滤并旋干。粗品通过硅胶色谱法纯化(EA:PE=3:17~3:7)得到4-(3-氧代丙基)哌啶-1-羧酸苄酯。
1H NMR(400MHz,CDCl
3)δ9.78(s,1H),7.38-7.28(m,5H),5.12(s,2H),4.28-4.02(m,2H),2.90-2.65(m,2H),2.51-2.42(m,2H),1.74-1.54(m,4H),1.51-1.37(m,1H),1.21-1.03(m,2H).
步骤3:4-(3-(甲基氨基)丙基)哌啶-1-羧酸苄酯的制备
向4-(3-氧代丙基)哌啶-1-甲酸苄酯(1.50g,5.45mmol)的THF(10mL)溶液中加入甲胺(846mg,27.24mmol)和AcOH(0.1mL),并在30℃下反应4小时,然后加入NaBH
3CN(684mg,10.90mmol)继续反应16小时。反应完成后,反应液用饱和NaHCO
3(50mL)淬灭并用乙酸乙酯(100mLx3)萃取。合并有机相并用盐水(100mL)洗涤,经硫酸钠干燥,过滤并旋干。粗品通过硅胶色谱法纯化(用NH
3/MeOH:DCM=1:9~2:8)得到4-(3-(甲基氨基)丙基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=291.7.
步骤4:4-(3-((叔丁氧羰基)(甲基)氨基)丙基)哌啶-1-甲酸苄酯的制备
向4-(3-(甲基氨基)丙基)哌啶-1-羧酸苄酯(295mg,1.02mol)的DCM(3mL)溶液中加入(Boc)
2O(1.2mL,5.10mmol)并于室温反应16小时。反应完成后,反应液用水(50mL)淬灭并用乙酸乙酯(50mLx3)萃取。合并有机相并用盐水(100mL)洗涤,经硫酸钠干燥,过滤并旋干。粗品通过硅胶色谱法纯化(NH
3/MeOH:DCM=1:19~1:9)得到4-(3-((叔丁氧羰基)(甲基)氨基)丙基)哌啶-1-甲酸苄酯。
LC-MS:(ESI,m/z):[M-100+H]
+=291.2.
步骤5:甲基(3-哌啶-4-基)丙基)羧酸叔丁酯的制备
向4-(3-((叔丁氧基羰基)(甲基)氨基)丙基)哌啶-1-甲酸苄酯(291mg,0.75mmol)的MeOH(5mL)溶液中加入Pd/C(80mg)并用氢气置换三次,室温反应16小时。将反应液旋干,得到粗品甲基(3-哌啶-4-基)丙基)羧酸叔丁酯,无需进一步纯化即可用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=257.2.
步骤6:(3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)(甲基)羧酸叔丁酯的制备
向甲基(3-(哌啶-4-基)丙基)氨基甲酸叔丁酯(150mg,0.59mmol)的DMSO(2mL)溶液中加入DIEA(232mg,1.8mmol)和4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(381mg,0.88mmol),并于室温下反应16小时。反应完成后,反应液用水(50mL)淬灭并用乙酸乙酯(50mLx3)萃取。合并有机相并用盐水(100mL)洗涤,经硫酸钠干燥,过滤并旋干。粗品通过硅胶色谱法纯化(用NH
3/MeOH:DCM=1:19~1:9)得到目标化合物(3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)(甲基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+Na]
+=529.1.
步骤7:1-(2-氯-5-(4-(3-(甲基氨基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将化合物(3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)(甲基)羧酸叔丁酯(256mg,0.50mmol)溶于DCM(2mL)中,室温下加入TFA(1mL),反应0.5小时。将反应液液浓缩,得到粗品1-(2-氯-5-(4-(3-(甲基氨基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮,无需进一步纯化用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=407.0.
步骤8:(2-(5-((R)-1-((6-((1R,4R)-4-((3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)(甲基)羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苯基)(甲基)羧酸叔丁酯的制备
向化合物(1R,4R)-4-(4-(((R)-1-(4-(2-(((叔丁氧羰基)(甲基)氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(229mg,0.36mmol)的DMF(3mL)溶液中加入1-(2-氯-5-(4-(3-(甲基氨基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(216mg,0.53mmol),TCFH(249mg,0.89mmol)和NMI(146mg,1.78mmol),并于室温下反应16小时。反应完成后,反应液用水(20mL)淬灭并用乙酸乙酯(20mLx3)萃取。合并有机相并用盐水(50mL)洗涤,经硫酸钠干燥,过滤并真空浓缩。粗品通过硅胶色谱法纯化(NH
3/MeOH:DCM=1:19~1:9)得到目标化合物(2-(5-((R)-1-((6-((1R,4R)-4-((3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)(甲基)羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苯基)(甲基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1033.2.
步骤9:(1R,4R)-N-(3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-N-甲基环己烷-1-甲酰胺的制备
在室温下向化合物(2-(5-((R)-1-((6-((1R,4R)-4-((3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)(甲基)羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苯基)(甲基)羧酸叔丁酯(107mg,0.10mmol)的DCM(2mL)溶液中加入TFA(1mL),并反应0.5小时。将反应液液浓缩得粗品,通过高效液相制备色谱纯化得到目标化合物(1R,4R)-N-(3-(1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)丙基)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-N-甲基环己烷-1-甲酰胺。
LC-MS:(ESI,m/z):[M+H]
+=933.4.
1H NMR(400MHz,CD
3OD)δ7.99(s,1H),7.66-7.58(m,1H),7.54-7.48(m,1H),7.43-7.36(m,2H),7.33-7.26(m,3H),7.18(d,J=1.2Hz,1H),7.15-7.11(m,1H),7.01(m,1H),6.08-6.01(m,1H),4.65-4.53(m,1H),3.95(s,3H),3.81-3.69(m,5H),3.48-3.34(m,2H),3.16-3.04(m,4H),2.95-2.68(m,5H),2.52(s,3H),2.22(s,3H),2.00-1.57(m,16H),1.35-1.11(m,4H).
实施例23:1-(2-氯-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基))))苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(2-((1-(叔丁氧羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸苄酯的制备
将化合物4-(2-羟基乙基)哌啶-1-羧酸苄酯(400mg,1.52mmol)溶于THF(5mL)中,加入三乙胺(230mg,2.28mmol)。将反应液冷却至0℃,滴加甲磺酰氯(208mg,1.82mmol)。滴加完毕,升温至室温反应2小时。加入氯化铵水溶液淬灭,乙酸乙酯(20mLx3)萃取,合并有几层并用饱和盐水洗涤,无水硫酸钠干燥,过滤浓缩得中间体。将此中间产物溶于四氢呋喃,加入到叔丁醇钾(340mg,3.04mmol)和化合物4-(羟基甲基)哌啶-1-羧酸叔丁酯(652mg,3.04mmol)的THF(6mL)溶液中,30℃下继续反应16小时。加入水稀释,用乙酸乙酯(20mLx3)萃取,合并有几层并用饱和盐水洗涤,无水硫酸钠干燥,过滤浓缩经柱层析(PE:EA=5:1)纯化得到目标产物4-(2-((1-(叔丁氧羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+Na]
+=483.2.
步骤2:4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸叔丁酯的制备
将化合物4-(2-((1-(叔丁氧羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸苄酯溶于甲醇(180mg,0.39mmol)中,加入钯碳(70mg)。氢气(1个大气压)保护下置换三次,室温下继续反应16小时,硅藻土过滤,滤液浓缩得粗产品4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸叔丁酯,直接用于下一步。
步骤3:4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2- 甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸叔丁酯的制备
向化合物(1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(130mg,0.23mmol)的DMF(2mL)溶液中加入化合物4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸叔丁酯(114mg,0.35mmol),TcFH(162mg,0.58mmol)和NMI(94mg,1.15mmol),并于室温下反应16小时。反应完成后,反应液用水(20mL)淬灭并用乙酸乙酯(20mLx3)萃取。合并有机相并用盐水(50mL)洗涤,经硫酸钠干燥,过滤并真空浓缩。粗品通过柱层析纯化(NH
3/MeOH:DCM=1:19~1:9)得到得目标产物4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=867.3.
步骤4:((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-基)甲酮的制备
室温下将化合物4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羧酸叔丁酯(40mg,0.05mmol)溶于DCM(2mL)中,加入TFA(1mL)。室温下继续反应0.5小时。将反应液浓缩得到粗品((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-基)甲酮,无需进一步纯化直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=767.3.
步骤5:1-(2-氯-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基))))苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
向((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-基)甲酮(50mg,0.07mmol)的DMSO(2mL)溶液中加入DIEA(103mg,0.80mmol)和4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(42mg,0.10mmol),并于室温下反应16小时。反应完成后,反应液用水(10mL)淬灭并用乙酸乙酯(10mLx3)萃取。合并有机相 并用盐水(10mL)洗涤,经硫酸钠干燥,过滤并旋干。粗品通过制备纯化得到1-(2-氯-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基))))苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1017.3.
1H NMR(400MHz,CD
3OD)δ7.99(s,1H),7.65-7.59(m,1H),7.52(s,1H),7.44-7.26(m,5H),7.24-7.16(m,2H),7.01(s,1H),6.11-6.01(m,1H),4.66-4.46(m,2H),4.09-3.98(m,1H),3.95(s,3H),3.81-3.67(m,3H),3.53-3.40(m,4H),3.16-3.00(m,3H),2.93-2.57(m,5H),2.52(s,3H),2.23-2.05(m,7H),1.95-1.57(m,15H),1.56-1.51(m,2H),1.34-1.00(m,7H).
实施例24:(1R,4R)-N-(3-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)丙基)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-N-甲基环己烷-1-甲酰胺
步骤1:(E)-9-(3-乙氧基-3-氧代丙-1-烯-1-基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
0℃下,将NaH(214mg,5.33mmol,60%)加入到DMF(15mL)中,然后加入2-(二乙氧基磷酰基)乙酸乙酯(1.20g,5.33mmol)。0℃反应30分钟,加入9-甲酰基-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1.00g,3.55mmol)并在室温搅拌3h。反应结束,反应液冷却至0℃,加入NH
4Cl水溶液(100mL)稀释,并用乙酸乙酯(100mLx3)萃取。将合并的有机层用食盐水(100mL)洗涤,经硫酸钠干燥,过滤并减压浓缩,经层析柱(PE:EA=0~1:4)纯化得到(E)-9-(3-乙氧基-3-氧代丙-1-烯-1-基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H-56]
+=296.2.
步骤2:9-(3-乙氧基-3-氧代丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将(E)-9-(3-乙氧基-3-氧代丙-1-烯-1-基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1.1g,3.13mmol)的EtOH(20mL)溶液在H
2气氛和室温下加入Pd/C(150mg)并搅拌过夜。将混合物过滤并浓缩得到9-(3-乙氧基-3-氧代丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H-56]
+=298.2.
1H NMR(400MHz,CDCl
3)δ4.12(q,J=7.2Hz,2H),3.40-3.30(m,4H),2.30(t,J=7.6Hz,2H),1.71-1.62(m,2H),1.58-1.52(m,5H),1.47-1.42(m,10H),1.31-1.22(m,6H),1.13-1.02(m,4H).
步骤3:9-(3-羟丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将9-(3-乙氧基-3-氧代丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1g,2.83mmol)溶于THF(25mL)中,0℃下滴加LAH(3.4mmol,3.4mL,1M/THF)。在0℃下继续反应1h,然后加入Na
2SO
4.10H
2O淬灭,并搅拌20分钟以上。将混合物过滤,滤液浓缩得到9-(3-羟丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯,直接用于下一步反应。
1H NMR(400MHz,CDCl
3)δ3.63(t,J=7.2Hz,2H),3.42-3.29(m,4H),1.69-1.53(m,6H),1.46-1.42(m,10H),1.32-1.22(m,6H),1.12-1.03(m,4H).
步骤4:9-(3-氧代丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
向9-(3-羟丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(850mg,2.7mmol)的DCM(25mL)溶液中分批加入戴斯-马丁氧化剂(1.37g,3.3mmol)。将混合物在室温搅拌1.5h。加入Na
2SO
3(50mL)和NaHCO
3(50mL)水溶液淬灭,并用DCM(100mLx3)萃取。合并的有机层用无水硫酸钠干燥,过滤,滤液浓缩并通过硅胶柱层析(PE:EtOAc=20:1~2:1)纯化得到9-(3-氧代丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H-100]
+=210.2.
步骤5:9-(3-((4-甲氧基苄基)(甲基)氨基)丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将9-(3-氧代丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(400mg,1.29mmol)和1-(4-甲氧基苯基)-N-甲基甲胺(0.39g,2.58mmol)溶于DCM/AcOH(25mL/0.5mL)中,室温搅拌1h。然后加入NaBH
3CN(162mg,2.58mmol),室温反应16小时。反应液加入NH
4Cl水溶液(50mL)稀释,并用DCM(50mLx3)萃取。合并的有机层经硫酸钠干燥,过滤,滤液浓缩并经层析柱(DCM:MeOH=200:1~5:1)纯化得到9-(3-((4-甲氧基苄基)(甲基)氨基)丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=445.4.
步骤6:N-(4-甲氧基苄基)-N-甲基-3-(3-氮杂螺[5.5]十一烷-9-基)丙烷-1-胺的制备
将9-(3-((4-甲氧基苄基)(甲基)氨基)丙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(400mg,0.89mmol)溶于DCM(4.5mL)中,加入TFA(1.5mL)。反应液室温搅拌2h,浓缩得到N-(4-甲氧基苄基)-N-甲基-3-(3-氮杂螺[5.5]十一烷-9-基)丙烷-1-胺,直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=345.3.
步骤7:1-(2-氯-5-(9-(3-((4-甲氧基苄基)(甲基)氨基)丙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
向N-(4-甲氧基苄基)-N-甲基-3-(3-氮杂螺[5.5]十一烷-9-基)丙烷-1-胺(400mg,0.9mmol)的DMSO(2mL)溶液中加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸全五氟苯酯(470mg,1.08mmol)和DIEA(350mg,2.7mmol)。将反应液在室温搅拌2h。加入水(10mL),并用EtOAc(20mLx2)萃取。合并有机层并用饱和盐水(50mLx3)洗涤,经无水硫酸钠干燥,过滤,滤液浓缩并经柱层析(DCM:MeOH=200:1~5:1)纯化 得到1-(2-氯-5-(9-(3-((4-甲氧基苄基)(甲基)氨基)丙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=595.2.
步骤8:1-(2-氯-5-(9-(3-(甲基氨基)丙基)-3-)氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1-(2-氯-5-(9-(3-((4-甲氧基苄基)(甲基)氨基)丙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(130mg,0.218mmol)和DIEA(14mg,0.11mmol)溶于DCM(3mL)中,0℃滴加氯甲酸2-氯乙酯(47mg,0.33mmol)。将混合物在室温下搅拌2h。然后加入MeOH(3mL),在65℃下反应1h。将混合物浓缩并经柱层析(DCM:MeOH=200:1~5:1)纯化得到1-(2-氯-5-(9-(3-(甲基氨基)丙基)-3-)氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=475.2.
步骤9:(2-(5-((R)-1-((6-((1R,4R)-4-((3-(3-(4-氯-3-(2,4-二氧四氢嘧啶))-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)丙基)(甲基)氨基甲酰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)氨基羧酸叔丁酯的制备
将1-(2-氯-5-(9-(3-(甲基氨基)丙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(100mg,0.21mmol)溶于DMSO(2mL)中,加入(1R,4R)-4-(4-(((R)-1-(4-(2-(((叔丁氧羰基)(甲基)氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸五氟苯酯(187mg,0.23mmol)和DIEA(82mg,0.63mmol),室温下反应2h。反应结束,加入水(2mL)并用乙酸乙酯和水萃取。合并的有机层用硫酸钠干燥,过滤并浓缩,经层析柱(DCM:MeOH=100:1~5:1)纯化得到目标化合物(2-(5-((R)-1-((6-((1R,4R)-4-((3-(3-(4-氯-3-(2,4-二氧四氢嘧啶))-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)丙基)(甲基)氨基甲酰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)氨基羧酸叔丁酯。
LC-MS:(ESI,m/z):[1/2(M-100)+H]
+=501.2.
步骤10:(1R,4R)-N-(3-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)丙基)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-N-甲基环己烷-1-甲酰胺的制备
化合物(2-(5-((R)-1-((6-((1R,4R)-4-((3-(3-(4-氯-3-(2,4-二氧四氢嘧啶))-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)丙基)(甲基)氨基甲酰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)氨基羧酸叔丁酯(170mg,粗品)溶于DCM(4.5mL),加入TFA(1.5mL)。将混合物在室温搅拌2h,浓缩并通过高效液相色谱制备纯化得到(1R,4R)-N-(3-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)丙基)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-N-甲基环己烷-1-甲酰胺。
LC-MS:(ESI,m/z):[M+H]
+=1001.4.
1H NMR(400MHz,CD
3OD)δ8.02-7.96(m,1H),7.65-7.58(m,1H),7.54-7.48(m,1H),7.42-7.36(m,2H),7.32-7.26(m,3H),7.20-7.10(m,2H),7.01(s,1H),6.06(q,J=6.8Hz,1H),3.95(s,3H),3.80-3.63(m,6H),3.48-3.34(m,4H),3.16-2.99(m,3H),2.93-2.82(m,3H),2.76-2.62(m,1H),2.52(s,3H),2.22(s,3H),2.03-1.85(m,4H),1.80-1.42(m,16H),1.37-1.15(m,8H).
实施例25:1-(2-氯-5-(9-(2-(4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-))4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:9-(2-乙氧基-2-氧代亚乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
向搅拌的NaH(230mg,5.61mmol,60%)的DMF(15mL)溶液中加入2-(二乙氧基磷酰基)乙酸乙酯(1.26g,5.61mmol)。将混合物在0℃搅拌30分钟,然后加入9-氧代-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1g,3.74mmol)并在室温搅拌3h。混合物用NH
4Cl(100mL)水溶液,并用乙酸乙酯(100mLx3)萃取。将合并的有机层用盐水(100mL)洗涤,经硫酸钠干燥,过滤并减压浓缩,经柱层析纯化(EA:PE=0~1:4)得到9-(2-乙氧基-2-氧代亚乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=338.3.
步骤2:9-(2-乙氧基-2-氧代乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将9-(2-乙氧基-2-氧代亚乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1.1g,3.26mmol)溶于EtOH(20mL)中,在H
2氛围下搅拌过夜。将混合物过滤并浓缩得到9-(2-乙氧基-2-氧代乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H-56]
+=284.2.
步骤3:9-(2-羟基乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
搅拌下向9-(2-乙氧基-2-氧代乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1g,3mmol)的THF(25mL)溶液中加入LAH(3.6mmol,3.6mL,1M/THF),在0℃至室温下反应1h。室温下向混合物中加入Na
2SO
4.10H
2O并搅拌1h以上。将混合物过滤并浓缩得到目标化合物9-(2-羟基乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H-56]
+=242.2.
步骤4:9-(2-氧代乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
搅拌下向9-(2-羟基乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(850mg,2.5mmol)DCM(25mL)溶液中加入戴斯-马丁氧化剂(1.42g,3.6mmol)。将混合物在室温搅拌1.5h。混合物用Na
2SO
3(50mL)和NaHCO
3(50mL)水溶液稀释,并用DCM(100mLx3)萃取。合并的有机层用硫酸钠干燥,过滤并减压浓缩,经柱层析(EA:PE=0~3:2)纯化得到9-(2-氧代乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H-56]
+=240.2.
步骤5:9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
搅拌下向9-(2-氧代乙基)-3-氮杂螺[5.5]十一烷-3-甲酸叔丁酯(750mg,2.54mmol)的DCM/HAc(25mL/0.5mL)溶液中加入1-(4-甲氧基苄基)哌嗪(0.79g,3.81mmol)。将混合物在室温搅拌1h。然后加入NaBH
3CN(320mg,5.08mmol)。混合物用NH
4Cl(50mL)水溶液稀释,并用DCM(50mLx3)萃取。合并的有机层用硫酸钠干燥,过滤并减压浓缩,经柱层析(DCM:MeOH=0~1:4)纯化得到9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=486.4.
步骤6:9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷的制备
搅拌下向9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(100mg,0.21mmol)的DCM(1.5mL)溶液中滴加TFA(0.5mL)。将混合物在室温搅拌2h,反应液减压浓缩得到9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷。
LC-MS:(ESI,m/z):[M+H]
+=386.4.
步骤7:1-(2-氯-5-(9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
向9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷(100mg,粗品)在DMSO(2mL)中的搅拌溶液中加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(99mg,0.23mmol)和DIEA(80mg,0.62mmol)。将混合物在室温搅拌2h并用EA和水萃取。合并的有机层经硫酸钠干燥,过滤并减压浓缩,经柱层析(DCM:MeOH=0~1:4)纯化得到1-(2-氯-5-(9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=636.4.
步骤8:1-(2-氯-5-(9-(2-(哌嗪-1-基)乙基)))-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1-(2-氯-5-(9-(2-(4-(4-甲氧基苄基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(90mg,0.14mmol)溶于DCM(2mL)中,加入氯甲酸2-氯乙酯(30mg,0.22mmol)和DIEA(9mg,0.071mmol)。将混合物在0℃至室温下搅拌2h。然后在65℃下再加入MeOH(3mL)并继续搅拌1h。将混合物浓缩并经柱层析(DCM:MeOH=0~1:4)纯化得到1-(2-氯-5-(9-(2-(哌嗪-1-基)乙基)))-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=516.3.
步骤9:(2-(5-((R)-1-((6-((1R,4R)-4-(4-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)乙基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)氨基羧酸叔丁酯的制备
将1-(2-氯-5-(9-(2-(哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(63mg,0.12mmol)溶于DMSO(2mL)中,加入(1R,4R)-4-(4-(((R)-1-(4-(2-(((叔丁氧基羰基)(甲基)氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸五氟苯酯(109mg,0.13mmol)和DIEA(48mg,0.36mmol)。将混合物在室温搅拌2h并用EA和水萃取。合并的有机层用硫酸钠干燥,过滤并浓缩得到(2-(5-((R)-1-((6-((1R,4R)-4-(4-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)乙基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)氨基羧酸叔丁酯。
LC-MS:(ESI,m/z):[(M-56)/2+H]+=544.3.
步骤10:1-(2-氯-5-(9-(2-(4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-))4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶- 2,4(1H,3H)-二酮的制备
将(2-(5-((R)-1-((6-((1R,4R)-4-(4-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰基)-3-氮杂螺[5.5]十一烷-9-基)乙基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)氨基甲羧酸叔丁酯(160mg,粗品)溶于DCM(4.5mL)中,加入TFA(1.5mL)。将混合物在室温搅拌2h,浓缩并通过制备纯化得到1-(2-氯-5-(9-(2-(4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-))4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1042.4.
1H NMR(400MHz,CD
3OD)δ7.98(s,1H),7.68-7.56(m,1H),7.57-7.48(m,1H),7.45-7.35(m,2H),7.34-7.24(m,3H),7.22-7.10(m,2H),7.01(s,1H),6.06(q,J=6.9Hz,1H),3.95(s,3H),3.83-3.73(m,2H),3.74-3.68(m,3H),3.66-3.55(m,4H),3.45-3.34(m,2H),3.12-3.01(m,1H),2.93-2.76(m,2H),2.76-2.66(m,1H),2.55-2.39(m,8H),2.21(s,3H),2.03-1.86(m,4H),1.81-1.75(m,4H),1.70-1.57(m,6H),1.45-1.16(m,14H).
实施例26:1-(5-(9-((4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:9-((4-(叔丁氧羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯的制备
将9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯(400mg,1.04mmol)用DCM(10mL)溶解,分别加入(Boc)
2O(272mg,1.25mmol),DMAP(13mg,0.1mmol)和TEA(315mg,3.12mmol),反应液室温下搅拌过夜,直接减压浓缩。粗品使用柱层析(PE:EA=1:1)纯化得到9-((4-(叔丁氧羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=486.3.
步骤2:4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸叔丁酯的制备
将9-((4-(叔丁氧羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯(300mg,0.62mmol)用乙酸乙酯(10mL)溶解,加入Pd(OH)
2/C(100mg),反应液70℃下搅拌3小时,冷却,过滤,固体用乙酸乙酯(10mL×3)洗三次,减压浓缩,得到粗品4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=352.2.
步骤3:4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸叔丁酯的制备
将4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸叔丁酯(200mg,0.57mmol)用DMSO(10mL)溶解,加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-yl)苯甲酸五氟苯酯(247mg,0.57mmol)和DIEA(220mg,1.71mmol),反应液室温下搅拌2小时,加入水(50mL),用乙酸乙酯(25mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,粗品使用柱层析(PE:EA=1:10)纯化得到4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=602.2.
步骤4:1-(2-氯-5-(9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸叔丁酯(350mg,0.58mmol)用DCM(5mL)溶解,加入TFA(1mL),然后反应液室温搅拌2小时,减压浓缩,残余物用水(20mL)稀释,缓慢滴加饱和碳酸氢钠溶液将反应液调至中性,用乙酸乙酯(25mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩得到粗品1-(2-氯-5-(9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=502.3.
步骤5:(3-((1R)-1-((6-(4-(4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己烷-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
将1-(2-氯-5-(9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(125mg,0.25mmol)用DMF(10mL)溶解,分别加入4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸(140mg,0.23mmol),HATU(114mg,0.30mmol)和DIEA(129mg,1.00mmol),反应液室温搅拌2小时,加入水(100mL),析出固体,过滤,水洗3次,用二氯甲烷溶解,无水硫酸钠干燥,减压浓缩,粗品使用柱层析(MeOH:DCM=1:10)纯化得到(3-((1R)-1-((6-(4-(4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己烷-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1095.5.
步骤6:1-(5-(9-((4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((1R)-1-((6-(4-(4-((3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己烷-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(100mg,0.09mmol)用DCM(5mL)溶解,加入TFA(1mL),然后反应液室温搅拌过夜,减压浓缩,用水(20mL)稀释,缓慢滴加碳酸氢钠溶液将反应液调至中性,用二氯甲烷(25mL×4)萃取,无水硫酸钠干燥,减压浓缩,粗品使用反相制备纯化得到1-(5-(9-((4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2- 甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=984.3.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.18(s,1H),8.06(s,1H),7.63(d,J=8.2Hz,1H),7.55(d,J=1.7Hz,1H),7.39(d,J=8.3Hz,1H),6.99(s,1H),6.89(s,1H),6.85(s,1H),6.69(s,1H),5.83(s,1H),5.59-5.47(m,3H),3.85(s,3H),3.80-3.70(m,1H),3.67-3.45(m,7H),2.94-2.82(m,1H),2.77-2.71(m,2H),,2.42-2.10(m,13H),1.89-1.81(m,1H),1.73-1.25(m,15H),1.18-0.94(m,4H).
实施例27:3-(4-(9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)哌啶-2,6-二酮
步骤1:9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将9-醛-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(200mg,0.71mmol)溶于四氢呋喃(4mL)溶液中,加入哌嗪-1-羧酸(9H-芴-9-基)甲基酯(219mg,0.71mmol)和三乙酰氧基硼氢化钠(449mg,2.13mmol),反应液在常温下搅拌过夜,用水(40mL)稀释,乙酸乙酯(80mL×2)萃取,无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(乙酸乙酯:石油醚=1:1)纯化得到9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=574.4.
步骤2:4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸(9H-芴-9-基)甲基酯的制备
将9-((4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(400mg,0.7mmol)溶于氯化氢的1,4-二氧六环(4mmol/L,5mL)溶液中,反应液在室温下搅拌1小时,直接减压浓缩得到4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸(9H-芴-9-基)甲基酯。
LC-MS:(ESI,m/z):[M+H]
+=474.5.
步骤3:4-((3-(4-(2,6-二氧代哌啶-3-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸(9H-芴-9-基)甲基酯的制备
将4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸(9H-芴-9-基)甲基酯(340mg,0.72mmol)用DMSO(4mL)溶解,4-(2,6-二氧代哌啶-3-基)苯甲酸五氟苯酯(287mg,0.72mmol)和DIEA(371mg,2.87mmol)加入,反应液在室温下搅拌过夜,用水(40mL)稀释,乙酸乙酯(40mL×3)萃取,有机相用饱和食盐水(40mL)洗,无水硫酸钠干燥,减压浓缩,粗品使用柱层析(PE:EA=1:2)纯化得到4-((3-(4-(2,6-二氧代哌啶-3-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸(9H-芴-9-基)甲基酯。
LC-MS:(ESI,m/z):[M+H]
+=689.5.
步骤4:3-(4-(9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)哌啶-2,6-二酮的制备
将4-((3-(4-(2,6-二氧代哌啶-3-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羧酸(9H-芴-9-基)甲基酯(250mg,0.36mmol)用二氯甲烷(4mL)溶解,然后加入哌啶(0.25mL),反应液在室温搅拌3小时,直接解压浓缩得到3-(4-(9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)哌啶-2,6-二酮。
LC-MS:(ESI,m/z):[M+H]
+=467.4.
步骤5:3-(4-(9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)哌啶-2,6-二酮的制备
将3-(4-(9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)哌啶-2,6-二酮(200mg,0.43mmol)用DMF(3mL)溶解,(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(254mg,0.43mmol),HATU(196mg,0.52mmol)和DIEA(221mg,1.7mmol)分别加入,反应液室温搅拌3小时,用水(40mL)稀释,乙酸乙酯(40mL×3)萃取,有机相用饱和食盐水(40mL)洗,无水硫酸钠干燥,减压浓缩,粗品使用Prep-HPLC纯化得到3-(4-(9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)哌啶-2,6-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1041.6.
1H NMR(400MHz,DMSO-d
6)δ10.86(s,1H),8.31(d,J=8.5Hz,1H),8.05(s,1H),7.45–7.40(s,2H),7.36–7.32(s,3H),7.28(d,J=8.1Hz,2H),7.24(d,J=1.2Hz,1H),7.01(s,1H),6.96(s,1H),5.99–5.94(m,1H),3.94–3.87(m,4H),3.57(s,2H),3.46(s,5H),3.12(s,2H),2.94(s,1H),2.74–2.59(m,4H),2.42(s,3H),2.23(d,J=13.2Hz,5H),2.17–2.04(m,4H),2.01(s,7H),1.88–1.76(m,5H),1.71(d,J=6.9Hz,4H),1.68(s,1H),1.64–1.48(m,8H),1.23(s,2H),1.07(s,3H).
实施例28:1-(5-(4-((2-(4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌嗪-1-羧酸叔丁酯的制备
将4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(140mg,0.32mmol)用DMSO(5mL)溶解,加入4-(2-(哌啶-4-基甲氧基)乙基)哌嗪-1-羧酸叔丁酯(116mg,0.35mmol)和DIEA(124mg,0.96mmol),室温搅拌2小时,加水(50mL)并搅拌5分钟,用乙酸乙酯(30mLx3)提取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=578.2.
步骤2:1-(2-氯-5-(4-((2-(哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌嗪-1-羧酸叔丁酯(170mg,0.29mmol)溶于DCM(5mL)中,加入TFA(1mL),室温搅拌2小时,减压浓缩得到1-(2-氯-5-(4-((2-(哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮,直接用于下一步。
LC-MS:(ESI,m/z):[M+H]
+=478.2.
步骤3:(3-((1R)-1-((6-(4-(4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌嗪-1-羰基)环己-1-烯-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)本家)羧酸叔丁酯的制备
将1-(2-氯-5-(4-((2-(哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(170mg,0.36mmol)溶于DMF(5mL),加入4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸(150mg,0.25mmol),HATU(124mg,0.32mmol)和DIEA(161mg,1.25mmol),室温搅拌2小时,加水(50mL)并搅拌5分钟,用乙酸乙酯(30mLx3)提取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到(3-((1R)-1-((6-(4-(4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌嗪-1-羰基)环己-1-烯-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)本家)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1060.4.
步骤4:1-(5-(4-((2-(4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((1R)-1-((6-(4-(4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌嗪-1-羰基)环己-1-烯-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)本家)羧酸叔丁酯(140mg,0.13mmol)溶于DCM(5mL)中,加入TFA(1mL),室温搅拌2小时,减压浓缩后,加入MeOH/DCM(1/9,20mL)溶解,再加入饱和碳酸氢钠水溶液(20mL)调节pH至中性,搅拌10分钟后,用MeOH/DCM(1/9,20mL×3)提取,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相制备纯化得到1-(5-(4-((2-(4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=960.4.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.18(d,J=7.8Hz,1H),8.06(s,1H),7.63(d,J=8.2Hz,1H),7.54(d,J=2.0Hz,1H),7.38(dd,J=8.2,2.0Hz,1H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.69(s,1H),5.83(s,1H),5.55–5.45(m,3H),4.50-4.36(m,1H),3.85(s,3H),3.75(d,J=7.2Hz,1H),3.67–3.37(m,9H), 3.06(s,1H),2.87(s,1H),2.81–2.69(m,3H),2.47–2.16(m,13H),1.89–1.41(m,9H),1.20–1.13(m,2H).
实施例29:1-(2-氯-5-(4-(3-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(3-(对甲苯磺酰)丙基)哌啶-1-羧酸叔丁酯的制备
将4-(3-羟基丙基)哌啶-1-羧酸叔丁酯(3.6g,14.81mmol)用二氯甲烷(20mL)溶解,分别加入TsCl(3.4g,17.80mmol),DMAP(180mg,1.48mmol)和TEA(4.5g,44.43mmol),反应液室温搅拌过夜,反应液直接减压浓缩,粗品经柱层析(PE:EA=5:1)纯化得到4-(3-(对甲苯磺酰)丙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=398.1.
步骤2:4-(3-(1-(叔丁氧羰基)哌啶-4-基)丙氧基)哌啶-1-羧酸苄酯的制备
将4-羟基哌啶-1-羧酸苄酯(4.4g,18.51mmol)用无水DMF(10mL)溶解并冷却到0℃,加入NaH(0.6g,24.68mmol),搅拌0.5小时,然后室温搅拌1小时,4-(3-(对甲苯磺酰)丙基)哌啶-1-羧酸叔丁酯(4.9g,12.34mmol)加入,反应液室温搅拌过夜。水(100mL)加入,用乙酸乙酯(100mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,粗品经柱层析(PE:EA=5:1)纯化得到4-(3-(1-(叔丁氧羰基)哌啶-4-基)丙氧基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=461.2.
步骤3:4-(3-(哌啶-4-氧基)丙基)哌啶-1-羧酸叔丁酯的制备
将4-(3-(1-(叔丁氧羰基)哌啶-4-基)丙氧基)哌啶-1-羧酸苄酯(540mg,1.17mmol)用乙酸乙酯(10mL)溶解,加入Pd(OH)
2/C(20%,170mg),反应液加热到70℃搅拌3小时,冷却,过滤,固体用乙酸乙酯(20mL×3)洗三次,减压浓缩得到粗品4-(3-(哌啶-4-氧基)丙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=327.3.
步骤4:4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧基)丙基)哌啶-1-羧酸叔丁酯的制备
将4-(3-(哌啶-4-氧基)丙基)哌啶-1-羧酸叔丁酯(150mg,0.46mmol)用DMSO(10mL)溶解,分别加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(200mg,0.46mmol)和DIEA(178mg,1.38mmol),反应液室温搅拌2小时,加入水(50mL),用乙酸乙酯(25mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,粗品经柱层析(PE:EA=1:10)纯化得到4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧基)丙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=577.3.
步骤5:1-(2-氯-5-(4-(3-(哌啶-4-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧基)丙基)哌啶-1-羧酸叔丁酯(220mg,0.58mmol)用DCM(5mL)溶解,加入TFA(1mL),反应液室温搅拌过夜,减压浓缩,用水(10mL)稀释,缓慢滴加饱和碳酸氢钠溶液,将反应液调至中性,用乙酸乙酯(25mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩得到粗品1-(2-氯-5-(4-(3-(哌啶-4-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=477.2.
步骤6:1-(2-氯-5-(4-(3-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1-(2-氯-5-(4-(3-(哌啶-4-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(71mg,0.14mmol),HATU(63mg,0.17mmol)和DIEA(54mg,0.42mmol)加入到(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(80mg,0.14mmol)的DMF(10mL)溶液中,反应液室温搅拌2小时,加入水(100mL),用乙酸乙酯(25mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,粗品使用反相制备纯化得到1-(2-氯-5-(4-(3-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1051.4.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.31(d,J=8.4Hz,1H),8.06(s,1H),7.64(d,J=8.2Hz,1H),7.57(s,1H),7.42(d,J=8.5Hz,2H),7.36(d,J=7.8Hz,1H),7.24(s,1H),7.02(s,1H),6.97(s,1H),5.97(s,1H),4.45-4.35(m,1H),3.98-3.84(m,5H),3.82-3.71(m,1H),3.67-3.57(m,1H),3.61-3.50(m,2H),3.41(t,J=6.3Hz,3H),3.18-2.90(m,6H),2.78-2.70(m,1H),2.70-2.60(m,1H),2.43(s,3H),2.02(s,6H),1.90-1.40(m,20H),1.30-1.21(m,2H),1.08-0.87(m,2H).
实施例30:1-(2-氯-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(1,1-二氧化物-2,3-二氢苯并[b]噻吩-4-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
4-(4-((1-(1,1-二氧化物-2,3-二氢苯并[b]噻吩-4-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(70mg,0.14mmol)用DMF(3mL)溶解,1-(2-氯-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(73.3mg,0.15mmol),HATU(79.8mg,0.21mmol)和DIEA(91mg,0.7mmol)分别加 入,反应液室温搅拌1小时,用水(40mL)稀释,乙酸乙酯(40mL×3)萃取,有机相用饱和食盐水(40mL)洗,无水硫酸钠干燥,减压浓缩,粗品使用prep-HPLC纯化得到1-(2-氯-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(1,1-二氧化物-2,3-二氢苯并[b]噻吩-4-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=968.4.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.27(d,J=7.0Hz,1H),8.06(s,1H),7.80(d,J=7.6Hz,1H),7.67-7.57(m,2H),7.56–7.48(m,2H),7.38(d,J=8.4Hz,1H),6.98(s,1H),5.59(t,J=7.4Hz,1H),4.39(d,J=11.8Hz,2H),3.91(s,1H),3.87(s,3H),3.81-3.70(m,2H),3.67–3.59(m,3H),3.54-3.46(m,1H),3.42(t,J=6.4Hz,2H),3.29(s,1H),3.24(d,J=6.4Hz,2H),3.11–2.90(m,3H),2.82-2.62(m,4H),2.32(s,3H),2.12–1.23(m,20H),1.20-0.90(m,4H).
实施例31:1-(2-氯-5-(4-(4-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丁基)哌嗪-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(4-(4-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌嗪-1-基)丁基)哌啶-1-羧酸叔丁酯的制备
将4-(4-(哌嗪-1-基)丁基)哌啶-1-羧酸叔丁酯(100mg,0.31mmol)和4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(133mg,0.31mmol)溶于DMSO(3mL)中,搅拌下加入DIEA(198mg,1.54mmol),室温下搅拌1小时。反应结束后反应液倒入水(30mL)中,EA萃取(30mL×3),合并有机相,并用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,粗品使用柱层析(DCM:MeOH=10:1)纯化得到4-(4-(4-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌嗪-1-基)丁基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=576.3.
步骤2:1-(2-氯-5-(4-(4-(哌啶-4-基)丁基)哌嗪-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-(4-(4-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌嗪-1-基)丁基)哌啶-1-羧酸叔丁酯(112mg,0.19mmol)溶于DCM(2mL)中,加入0.2mL TFA,反应液室温下反应1小时,直接减压浓缩得到1-(2-氯-5-(4-(4-(哌啶-4-基)丁基)哌嗪-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=476.3
步骤3:1-(2-氯-5-(4-(4-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丁基)哌嗪-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1-(2-氯-5-(4-(4-(哌啶-4-基)丁基)哌嗪-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(165mg,0.195mmol)和(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(115mg,0.195mmol),溶于DMF(3mL)中,搅拌下加入HATU(86mg,0.227mmol)和DIEA(75mg,0.584mmol),室温下反应1h。反应结束后反应液倒入水(50mL)中,EA萃取(30mL×3),合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,粗品使用prep-HPLC纯化得到1-(2-氯-5-(4-(4-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丁基)哌嗪-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮.
LC-MS:(ESI,m/z):[M+H]
+=1050.7.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.30(d,J=8.3Hz,1H),8.05(s,1H),7.64(d,J=8.2Hz,1H),7.56(d,J=2.0Hz,1H),7.46–7.30(m,4H),7.24(d,J=1.4Hz,1H),7.02(s,1H),6.96(s,1H),5.96(dd,J=14.4,7.2Hz,1H),4.40(d,J=11.5Hz,1H),3.89(s,4H),3.78–3.71(m,1H),3.62(d,J=6.0Hz,3H),3.11(d,J=15.8Hz,2H),3.01-2.92(m,2H),2.76-2.63(m,2H),2.68–2.58(m,2H),2.42(s,6H),2.34–2.18(m,4H),2.01(s,6H),1.85(d,J=9.6Hz,2H),1.79(d,J=11.5Hz,2H),1.72(d,J=7.0Hz,4H),1.65(d,J=12.4Hz,2H),1.60–1.50(m,3H),1.42(d,J=7.4Hz,3H),1.34–1.14(m,5H),1.02–0.82(m,2H).
实施例32:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-(三氟甲基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯的制备
将4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯(100mg,0.31mmol),3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-(三氟甲基)苯甲酸五氟苯酯(133mg,0.31mmol)溶于DMSO(3mL)中,搅拌下加入DIEA(198mg,1.54mmol),室温下反应1小时。反应结束后用水(30mL)稀释,乙酸乙酯萃取(30mL×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析分离得到4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-(三氟甲基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+Na]
+=633.2.
步骤2:1-(5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-(三氟甲基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯(112mg,0.19mmol)溶于二氯甲烷(2mL)中,加入三氟乙酸(0.8mL),反应液室温下反应1h。反应结束后反应液减压浓缩得到1-(5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮,无需纯化直接用于下一步反应。
步骤3:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1-(5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(TFA盐,165mg,0.195mmol)和(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(115.3mg,0.195mmol)溶于DMF(3mL)中,搅拌下加入HATU(86.3mg,0.227mmol)和DIEA(75.4mg,0.584mmol)。反应液室温下反应1h。反应结束后用水(30mL)稀释,乙酸乙酯萃取(30mL×3),合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品使用prep-HPLC纯化得到1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1085.5.
1H NMR(400MHz,DMSO-d
6)δ10.53(s,1H),8.31(d,J=8.1Hz,1H),8.05(s,1H),7.87(d,J=8.1Hz,1H),7.70(s,1H),7.58(d,J=8.0Hz,1H),7.43(t,J=8.0Hz,2H),7.37–7.31(m,1H),7.24(d,J=1.3Hz,1H),7.02(s,1H),6.96(s,1H),6.00-5.92(m,1H),4.53-4.31(m,2H),3.94–3.82(m,5H),3.52-3.37(m,4H),3.23(d,J=6.1Hz,2H),3.12(d,J=2.1Hz,2H),3.07–2.90(m,3H),2.85-2.74(m,1H),2.72-2.58(m,3H),2.42(s,3H),2.01(s,6H),1.89-1.50(m,18H),1.48-1.40(m,2H),1.21-0.91(m,4H).
实施例33:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-(三氟甲氧基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯的制备
将3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-(三氟甲氧基)苯甲酸五氟苯酯(150mg,0.31mmol)和4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯(100mg,0.31mmol)溶于DMSO(3mL)中,搅拌下加入DIEA(198mg,1.54mmol),室温下搅拌1小时。反应结束后反应液倒入水(30mL)中,EA萃取(30mL×3),合并有机相,并用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,粗品使用柱层析(DCM:MeOH=10:1)纯化得到4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-(三氟甲氧基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+Na]
+=649.3.
步骤2:1-(5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-(2-((1-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-(三氟甲氧基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯(110mg,0.17mmol)溶于DCM(2mL)中,加入TFA(0.2mL),反应液室温下反应1小时,直接减压浓缩得到1-(5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=527.3
步骤3:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1-(5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(90mg,0.17mmol)和(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(100mg,0.17mmol),溶于DMF(3mL)中,搅拌下加入HATU(84mg,0.22mmol)和DIEA(66mg,0.51mmol),室温下反应1h。反应结束后反应液倒入水(50mL)中,EA萃取(30mL×3),合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,粗品使用prep-HPLC纯化得到1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲氧基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1101.5.
1H NMR(400MHz,DMSO-d
6)δ10.54(s,1H),8.31(d,J=8.2Hz,1H),8.05(s,1H),7.59(d,J=2.0Hz,1H),7.52(dd,J=8.4,1.4Hz,1H),7.49-7.30(m,4H),7.24(d,J=1.3Hz,1H),7.02(s,1H),6.96(s,1H),6.02–5.91(m,1H),4.52–4.33(m,2H),3.98-3.90(m,4H),3.80-3.65(m,2H),3.61-3.51(m,1H),3.41(t,J=6.3Hz,2H),3.23(d,J=6.2Hz,2H),3.15–2.89(m,5H),2.82-2.60(m,4H),2.42(s,3H),2.01(s,6H),1.89–1.40(m,20H),1.20-0.90(m,4H).
实施例34:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-甲氧基苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:9-((4-((苄氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
9-醛基-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(300mg,1.06mmol)和哌嗪-1-羧酸苄酯(235mg,1.06mmol)用四氢呋喃(10mL)溶解,搅拌下加入三乙酰氧基硼氢化钠(674mg,3.18mmol)。室温下搅拌2小时后,加水(50mL),用二氯甲烷(30mLx3)提取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到9-((4-((苄氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=486.2.
步骤2:9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
9-((4-((苄氧基)羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(500mg,1.02mmol)溶解于乙酸乙酯(15mL)中,加入Pd(OH)
2/C(250mg,0.35mmol),在氢气氛围下升温至70℃,搅拌过夜。反应液冷却至室温,过滤,滤液减压浓缩得到9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯,粗品无需纯化直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=352.2.
步骤3:9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(130mg,0.36mmol)溶解于DMF(10mL)中,加入(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(200mg,0.33mmol),HATU(188mg,0.49mmol)和DIEA(127mg,0.99mmol),室温下搅拌1小时。反应液加入水(100mL),用乙酸乙酯(3x30mL)提取,有机相用饱和食盐水(100mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=926.4.
步骤4:(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-基)((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)甲酮的制备
9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(230mg,0.25mmol)溶解于DCM(3mL)中,加入TFA(1mL),室温下搅拌2小时。反应液直接减压浓缩得到(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-基)((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)甲酮。
LC-MS:(ESI,m/z):[M+H]
+=826.5.
步骤5:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-甲氧基苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-基)((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)甲酮(110mg,0.12mmol)溶于DMSO(10mL)中,加入3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酸五氟苯酯(57mg,0.13mmol)和DIEA(46mg,0.36mmol),室温下搅拌2小时。向反应液加入水(100mL),用二氯甲烷(30mLx3)萃取,有机相用饱和氯化钠水溶液(100mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经pre-HPLC(CH
3CN/0.08%NH
4HCO
3水溶液,5%~95%)纯化得到1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-甲氧基苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1072.5.
1H NMR(400MHz,DMSO-d
6)δ10.32(s,1H),8.32(d,J=8.1Hz,1H),8.05(s,1H),7.43(t,J=8.1Hz,2H),7.38–7.33(m,2H),7.32(d,J=2.0Hz,1H),7.24(s,1H),7.15(d,J=8.6Hz,1H),7.02(s,1H),6.96(s,1H),6.00–5.92(m,1H),3.89(s,3H),3.84(s,3H),3.59(t,J=6.6Hz,2H),3.49-3.37(m,4H),3.17–3.09(m,2H),2.94(t,J=12.0Hz,1H),2.68(t,J=6.6Hz,2H),2.65-2.43(m,2H),2.42(s,3H),2.33-2.26(m,4H),2.16-2.08(m,2H),2.02(s,6H),1.83-1.46(m,21H),1.35-1.24(m,2H),1.16-0.90(m,4H).
实施例35:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氟苯基)二氢嘧啶-2,4(1H,3H)-二酮
(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-基)((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)甲酮(110mg,0.12mmol)溶于DMSO(5mL)中,加3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-氟苯甲酸五氟苯酯(54mg,0.13mmol)和DIEA(46mg,0.36mmol),室温下搅拌2小时。向反应液加入水(50mL),用二氯甲烷(30mLx3)提取,有机相用饱和氯化钠水溶液(50mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩得到粗品。粗品经pre-HPLC(CH
3CN/0.08%NH
4HCO
3水溶液,5%~95%)纯化得到1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氟苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1060.5.
1H NMR(400MHz,DMSO-d
6)δ10.52(s,1H),8.32(d,J=8.3Hz,1H),8.05(s,1H),7.50(d,J=7.9Hz,1H),7.38(m,5H),7.24(s,1H),7.02(s,1H),6.96(s,1H),6.04–5.88(m,1H),3.89(s,3H),3.75(t,J=6.6Hz,2H),3.57(s,2H),3.46(s,4H),3.30–3.26(m,1H),3.11(d,J=15.1Hz,2H),2.94(m,1H),2.73(t,J=6.6Hz,2H),2.63(m,1H),2.42(s,3H),2.32(s,2H),2.29(s,2H),2.11(s,2H),2.01(s,6H),1.90–1.39(m,19H),1.34(m,2H),1.07(m,4H).
实施例36:1-(2-氯-5-(4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)氧)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)氧)丙基)哌啶-1-羧酸叔丁酯的制备
将4-(3-(哌啶-4-氧基)丙基)哌啶-1-羧酸叔丁酯(105mg,0.32mmol),HATU(145mg,0.38mmol)和DIEA(123mg,0.96mmol)加入到(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(190mg,0.32mmol)的DMF(5mL)溶液中,室温搅拌2小时,用水(50mL)稀释,乙酸乙酯(25mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,得到粗品4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)氧)丙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=901.4.
步骤2:((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(3-(哌啶-4-基)丙氧基)哌啶-1-基)甲酮的制备
将4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)氧)丙基)哌啶-1-羧酸叔丁酯(170mg,0.19mmol)用DCM(5mL)溶解,加入TFA(1mL),室温搅拌2小时,反应液直接减压浓缩得到粗品((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(3-(哌啶-4-基)丙氧基)哌啶-1-基)甲酮。
LC-MS:(ESI,m/z):[M+H]
+=801.4.
步骤3:1-(2-氯-5-(4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)氧)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(3-(哌啶-4-基)丙氧基)哌啶-1-基)甲酮(150mg,0.19mmol)用DMSO(10mL)溶解,分别加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(97mg,0.23mmol)和DIEA(72mg,0.56mmol),室温搅拌2小时,用水(50mL)稀释,乙酸乙酯(25mL×4)萃取,饱和食盐水洗净,无水硫酸钠干燥,减压浓缩,粗品使用反相制备纯化得到1-(2-氯-5-(4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)氧)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1051.4.
1H NMR(400MHz,DMSO-d
6)δ10.49(s,1H),8.30(d,J=8.2Hz,1H),8.05(s,1H),7.63(d,J=8.2Hz,1H),7.54(d,J=1.7Hz,1H),7.48–7.30(m,4H),7.24(s,1H),7.02(s,1H),6.96(s,1H),6.03-5.87(m,1H),4.53-4.33(m,1H),3.93-3.81(m,4H),3.79-3.45(m,5H),3.41(t,J=6.2Hz,2H),3.27–3.20(m,1H),3.18–2.99(m,4H),2.99-2.89(m,1H),2.80-2.60(m,4H),2.42(s,3H),2.01(s,6H),1.88–1.23(m,22H),1.10-1.00(m,2H).
实施例37:1-(2-氯-5-(9-(2-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(2-(3-氮杂螺[5.5]十一烷-9-基)乙基)哌啶-1-羧酸(9H-芴-9-基)甲酯的制备
将化合物9-(2-(4-(((9H-芴-9-基)甲氧基)羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(70mg,0.12mmol)溶于氯化氢的1,4-二氧六环(4M,7mL)溶液中,室温搅拌1小时,直接减压浓缩得到4-(2-(3- 氮杂螺[5.5]十一烷-9-基)乙基)哌啶-1-羧酸(9H-芴-9-基)甲酯。
LC-MS:(ESI,m/z):[M+H]
+=488.5.
步骤2:4-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)乙基)哌嗪-1-羧酸(9H-芴-9-基)甲酯的制备
4-(2-(3-氮杂螺[5.5]十一烷-9-基)乙基)哌啶-1-羧酸(9H-芴-9-基)甲酯(70mg,0.12mmol)和4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(52mg,0.12mmol)用DMSO(4mL)溶解,加入DIPEA(46mg,0.36mmol),反应液室温搅拌过夜。用水(40mL)稀释,乙酸乙酯(30mL×2)萃取,无水硫酸钠干燥,过滤,浓缩,粗品使用柱层析(EA in PE=0-4:1)纯化得到4-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)乙基)哌嗪-1-羧酸(9H-芴-9-基)甲酯。
LC-MS:(ESI,m/z):[M+H]
+=738.5.
步骤3:1-(2-氯-5-(9-(2-(哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
4-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)乙基)哌嗪-1-羧酸(9H-芴-9-基)甲酯(70mg,0.09mmol)用DCM(2mL)溶解,加入哌啶(0.3mL),反应液室温搅拌3小时,用水(20mL)稀释,二氯甲烷(30mL×2)萃取,无水硫酸钠干燥,过滤,浓缩,粗品使用柱层析(DCM:MeOH=95:5)纯化得到1-(2-氯-5-(9-(2-(哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+Na]
+=516.3.
步骤4:1-(2-氯-5-(9-(2-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
1-(2-氯-5-(9-(2-(哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(30mg,0.06mmol)和(1R,4R)-4-(4-(((R)-1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(34mg,0.06mmol)用DMF(3mL)溶解,加入HATU(27mg,0.07mmol)和DIEA(23 mg,0.18mmol),反应液室温搅拌过夜。用水(30mL)稀释,乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥,减压,浓缩,粗品使用prep-HPLC纯化得到1-(2-氯-5-(9-(2-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1090.5.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.30(d,J=8.1Hz,1H),8.05(s,1H),7.63(d,J=8.2Hz,1H),7.54(s,1H),7.47–7.28(m,4H),7.24(s,1H),7.02(s,1H),6.96(s,1H),6.00-5.92(m,1H),3.89(s,3H),3.80-3.71(m,1H),3.66-3.42(m,8H),3.12(s,2H),3.00-2.90(m,1H),2.78-2.71(m,2H),2.65-2.57(m,2H),2.42(s,3H),2.36-2.23(m,6H),2.01(s,6H),1.89-1.75(m,4H),1.72-1.29(m,18H),1.16-1.00(m,4H).
实施例38:1-(5-(4-((3-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(3-羟基丙基)哌啶-1-羧酸叔丁酯的制备
将3-(哌啶-4-基)丙烷-1-醇(700mg,4.9mmol)溶于1,4-二氧六环(7mL)中,然后加入Boc酸酐(2.1g,9.8mmol)和DMAP(30mg,0.24mmol),反应液加热到80℃过夜。反应结束后倒入水(60mL)中,乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥,有机相旋干,粗品使用柱层析(EA:PE=0-3:7)纯化得到4-(3-羟基丙基)哌啶-1-羧酸叔丁酯。
1H NMR(400MHz,DMSO-d
6)δ4.34(t,J=5.1Hz,1H),3.91(d,J=12.3Hz,2H),3.37(dd,J=11.9,6.3Hz,2H),2.66(s,2H),1.61(d,J=12.3Hz,2H),1.50–1.28(m,12H),1.20(dd,J=15.2,6.9Hz,2H),0.93(m,2H).
步骤2:4-(3-丙醛)哌啶-1-羧酸叔丁酯的制备
把4-(3-羟基丙基)哌啶-1-羧酸叔丁酯(300mg,1.2mmol)溶于乙腈(5mL),然后加入IBX(567mg,2.4mmol),反应液加热到70℃反应2个小时,过滤,滤饼用乙酸乙酯(10mL×2)洗涤,有机相旋干,粗品使用柱层析(EA:PE=0-1:4)纯化得到4-(3-丙醛)哌啶-1-羧酸叔丁酯。
1H NMR(400MHz,DMSO-d
6)δ9.68(t,J=1.5Hz,1H),3.91(d,J=12.0Hz,2H),2.65(m,2H),2.46(td,J=7.5,1.5Hz,2H),1.61(d,J=13.0Hz,2H),1.46(dd,J=14.5,7.3Hz,2H),1.42–1.33(m,10H),0.94(m,2H).
步骤3:4-((3-(1-(叔丁氧羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯的制备
把4-(3-丙醛)哌啶-1-羧酸叔丁酯(200mg,0.82mmol)和4-(甲基氨基)哌啶-1-羧酸苄酯(205mg,0.82mmol)溶于四氢呋喃(4mL)中,然后加入三乙酰氧基硼氢化钠(525mg,2.48mmol),反应液室温搅拌过夜。用水(40mL)稀释,乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥,过滤,浓缩,粗品使用柱层析(EA:PE=0-3:7)纯化得到白色油状物4-((3-(1-(叔丁氧羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=474.3.
步骤4:4-(甲基(3-(哌啶-4-基)丙基)氨基)哌啶-1-羧酸苄酯的制备
把4-((3-(1-(叔丁氧羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯(90mg,0.19mmol)溶于DCM(5mL)中,然后三氟乙酸(0.5mL)加入,反应液在室温下搅拌1个小时,直接减压浓缩得到油状物4-(甲基(3-(哌啶-4-基)丙基)氨基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=374.1.
步骤5:4-((3-(1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯的制备
把(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(110mg,0.18mmol)和4-(甲基(3-(哌啶-4-基)丙基)氨基)哌啶-1-羧酸苄酯(三氟乙酸盐,90mg,0.18mmol)溶于DMF(3mL)中,HATU(83mg,0.22mmol)和DIEA(70mg,0.54mmol)加入,反应液室温搅拌过夜,用水(30mL)稀释,乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥,过滤,浓缩,粗品使用柱层析(MeOH:DCM=0-1:9)纯化得到4-((3-(1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=958.2.
步骤6:(3-((R)-1-((7-甲氧基-2-甲基-6-((1R,4R)-4-(4-(3-(甲基(哌啶-4-基)氨基)丙基)哌啶-1-羰基)环己基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
把4-((3-(1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羧酸苄酯(100mg,0.1mmol)溶于MeOH(5mL)中,加入Pd/C(20mg),置换3次氢气,在氢气保护下室温搅拌1小时。过滤,滤饼用甲醇(5mL×3)洗涤,滤液减压浓缩得到(3-((R)-1-((7-甲氧基-2-甲基-6-((1R,4R)-4-(4-(3-(甲基(哌啶-4-基)氨基)丙基)哌啶-1-羰基)环己基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=824.1.
步骤7:(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
把化合物(3-((R)-1-((7-甲氧基-2-甲基-6-((1R,4R)-4-(4-(3-(甲基(哌啶-4-基)氨基)丙基)哌啶-1-羰基)环己基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(75mg,0.09mmol)和4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(39mg,0.09mmol)溶于DMSO(2mL)中,DIEA(35mg,0.27mmol)加入,反应液室温搅拌过夜。用水(20mL)稀释,乙酸乙酯(30mL×2)萃取,无水硫酸钠干燥,过滤,浓缩,粗品使用柱层析(MeOH:DCM=0-5:95)纯化得到(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1074.3.
步骤8:1-(5-(4-((3-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)(甲基)氨基)丙基)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(40mg,0.04mmol)溶于二氯甲烷(3mL)中,然后加入三氟乙酸(0.3mL),室温搅拌1个小时,直接减压浓缩,用饱和碳酸氢钠水溶液调pH到8-9,二氯甲烷(20mL×3)萃取,无水硫酸钠干燥,过滤,浓缩,粗品使用prep-HPLC纯化得到1-(5-(4-((3-(1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)(甲基)氨基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=974.3.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.15–8.02(m,2H),7.63(d,J=8.2Hz,1H),7.56(d,J=1.9Hz,1H),7.40(d,J=8.2Hz,1H),6.99(s,1H),6.86(d,J=10.8Hz,2H),6.70(s,1H),5.64–5.47(m,3H),4.54-4.48(m,2H),3.96-3.88(m,4H),3.88-3.80(m,1H),3.80-3.74(m,2H),3.05-2.95(m,3H),2.91-2.85(m,2H),2.40-2.30(m,6H),2.15(s,3H),1.91-1.42(m,23H),1.25-1.15(m,2H),1.06–0.84(m,2H).
实施例39:1-(5-(4-((2-(1-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯的制备
将6-溴-7-甲氧基-2-甲基喹唑啉-4-醇(6.2g,23.22mmol)加入到Pd(dppf)Cl
2(850mg,1.16mmol),碳 酸钠(4.9g,46.44mmol)和4-(4,4,5,5-四甲基-1,3-二氧戊烷-2-基)环己-3-烯-1-羧酸叔丁酯(8.1g,30.19mmol)的DMF/H
2O(80mL/8mL)混合溶液中,室温下搅拌过夜,待反应完全后,加水(800mL)稀释,用乙酸乙酯(200mL×5)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩。粗品使用柱层析(PE:EA=1:100)纯化得到4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=329.0.
步骤2:4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯的制备
将4-(4-羟基-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯(600mg,1.82mmol)加入到DBU(820mg,5.37mmol)和BOP(1.19g,2.69mmol)的DMF(10mL)溶液中,先室温下搅拌30min,(R)-(3-(1-氨基乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(600mg,1.97mmol)加入,反应液70℃下搅拌过夜。用水(100mL)稀释,析出固体,过滤,水洗三次,固体用二氯甲烷(100mL)溶解,无水硫酸钠干燥,减压浓缩,粗品使用柱层析(PE:EA=1:1)纯化得到4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=615.2.
步骤3:4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸的制备
将4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯(1.1g,1.79mmol)加到氢氧化锂(430mg,17.9mmol)的THF/H
2O(20mL/10mL)溶液中,氮气保护,50℃下搅拌过夜,在冰浴下,缓慢滴加10%柠檬酸,将溶液调至弱酸性或中性,用乙酸乙酯(100mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,得到粗产品4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=601.2.
步骤4:(3-((1R)-1-((6-(4-(4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己-1-烯-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
将4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羧酸(130mg,0.22mmol),HATU(100mg,0.26mmol)和DIEA(85mg,0.66mmol)加入到1-(2-氯-5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(140mg,0.23mmol)的DMF(10mL)溶液中,室温搅拌2小时,加入水(100mL),析出固体,过滤,水洗3次,用二氯甲烷溶解,无水硫酸钠干燥,减压浓缩,得到粗产品(3-((1R)-1-((6-(4-(4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己-1-烯-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1059.5.
步骤5:1-(5-(4-((2-(1-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((1R)-1-((6-(4-(4-(2-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)环己-1-烯-1-基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(190mg,0.18mmol)用二氯甲烷(5mL)溶解,加入三氟乙酸(1mL),反应液室温搅拌2小时,减压浓缩,粗品使用反相制备纯化得到1-(5-(4-((2-(1-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己-3-烯-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=959.2.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.19(s,1H),8.07(s,1H),7.63(d,J=8.3Hz,1H),7.54(d,J=1.8Hz,1H),7.38(dd,J=8.2,1.8Hz,1H),6.99(s,1H),6.89(s,1H),6.85(s,1H),6.69(s,1H),5.83(s,1H),5.61-5.43(m,3H),4.51-4.37(m,2H),4.00-3.90(m,1H),3.85(s,3H),3.80-3.70(m,1H),3.67-3.52(m,2H),3.41(t,J=6.3Hz,2H),3.24(d,J=6.4Hz,2H),3.12-2.97(m,2H),2.92-2.70(m,4H),2.42-2.16(m,7H),1.90-1.56(m,8H),1.56-1.41(m,5H),1.21-0.90(m,4H).
实施例40:1-(5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2-氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧)丙基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
将1-(2-氯-5-(4-(3-(哌嗪-1-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(90mg,0.13mmol),HATU(59mg,0.16mmol)和DIEA(50mg,0.39mmol)加入到(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(80mg,0.16mmol)的DMF(5mL)溶液中,室温搅拌2小时,加入水(50mL),析出固体,过滤,水洗3次,用二氯甲烷(20mL)溶解固体,无水硫酸钠干燥,减压浓缩,得到粗品(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2-氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧)丙基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1062.5.
步骤2:1-(5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-氯-3-(2-氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧)丙基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(130mg,0.12mmol)用二氯甲烷(5mL)溶解,加入三氟乙酸(1mL),然后反应液室温搅拌2小时,减压浓缩,粗品使用反相制备纯化得到1-(5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=962.5.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.10(d,J=8.2Hz,1H),8.06(s,1H),7.63(d,J=8.2Hz,1H),7.57(s,1H),7.47–7.34(m,1H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.64-5.46(m,3H),4.00-3.82(m,4H),3.80-3.67(m,1H),3.66-3.57(m,1H),3.56–3.39(m,8H),3.22-3.10(m,1H),3.00-2.89(m,1H),2.80–2.55(m,3H),2.40–2.25(m,9H),1.94–1.35(m,18H).
实施例41:1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(1,1-二氧化物-2,3-二氢苯并[b]噻吩-4-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
将1-(5-(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(120mg,0.24mmol)和(1R,4R)-4-(4-(((R)-1-(1,1-dioxido二氧化物-2,3-二氢苯并[b]噻吩-4-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(120mg,0.24mmol)用DMF(3mL)溶解,HATU(108mg,0.28mmol)和DIEA(90mg,0.71mmol)加入,反应液室温搅拌1小时。用水(30mL)稀释,乙酸乙酯萃取(30mL×3),合并有机相并用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,粗品使用prep-HPLC纯化得到1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(1,1-二氧化物-2,3-二氢苯并[b]噻吩-4-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)-2-(三氟甲基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1002.4.
1H NMR(400MHz,DMSO-d
6)δ10.53(s,1H),8.27(d,J=7.2Hz,1H),8.06(s,1H),7.87(d,J=8.2Hz,1H),7.80(d,J=7.1Hz,1H),7.70(s,1H),7.59(t,J=6.6Hz,2H),7.53(t,J=7.6Hz,1H),6.98(s,1H),5.58(t,J=7.0Hz,1H),4.57–4.33(m,2H),3.99–3.84(m,5H),3.81–3.70(m,1H),3.68–3.60(m,2H),3.52-3.40(m,5H),3.24(d,J=6.2Hz,2H),3.14–2.89(m,3H),2.85-2.65(m,4H),2.32(s,3H),1.92–1.40(m,20H),1.23–0.89(m,4H).
实施例42:1-(2-氯-5-(4-((2-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶- 2,4(1H,3H)-二酮
将1-(2-氯-5-(4-((2-(哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(150mg,粗品)溶于DMF(5mL),(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(94mg,0.22mmol),HATU(107mg,0.28mmol)和DIEA(145mg,1.1mmol)分别加入,室温搅拌2小时,加水(50mL)并搅拌5分钟,用乙酸乙酯(30mLx3)萃取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相制备纯化得到1-(2-氯-5-(4-((2-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1052.4.
1H NMR(400MHz,DMSO-d
6)δ10.48(s,1H),8.29(d,J=8.3Hz,1H),8.04(s,1H),7.62(d,J=8.1Hz,1H),7.53(d,J=1.6Hz,1H),7.45–7.31(m,4H),7.23(s,1H),7.02(s,1H),6.96(s,1H),5.96(t,J=7.1Hz,1H),4.52–4.28(m,1H),3.89(s,3H),3.80–3.40(m,10H),3.26(d,J=6.3Hz,2H),3.12(s,2H),2.97–2.88(m,1H),2.79–2.59(m,4H),2.45–2.39(m,5H),2.38–2.33(m,2H),2.01(s,6H),1.94–1.46(m,16H),1.13(d,J=10.9Hz,2H).
实施例43:1-(2-氯-5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(3-(哌啶-4-基氧)丙基)哌嗪-1-羧酸叔丁酯的制备
将4-(3-((1-((苄氧)羰基)哌啶-4-基)氧)丙基)哌嗪-1-羧酸叔丁酯(400mg,0.87mmol)和Pd/C(10%,100mg)用乙酸乙酯(10mL)溶解,反应液加热到70℃并搅拌3小时,过滤,固体用乙酸乙酯(10mL×3)洗三次,减压浓缩得到4-(3-(哌啶-4-基氧)丙基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=328.3.
步骤2:4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧)丙基)哌嗪-1-羧酸叔丁酯的制备
将4-(3-(哌啶-4-基氧)丙基)哌嗪-1-羧酸叔丁酯(230mg,0.70mmol)用DMSO(10mL)溶解,4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(360mg,0.82mmol)和DIEA(271mg,2.10mmol)分别加入,室温搅拌过夜,用水(50mL)稀释,乙酸乙酯(25mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,粗品使用柱层析(PE:EA=1:10)纯化得到4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧)丙基)哌嗪-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=578.3.
步骤3:1-(2-氯-5-(4-(3-(哌嗪-1-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-(3-((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)氧)丙基)哌嗪-1-羧酸叔丁酯(220mg,0.47mmol)用二氯甲烷(5mL)溶解,加入三氟乙酸(1mL),反应液室温搅拌过夜,缓慢滴加饱和碳酸氢钠水溶液,将反应液pH值调至7-8,用二氯甲烷与异丙醇五比一混合溶液(25mL×4)萃取,无水硫酸钠干燥,过滤,减压浓缩得到1-(2-氯-5-(4-(3-(哌嗪-1-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=478.2.
步骤4:1-(2-氯-5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1-(2-氯-5-(4-(3-(哌嗪-1-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(90mg,0.19mmol),HATU(87mg,0.23mmol)和DIEA(74mg,0.57mmol)分别加入到(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(106mg,0.19mmol)的DMF(10mL)溶液中,室温搅拌2小时,用水(100mL)稀释,析出固体,过滤,水洗3次,用二氯甲烷溶解固体,无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相制备纯化得到1-(2-氯-5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丙氧基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1052.4.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.32(d,J=7.7Hz,1H),8.05(s,1H),7.63(d,J=8.3Hz,1H),7.57(s,1H),7.47–7.30(m,4H),7.24(s,1H),7.02(s,1H),6.97(s,1H),5.97(t,J=7.2Hz,1H),4.00-3.84(s,4H),3.80-3.71(m,1H),3.66-3.57(m,1H),3.49-3.35(m,8H),3.20-3.07(m,3H),3.00-2.84(m,1H),2.78-2.58(m,3H),2.42(s,3H),2.40-2.26(m,6H),2.01(s,6H),1.92-1.75(m,6H),1.75–1.38(m,12H).
实施例44:1-(2-氯-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶- 2,4(1H,3H)-二酮
步骤1:(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸叔丁酯的制备
将化合物(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-醛苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(450mg,0.78mmol)和甲胺(2M/THF溶液,7.8mmol)溶于二氯乙烷(10mL)中,三乙酰基硼氢化钠(496mg,2.34mmol)加入。反应液加热到80℃并搅拌1小时。直接减压浓缩,粗品使用柱层析(MeOH:DCM=1:10,流速40ml/min)纯化得到(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=593.3.
步骤2:(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸的制备
将(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸叔丁酯(300mg,0.5mmol)和氢氧化锂(60mg,2.5mmol)用混合溶液(MeOH/H
2O=10/1,5mL)溶解。反应液加热到70℃并搅拌2小时。冷却,使用1M HCl将反应液pH值调到3~4,再使用饱和碳酸氢钠水溶液将反应液pH值调到7~8,使用乙酸乙酯(100mL×3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相(ACN:H
2O=1:1)纯化得到(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=579.2.
步骤3:1-(2-氯-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(80mg,0.14mmol)用DMF(5mL)溶解,HATU(65mg,0.17mmol),1-(2-氯-5-(4-((2-(哌 啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(80mg,0.17mmol)和DIEA(54mg,0.42mmol)加入,反应液室温搅拌1小时,用水(20mL)稀释,乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(40mL)洗,无水硫酸钠干燥,过滤,减压浓缩,粗品使用prep-HPLC纯化得到1-(2-氯-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)乙氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1037.4.
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.32(d,J=8.3Hz,1H),8.05(s,1H),7.63(d,J=8.2Hz,1H),7.54(d,J=1.7Hz,1H),7.45(d,J=7.5Hz,1H),7.42–7.30(m,3H),7.28(s,1H),7.02(s,1H),6.98(s,1H),6.07–5.86(m,1H),4.38(d,J=12.6Hz,2H),3.89(s,4H),3.73(d,J=7.1Hz,1H),3.66–3.51(m,2H),3.44–3.36(m,4H),3.23(d,J=6.2Hz,2H),3.11–2.88(m,3H),2.78–2.59(m,4H),2.42(s,3H),2.12(s,3H),1.92–1.39(m,21H),1.18–0.87(m,4H).
实施例45:1-(2-氯-5-(4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯的制备
将(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(80mg,0.13mmol),HATU(62mg,0.16mmol)和DIEA(50mg,0.39mmol)加入到4-(2-(哌啶-4-基甲氧基)乙基)哌啶-1-羧酸叔丁酯(43mg,0.13mmol)的DMF(5mL)溶液中,室温搅拌1小时,用水(50mL)稀释,析出固体,过滤,水洗3次,用二氯甲烷溶解固体,无水硫酸钠干燥,减压浓缩,粗品使用反相制备纯化得到4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=901.4.
步骤2:((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)甲酮的制备
将4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羧酸叔丁酯(80mg,0.09mmol)加入到氯化氢的二氧六环(4M,2mL)溶液中,反应液室温搅拌1小时,直接减压浓缩得到粗品((1R,4R)-4-(4-(((R)- 1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)甲酮。
LC-MS:(ESI,m/z):[M+H]
+=801.3.
步骤3:1-(2-氯-5-(4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-((2-(哌啶-4-基)乙氧基)甲基)哌啶-1-基)甲酮(70mg,0.09mmol)加入到4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(39mg,0.08mmol)和DIEA(35mg,0.27mmol)的DMSO(5mL)溶液中,室温搅拌过夜,用水(50mL)稀释,乙酸乙酯(25mL×4)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,粗品使用反相制备纯化得到1-(2-氯-5-(4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)乙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1051.5.
1H NMR(400MHz,DMSO-d
6)δ10.49(s,1H),8.30(d,J=8.1Hz,1H),8.05(s,1H),7.62(d,J=8.2Hz,1H),7.53(d,J=2.0Hz,1H),7.45-7.31(m,4H),7.24(d,J=1.3Hz,1H),7.02(s,1H),6.96(s,1H),6.03–5.89(m,1H),4.48-4.32(m,2H),3.97-3.85(m,4H),3.79-3.68(m,1H),3.66-3.52(m,2H),3.40(t,J=6.4Hz,2H),3.21(d,J=6.1Hz,2H),3.16–2.90(m,5H),2.82–2.52(m,7H),2.42(s,3H),2.01(s,6H),1.88–1.43(m,20H),1.19–0.90(m,4H).
实施例46:1-(2-氯-5-(4-(4-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丁基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(4-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丁基)哌啶-1-羧酸叔丁酯的制备
将(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(120mg,0.20mmol),4-(4-(哌嗪-1-基)丁基)哌啶-1-羧酸叔丁酯(66mg,0.20mmol)和HATU(91mg,0.24mmol)溶于DMF(3mL)中,加入DIEA(78mg,0.61mmol),反应液室温搅拌1小时,用水(30mL)稀释,乙酸乙酯萃取(30mL×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,粗品使用柱层析(DCM:MeOH=10:1)得到4-(4-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丁基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=900.6.
步骤2:((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(4-(哌啶-4-基)丁基)哌嗪-1-基)甲酮的制备
将4-(4-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丁基)哌啶-1-羧酸叔丁酯(149mg,0.17mmol)用氯化氢的1,4-二氧六环溶液(4M,5mL)溶解,室温搅拌1小时,直接减压浓缩得到((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(4-(哌啶-4-基)丁基)哌嗪-1-基)甲酮。
LC-MS:(ESI,m/z):[M+H]
+=800.4.
步骤3:1-(2-氯-5-(4-(4-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丁基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-(4-(哌啶-4-基)丁基)哌嗪-1-基)甲酮(158mg,0.11mmol),4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(47mg,0.11mmol)溶于DMSO(2mL)中,搅拌下加入DIEA(42mg,0.32mmol),室温搅拌1小时。用水(30mL)稀释,乙酸乙酯萃取(30mL×3),合并上有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品使用prep-HPLC纯化得到1-(2-氯-5-(4-(4-(4-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)丁基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1050.5.
1H NMR(400MHz,DMSO-d
6)δ10.49(s,1H),8.30(d,J=7.7Hz,1H),8.05(s,1H),7.63(d,J=8.3Hz,1H),7.54(s,1H),7.47–7.31(m,4H),7.24(s,1H),7.02(s,1H),6.96(s,1H),6.01–5.90(m,1H),4.50-4.42(m,1H),3.89(s,3H),3.80-3.68(m,1H),3.66-3.52(m,2H),3.50-3.40(m,4H),3.18-3.10(m,2H),3.02-2.90(m,2H),2.80-2.65(m,4H),2.42(s,3H),2.38-2.20(m,6H),2.01(s,6H),1.82-1.42(m,18H),1.30-1.22(m,4H),1.13-0.96(m,2H).
实施例47:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(4-羟基-2,7-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯的制备
6-溴-2,7-二甲基喹唑啉-4-醇(900mg,3.56mmol)用DMF/H
2O(22mL,10/1)溶解,加入4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)环己-3-烯-1-羧酸甲酯(1135mg,4.27mmol),碳酸钠(755mg,7.12mmol)和Pd(dppf)Cl
2(264mg,0.36mmol),在氮气保护下110℃搅拌过夜,加水(100mL)并搅拌5分钟,用乙酸乙酯(100mLx3)萃取,饱和食盐水(200mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9)纯化得到4-(4-羟基-2,7-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=313.1.
步骤2:(1R,4R)-4-(4-羟基-2,7-二甲基喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
在的高压釜(100mL)中,加入4-(4-羟基-2,7-甲基喹唑啉-6-基)环己-3-烯-1-羧酸甲酯(380mg,1.22mmol),用MeOH(30mL)溶解后,加入Pd(OH)
2/C(115mg,30%),在氢气环境中(2MPa)于70℃反应48h,过滤,减压浓缩,粗品使用反相制备纯化得到(1R,4R)-4-(4-羟基-2,7-二甲基喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=315.2.
1H NMR(400MHz,DMSO)δ12.09(s,1H),8.15(s,1H),7.56(s,1H),3.92(s,3H),2.95(t,J=11.6Hz,1H),2.43(s,3H),2.36(s,3H),2.35–2.24(m,1H),2.06(d,J=10.7Hz,2H),1.90–1.84(m,2H),1.67–1.40(m,4H).
步骤3:(1R,4R)-4-(2,7-二甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸甲酯的制备
将(1R,4R)-4-(4-羟基-2,7-二甲基喹唑啉-6-基)环己烷-1-羧酸甲酯(250mg,0.80mmol)溶于DMF(5mL),加入BOP(506mg,1.19mmol)和DBU(303mg,1.99mmol),室温搅拌0.5小时后,加入(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺(224mg,0.96mmol),加热至70℃搅拌过夜,加水(50mL)并搅拌5分钟,用乙酸乙酯(30mLx3)萃取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相纯化得到(1R,4R)-4-(2,7-二甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸甲酯。
LC-MS:(ESI,m/z):[M+H]
+=531.3.
步骤4:(1R,4R)-4-(2,7-二甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸的制备
将(1R,4R)-4-(2,7-二甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸甲酯(210mg,0.40mmol)溶于THF/H
2O(15mL,2:1)中,加入氢氧化锂(190mg,8.00mmol),50℃搅拌过夜,加水(20mL),用1M盐酸调节pH至6,用MeOH/DCM(1/9,30mL×3)萃取,经无水硫酸钠干燥,过滤,减压浓缩,得到(1R,4R)-4-(2,7-二甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸,直接用于下一步。
LC-MS:(ESI,m/z):[M+H]
+=517.4.
步骤5:(1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)环己烷-1-羧酸的制备
将(1R,4R)-4-(2,7-二甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)环己烷-1-羧酸(150mg,0.29mmol),溶于乙醇(10mL),加入Raney-Ni(0.5mL)和N
2H
4-H
2O(85%,0.5mL),室温反应0.5小时,过滤,减压浓缩,得到(1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)环己烷-1-羧酸。
LC-MS:(ESI,m/z):[M+H]
+=487.2.
步骤6:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)环己烷-1-羧酸(70mg,0.14mmol)溶于DMF(5mL),加入1-(2-氯-5-(9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(84mg,0.17mmol),DIEA(55mg,0.42mmol)和pyBOP(88mg,0.17mmol),室温反应1h,加水(50mL)并搅拌5分钟,用乙酸乙酯(30mL×3)萃取,饱和食盐水(50mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相制备纯化得到1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2,7-二甲基喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=970.4.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.19(d,J=8.0Hz,1H),8.08(s,1H),7.64(d,J=8.2Hz,1H),7.55(d,J=1.9Hz,1H),7.45–7.31(m,2H),6.87(d,J=11.3Hz,2H),6.70(s,1H),5.67–5.45(m,3H), 3.82-3.70(m,1H),3.67–3.42(m,8H),2.87–2.64(m,5H),2.43(s,3H),2.39-2.22(m,7H),2.18-2.09(m,2H),1.90-1.78(m,4H),1.73-1.24(m,14H),1.18-0.94(m,4H).
实施例48:1-(2-甲氧基-5-(9-((4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:(2-(5-((R)-1-((6-((1R,4R)-4-(4-((3-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己烷)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)羧酸叔丁酯的制备
将3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酸五氟苯酯(118mg,0.27mmol)和(2-(5-((R)-1-((6-((1R,4R)-4-(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)羧酸(300mg,0.34mmol)溶解在DMSO(6mL)中,然后加入DIEA(132mg,1.02mmol)。反应液在室温搅拌2h。反应用水(50mL)稀释,用EA(50mLx3)。合并有机相,用食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗品经柱层析(/MeOH(NH
3)/DCM 0%~20%)纯化得到(2-(5-((R)-1-((6-((1R,4R)-4-(4-((3-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己烷)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M/2+H]
+=563.5.
步骤2:1-(2-甲氧基-5-(9-((4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
室温时,搅拌下向(2-(5-((R)-1-((6-((1R,4R)-4-(4-((3-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-甲氧基苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己烷)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)羧酸叔丁酯(72mg,0.064mmol)的DCM(3mL)溶液中加TFA(1ml),反应液在室温搅拌2h。反应液直接减压浓缩。粗品经prep-HPLC纯化得到1-(2-甲氧基-5-(9-((4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1024.4.
1H NMR(400MHz,CD
3OD)δ7.99(s,1H),7.46–7.36(m,3H),7.34–7.27(m,3H),7.22-7.12(m,3H),7.01(s,1H),6.10-6.02(m,1H),3.95-3.91(m,6H),3.75-3.45(m,12H),3.12-3.01(m,1H),2.80(t,J=6.7Hz,2H),2.75–2.66(m,1H),2.52(s,3H),2.44(m,2H),2.38(m,2H),2.25–2.16(m,5H),2.00–1.84(m,4H),1.79(d,J=7.0Hz,4H),1.71-1.54(m,9H),1.37-1.12(m,7H).
实施例49:1-(2-氟-5-(9-((4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:(2-(5-((R)-1-((6-((1R,4R)-4-(4-((3-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-氟苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)羧酸叔丁酯的制备
将3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-氟苯甲酸五氟苯酯(133mg,0.32mmol)和(2-(5-((R)-1-((6-((1R,4R)-4-(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)羧酸叔丁酯(350mg,0.39mmol)溶解在DMSO(6mL)中,然后加入DIEA(132mg,1.02mmol)。反应液在室温搅拌2h。反应结束后,反应液用水(50mL)稀释,并用EA(50mLx3)萃取。合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤并减压浓缩。粗品经柱层析(MeOH(NH
3)/DCM,0%~20%)纯化得到(2-(5-((R)-1-((6-((1R,4R)-4-(4-((3-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-氟苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M/2+H]
+=556.9.
步骤2:1-(2-氟-5-(9-((4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
室温下,向(2-(5-((R)-1-((6-((1R,4R)-4-(4-((3-(3-(2,4-二氧代四氢嘧啶-1(2H)-基)-4-氟苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-3-基)苄基)(甲基)羧酸叔丁酯(100mg,0.09mmol)的DCM(3mL)溶液中加入TFA(1ml)。反应液在室温搅拌2h。反应液直接浓缩。粗品经prep-HPLC纯化得到1-(2-氟-5-(9-((4-((1R,4R)-4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1012.3.
1H NMR(400MHz,CD
3OD)δ7.99(s,1H),7.52(dd,J=7.1,1.9Hz,1H),7.46-7.39(m,2H),7.36-7.27(m,4H),7.21-7.17(m,1H),7.15-7.11(m,1H),7.01(s,1H),6.08-6.03(m,1H),3.95(s,3H),3.83(t,J=6.7Hz,2H),3.77–3.55(m,8H),3.50-3.37(m,2H),3.10-3.00(m,1H),2.83(t,J=6.7Hz,2H),2.76-2.65(m,1H),2.52(s,3H),2.44(b,2H),2.38(b,2H),2.25-2.16(m,5H),2.00-1.83(m,4H),1.82-1.75(m,4H),1.69–1.46(m,9H),1.36-1.06(m,7H).
实施例50:1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(羟基甲基-d
2)哌啶-1-羧酸叔丁酯的制备
1-(叔丁基)4-乙基哌啶-1,4-二羧酸盐(500mg,1.93mmol)溶解于乙醇中(20mL),0℃下加入NaBD
4(325mg,7.75mmol)并搅拌2小时。反应液中加入水(30mL),用乙酸乙酯(30mLx3)萃取。有机相用饱和食盐水(100mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩。粗品使用柱层析(乙酸乙酯:石油醚=1:1)纯化得到4-(羟基甲基-d
2)哌啶-1-羧酸叔丁酯。
1H NMR(400MHz,DMSO-d
6)δ4.42(s,1H),3.93(d,J=11.9Hz,2H),2.67(s,2H),1.62(d,J=12.9Hz,2H),1.55–1.44(m,1H),1.39(s,9H),0.96(m,2H).
步骤2:4-((吡啶-4-基甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯的制备
4-(羟基甲基-d
2)哌啶-1-羧酸叔丁酯(250mg,1.14mmol)溶于无水四氢呋喃(10mL)中,氮气氛围下降温至0℃并加入NaH(364mg,9.12mmol),搅拌3小时后,加入4-(溴甲基)吡啶氢溴酸盐(576mg,2.28mmol),室温搅拌过夜。反应液中加入水(20mL),用乙酸乙酯(20mLx3)萃取。有机相用饱和食盐水(60mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩。粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到4-((吡啶-4-基甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=309.1
1H NMR(400MHz,DMSO-d
6)δ8.53(dd,J=4.5,1.5Hz,2H),7.31(d,J=5.8Hz,2H),4.51(s,2H),3.94(d,J=12.0Hz,2H),2.70(s,2H),1.76(m,1H),1.67(d,J=12.9Hz,2H),1.39(s,9H),1.06(m,2H).
步骤3:4-((哌啶-4-基甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯的制备
将4-((吡啶-4-基甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯(180mg,0.58mmol)溶于异丙醇(10mL)和水(10mL)中,加入Pd/C(60mg,0.058mmol),在氢气氛围下升温至70℃并搅拌过夜。反应液冷却至室温,过滤,滤液减压浓缩得到4-((哌啶-4-基甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯,粗品无需纯化直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=315.2.
步骤4:4-(((1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯的制备
将4-((哌啶-4-基甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯(130mg,0.41mmol)溶解于DMF(10mL)中,加入(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(150mg,0.25mmol),HATU(123mg,0.32mmol)和DIEA(96mg,0.74mmol),室温下搅拌1小时。反应液用水(100mL)稀释,用乙酸乙酯(30mLx3)萃取,有机相用饱和食盐水(50mL)洗涤,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到4-(((1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基) 甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=899.5.
步骤5:((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-((哌啶-4-基甲氧基-d
2)甲基)哌啶-1-基)甲酮的制备
将4-(((1-((1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯(200mg,0.22mmol)溶解于DCM(5mL)中,加入TFA(2mL),室温下搅拌2小时。反应液直接减压浓缩得到((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-((哌啶-4-基甲氧基-d
2)甲基)哌啶-1-基)甲酮。
LC-MS:(ESI,m/z):[M+H]
+=699.4
步骤6:1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己基)(4-((哌啶-4-基甲氧基-d
2)甲基)哌啶-1-基)甲酮(粗产品,200mg,0.22mmol)溶于DMSO(10mL)中,然后加4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(95mg,0.22mmol)和DIEA(86mg,0.66mmol),室温下搅拌2小时。向反应液中加入水(100mL),用二氯甲烷(30mLx3)萃取,有机相减压浓缩得到粗品。粗品经pre-HPLC(CH
3CN/0.08%NH
4HCO
3水溶液,5%~95%)纯化得到1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=949.4.
1H NMR(400MHz,DMSO-d
6)δδ10.50(s,1H),8.15–8.02(m,2H),7.63(d,J=8.2Hz,1H),7.54(d,J=1.8Hz,1H),7.38(dd,J=8.2,1.9Hz,1H),6.99(s,1H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.63–5.48(m,3H),4.51-4.36(m,2H),3.99–3.86(m,4H),3.78-3.71(m,1H),3.65-3.53(m,2H),3.23(d,J=6.1Hz,2H),3.09-2.90(m,3H),2.81-2.62(m,4H),2.35(s,3H),1.91–1.52(m,18H),1.18-0.92(m,4H).
实施例51:1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基-d
2)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯的制备
将4-((哌啶-4-基甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯(180mg,0.57mmol)用二甲亚砜(5mL)溶解,然后加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(247mg,0.57mmol)和N,N-二异丙基乙胺(220mg,1.71mmol),反应液室温下搅拌2小时,加水(50mL)稀释,用二氯甲烷(30mLx3)萃取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=565.2.
步骤2:1-(2-氯-5-(4-((哌啶-4-基甲氧基-d
2)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羧酸叔丁酯(220mg,0.39mmol)用二氯甲烷(5mL)溶解,然后加入三氟乙酸(2mL),反应液室温搅拌2小时,直接减压浓缩得到1-(2-氯-5-(4-((哌啶-4-基甲氧基-d
2)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮,无需纯化直接用于下一步反应。
LC-MS:(ESI,m/z):[M+H]
+=465.3.
步骤3:(3-((R)-1-((6-((1R,4R)-4-(4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯的制备
将1-(2-氯-5-(4-((哌啶-4-基甲氧基-d
2)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(220mg,0.39mmol)用DMF(10mL)溶解,然后分别加入(1R,4R)-4-(4-(((R)-1-(3-((叔丁氧羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(150mg,0.24mmol),HATU(118mg,0.31mmol)和N,N-二异丙基乙胺(93mg,0.72mmol),室温下搅拌2小时,加水(100mL),用乙酸乙酯(30mLx3)萃取,饱和食盐水(100mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(甲醇:二氯甲烷=1:9)纯化得到(3-((R)-1-((6-((1R,4R)-4-(4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=1049.3.
步骤4:1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基-d
2)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(3-((R)-1-((6-((1R,4R)-4-(4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基-d
2)哌啶-1-羰基)环己基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)羧酸叔丁酯(200mg,0.19mmol)用二氯甲烷(5mL)溶解,加入三氟乙酸(2mL),室温搅拌2小时后,反应液减压浓缩,所得粗产物用10%甲醇/二氯甲烷混合溶液(20mL)溶解,然后加入5%碳酸氢钠水溶液(20mL)并搅拌1小时,静置分离,有机相经无水硫酸钠干燥,过滤,减压浓缩得到粗品,粗品经pre-HPLC(CH
3CN/0.08%NH
4HCO
3水溶液,5%~95%)纯化得到1-(5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基-d
2)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=949.2.
1H NMR(400MHz,DMSO-d
6)δ10.49(s,1H),8.13(d,J=7.7Hz,1H),8.06(s,1H),7.63(d,J=8.2Hz,1H),7.54(d,J=2.0Hz,1H),7.37(dd,J=8.2,2.0Hz,1H),6.99(s,1H),6.86(d,J=10.1Hz,2H),6.70(s,1H),5.57(dd,J=17.7,10.2Hz,3H),4.42(d,J=12.0Hz,2H),3.92(m,4H),3.81–3.51(m,3H),3.24(d,J=6.2Hz,2H),3.09–2.88(m,3H),2.78–2.60(m,4H),2.36(s,3H),1.90–1.52(m,18H),1.19–0.92(m,4H).
实施例52:(R)-2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)-N-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)乙基)乙酰胺
步骤1:6-溴-2-甲基喹唑啉-4-醇的制备
将2-氨基-5-溴苯甲酰胺(4.0g,14.55mmol)加入到原乙酸三甲酯(17.46g,145.5mmol)的甲醇(100mL)溶液中,在闷罐中120℃搅拌过夜,冷却后减压浓缩,得到粗产品6-溴-2-甲基喹唑啉-4-醇,无需纯化直接用于下步反应。
LC-MS:(ESI,m/z):[M+H]
+=238.9.
步骤2:4-(4-羟基-2-甲基喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的制备
将6-溴-2-甲基喹唑啉-4-醇(5.00g,16.67mmol)用DMF/H
2O(200mL/20ml)溶解,然后分别加入碳酸钾(5.80g,42.03mmol),Pd(dppf)Cl
2(1.54g,2.10mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(7.79g,25.21mmol),反应液在氮气保护下110℃搅拌过夜,加水(500mL)稀释,用乙酸乙酯(200mL×3)萃取,有机相用饱和食盐水洗(200mL),无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(PE:EA=1:2)纯化得到4-(4-羟基-2-甲基喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=342.1.
步骤3:4-(4-羟基-2-甲基喹唑啉-6-基)哌啶-1-羧酸叔丁酯的制备
将4-(4-羟基-2-甲基喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(2.5g,14.55mmol)加入到Pd(OH)
2(800mg,20%)的甲醇(100mL)溶液中,在H
2氛围下高压釜中70℃搅拌过夜(10atm),冷却后过滤,减压浓缩,得到粗产品4-(4-羟基-2-甲基喹唑啉-6-基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=344.1.
步骤4:(R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯的制备
将BOP(3.30g,7.47mmol)和DBU(1.90g,12.5mmol)和(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺(1.53g,6.54mmol)分别加入到4-(4-羟基-2-甲基喹唑啉-6-基)哌啶-1-羧酸叔丁酯(1.73g,5.03mmol)的DMF(100mL)溶液中,反应液70℃搅拌过夜,用水(300mL)稀释,乙酸乙酯(100mL)萃取,饱和食盐水(150mL)洗涤有机相,经无水硫酸钠干燥,过滤,减压浓缩,粗品使用反相柱层析(H
2O:ACN=1:2)纯化得到(R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=560.4.
步骤5:(R)-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-基)喹唑啉-4-胺的制备
将(R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-羧酸叔丁酯(300mg,0.537mmol)加入到TFA(2mL)的二氯甲烷(20mL)中,常温搅拌1小时,减压浓缩,得到粗产品(R)-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-基)喹唑啉-4-胺。
LC-MS:(ESI,m/z):[M+H]
+=460.4.
步骤6:(R)-2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酸叔丁酯的制备
将(R)-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(哌啶-4-基)喹唑啉-4-胺(250mg,0.543mmol)和碳酸钾(300mg,2.17mmol)加入到2-溴乙酸叔丁酯(138mg,0.708mmol)的THF(20mL)溶液中并在70℃搅拌过夜,反应液用水稀释(50ml),用乙酸乙酯(50mL×3)萃取,用无水硫酸钠干燥,过滤,减压浓缩, 粗品经柱层析(PE:EA=5:1)纯化得到(R)-2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=574.3.
步骤7:(R)-2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酸的制备
将(R)-2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酸叔丁酯(300mg,0.524mmol)加入到HCl/1,4-二氧六环(4M,20mL)中,常温搅拌过夜,反应液直接减压浓缩,得到粗品(R)-2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酸。
LC-MS:(ESI,m/z):[M+H]
+=518.1.
步骤8:(R)-9-(2-(2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酰胺)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将(R)-2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酸(167mg,0.323mmol),HATU(154mg,0.405mmol)和DIEA(105mg,0.814mmol)加入到9-(2-氨乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(80mg,0.27mmol)的DMF(20mL)溶液中,反应液室温搅拌过夜,用水稀释(50mL),用乙酸乙酯(50mL×3)萃取,粗品使用反相柱层析(ACN:H
2O=1:3)纯化得到(R)-9-(2-(2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酰胺)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=796.4.
步骤9:(R)-9-(2-(2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)乙酰胺)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯的制备
将(R)-9-(2-(2-(4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)哌啶-1-基)乙酰胺)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(70mg,0.088mmol)用乙醇(10mL)溶解,然后分别加入Raney-Ni(0.3mL,水悬浮物),水合肼一水合物(0.2mL),反应液室温搅拌1小时,过滤,减压浓缩,得到粗品(R)-9-(2-(2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)乙酰胺)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=766.6.
步骤10:(R)-N-(2-(3-氮杂螺[5.5]十一烷-9-基)乙基)-2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)乙酰胺的制备
将(R)-9-(2-(2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)乙酰胺)乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(65mg,0.085mmol)用DCM(10mL)溶解,加入TFA(1mL),反应液常温搅拌1小时,直接减压浓缩,得到粗产品(R)-N-(2-(3-氮杂螺[5.5]十一烷-9-基)乙基)-2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)乙酰胺。
LC-MS:(ESI,m/z):[M+H]
+=666.4.
步骤11:(R)-2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)-N-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)乙基)乙酰胺的制备
将(R)-N-(2-(3-氮杂螺[5.5]十一烷-9-基)乙基)-2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)乙酰胺(50mg,0.075mmol)用DMSO(10mL)溶解,然后分别加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(40mg,0.092mmol)和DIEA(30mg,0.232mmol),反应液室温搅拌过夜,用水稀释(20mL),二氯甲烷萃取(30mL×3),有机相减压浓缩,粗品使用反相制备纯化得到(R)-2-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)哌啶-1-基)-N-(2-(3-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)-3-氮杂螺[5.5]十一烷-9-基)乙基)乙酰胺。
LC-MS:(ESI,m/z):[M+H]
+=916.5.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.27(d,J=7.9Hz,1H),8.21(s,1H),7.70-7.58(m,3H),7.52(d,J=8.7Hz,2H),7.37(dd,J=8.2,1.8Hz,1H),6.90(s,1H),6.86(s,1H),6.70(s,1H),5.64–5.43(m,3H),3.79–3.69(m,1H),3.59-3.45(m,3H),3.28–3.20(m,2H),3.17-3.07(m,2H),2.98-2.86(m,4H),2.77–2.70(m,2H),2.69–2.56(m,1H),2.38(s,3H),2.26-2.14(m,2H),1.92–1.77(m,4H),1.74-1.63(m,2H),1.56–1.20(m,12H),1.14-0.94(m,4H).
实施例53:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:9-((4-((1R,4R)-4-(2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯的制备
将(1R,4R)-4-(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羧 酸(170mg,0.337mmol),HATU(192mg,0.505mmol)和DIEA(130mg,1.01mmol)加入到9-(哌嗪-1-基甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯的DMF(30mL)溶液中,室温搅拌过夜,反应液用水稀释(50mL),二氯甲烷(50mL×3)萃取,粗品经反相柱层析(ACN:H
2O=1:2)纯化得到9-((4-((1R,4R)-4-(2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=871.6.
步骤2:9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯的制备
将9-((4-((1R,4R)-4-(2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯(240mg,0.276mmol)溶于乙醇(20mL),加入Raney-Ni(水悬浮物,0.3mL)和水合肼一水合物(85%,0.5mL),反应液室温搅拌1小时,过滤,减压浓缩,得到粗品9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯。
LC-MS:(ESI,m/z):[M+H]
+=841.6.
步骤3:(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-基)((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己基)甲酮的制备
将9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羧酸苄酯(220mg,0.262mmol)溶于乙酸乙酯(20mL),加入Pd(OH)
2(44mg,20%),反应液在H
2氛围下70℃搅拌过夜,过滤,减压浓缩,得到粗品(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-基)((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己基)甲酮。
LC-MS:(ESI,m/z):[M+H]
+=707.4.
步骤4:1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(4-((3-氮杂螺[5.5]十一烷-9-基)甲基)哌嗪-1-基)((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)环己基)甲酮(200mg,0.283mmol)用DMSO(20mL)溶解,分别加入perfluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate(147mg,0.338mmol)和DIEA(110mg,0.853mmol),反应液室温搅拌过夜,用水稀释(50mL),二氯甲烷萃取(50mL×3),有机相减压浓缩,粗品使用反相制备纯化得到1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基 吡啶并[3,4-d]嘧啶-6-基)环己烷-1-羰基)哌嗪-1-基)甲基)-3-氮杂螺[5.5]十一烷-3-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=957.4.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.91(s,1H),8.58(d,J=7.9Hz,1H),8.19(s,1H),8.10(s,1H),7.63(d,J=8.2Hz,1H),7.55(d,J=1.9Hz,1H),7.39(dd,J=8.2,1.9Hz,1H),6.89(s,1H),6.85(s,1H),6.71(s,1H),5.61–5.47(m,3H),3.78–3.72(m,1H),3.64–3.56(m,3H),3.54-3.41(m,6H),3.30-3.24(m,2H),2.82-2.71(m,3H),2.70-2.61(m,1H),2.43(s,3H),2.36-2.21(m,4H),2.17-2.07(m,2H),2.04–1.98(m,2H),1.85-1.71(m,2H),1.77-1.31(m,18H),1.16-0.90(m,4H).
实施例54:1-(2-氯-5-(4-(3-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:1-(2-氯-5-(4-(3-(哌啶-4-基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将1,3-二(哌啶-4-基)丙烷(193.5mg,0.92mmol)和DIEA(178mg,1.38mmol)溶于DMSO(10mL)中,加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(200mg,0.46mmol),室温反应30min。用水(30mL)稀释,乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(40mL)洗,无水硫酸钠干燥,减压浓缩,粗品使用柱层析(MeOH:DCM=1:9,流速40ml/min)纯化得到1-(2-氯-5-(4-(3-(哌啶-4-基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=461.2.
步骤2:1-(2-氯-5-(4-(3-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(100mg,0.17mmol),1-(2-氯-5-(4-(3-(哌啶-4-基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(80mg,0.17mmol)和DIEA(65.8mg,0.51mmol)用DMF(5mL)溶解,最后加入HATU(77.5mg,0.20mmol),反应液室温搅拌30min,用水(20mL)稀释,乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(40mL)洗,无水硫酸钠干燥,减压浓缩,粗品使用prep-HPLC纯化得到1-(2-氯-5-(4-(3-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)丙基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1035.5.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.31(d,J=8.1Hz,1H),8.05(s,1H),7.63(d,J=8.2Hz,1H),7.54(d,J=1.6Hz,1H),7.43-7.35(m,4H),7.24(s,1H),7.02(s,1H),6.96(s,1H),6.05-5.83(m,1H),4.52-4.35(m,2H),3.95-3.80(m,4H),3.80-3.69(m,1H),3.67-3.50(m,2H),3.20-3.08(m,2H),3.06-2.87(m,3H),2.83-2.70(m,3H),2.68-2.57(m,1H),2.42(s,3H),2.01(s,6H),1.92-1.39(m,18H),1.36-1.15(m,6H),1.13-0.82(m, 4H).
实施例55:1-(2-氯-5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
步骤1:4-((吡啶-4-基甲氧基)甲基)哌啶-1-羧酸叔丁酯的制备
将4-(羟基甲基)哌啶-1-羧酸叔丁酯(1.0g,4.65mmol)溶于THF(40mL)溶液中,0℃下加入NaH(744mg,18.6mmol,60%),搅拌2h,然后加入4-(溴甲基)吡啶(795mg,4.65mmol),反应液室温继续搅拌2h,用水(100mL)稀释,乙酸乙酯(100mL×2)萃取,无水硫酸钠干燥,过滤,减压浓缩,粗品使用柱层析(乙酸乙酯:石油醚=1:0)纯化得到4-((吡啶-4-基甲氧基)甲基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+Na]
+=329.1.
步骤2:4-((哌啶-4-基甲氧基)甲基)哌啶-1-羧酸叔丁酯的制备
将4-((吡啶-4-基甲氧基)甲基)哌啶-1-羧酸叔丁酯(300mg,0.98mmol)溶于i-PrOH/H
2O(6:7,26mL)溶液中,氢气氛围下,加入Pd(OH)/C(100mg,20%),反应液在75℃搅拌过夜,硅藻土过滤,滤液直接减压浓缩得到4-((哌啶-4-基甲氧基)甲基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+H]
+=313.2.
步骤3:4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基)哌啶-1-羧酸叔丁酯的制备
将4-((哌啶-4-基甲氧基)甲基)哌啶-1-羧酸叔丁酯(120mg,0.38mmol)和DIEA(147mg,1.14mmol)加入到DMSO(10mL)中,然后加入4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酸五氟苯酯(165mg,0.38mmol),反应液室温搅拌30min,用水(40mL)稀释,乙酸乙酯(40mL×3)萃取,有机相用饱和食盐水(40mL)洗,无水硫酸钠干燥,减压浓缩,粗品使用柱层析(PE:EA=10:1)纯化得到4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基)哌啶-1-羧酸叔丁酯。
LC-MS:(ESI,m/z):[M+NH
4]
+=580.2.
步骤4:1-(2-氯-5-(4-((哌啶-4-基甲氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
将4-(((1-(4-氯-3-(2,4-二氧代四氢嘧啶-1(2H)-基)苯甲酰)哌啶-4-基)甲氧基)甲基)哌啶-1-羧酸叔丁酯(80mg,0.14mmol)用二氯甲烷(5mL)溶解,加入氯化氢二氧六环溶液(4M,2mL),反应液室温搅拌3小时,直接减压浓缩得到1-(2-氯-5-(4-((哌啶-4-基甲氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=463.1.
步骤5:1-(2-氯-5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
(1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羧酸(65mg,0.11mmol)用DMF(5mL)溶解,HATU(50mg,0.13mmol),DIEA(50mg,0.39mmol)和1-(2-氯-5-(4-((哌啶-4-基甲氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮(60mg,0.13mmol)分别加入,反应液室温搅拌30min,用水(20mL)稀释,乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(20mL)洗,无水硫酸钠干燥,减压浓缩,粗品使用prep-HPLC纯化得到1-(2-氯-5-(4-(((1-((1R,4R)-4-(4-(((R)-1-(4-(2-氯-6-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)环己烷-1-羰基)哌啶-4-基)甲氧基)甲基)哌啶-1-羰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮。
LC-MS:(ESI,m/z):[M+H]
+=1037.4.
1H NMR(400MHz,DMSO-d
6)δ10.51(s,1H),8.31(d,J=8.1Hz,1H),8.05(s,1H),7.63(d,J=8.2Hz,1H),7.54(d,J=1.8Hz,1H),7.47-7.29(m,4H),7.24(s,1H),7.02(s,1H),6.96(s,1H),6.02-5.90(m,1H),4.52-4.32(m,2H),3.98-3.91(m,1H),3.89(s,3H),3.80-3.69(m,1H),3.66-3.54(m,2H),3.28-3.17(m,4H),3.15-3.09(m,2H),3.09-2.89(m,3H),2.84-2.69(m,3H),2.69-2.60(m,2H),2.42(s,3H),2.01(s,6H),1.91-1.46(m,17H),1.20-0.89(m,4H).
Ⅱ生物活性测试实施例
测试实施例1:KRAS G12C/SOS1结合试验
以下方法用于测定本发明优选化合物在体外条件下对KRAS-G12C/SOS1结合抑制程度。本方法使用KRAS-G12C/SOS1结合试验试剂盒(Cisbio,63ADK000CB16PEG),以均相时间分辨荧光技术(HTRF)测定优选化合物对KRAS-G12C/SOS1结合竞争抑制测定。
实验流程如下(详细方法参考试剂盒说明书):将本发明中的化合物先溶解于DMSO中,浓度为20mM,用试剂盒中的缓冲液进行等梯度稀释,使受试化合物在反应体系中的终浓度范围为10000nM~0.04nM,DMSO的终浓度为0.5%。将2μL化合物与4μL 1x Tag1-SOS1、4μL 1xTag2-KRAS-G12C(含10μM三磷酸鸟苷,GTP)在25℃下孵育15min,随后向反应体系中加入5μL 1x Anti-Tag1-Tb3+以及5μL 1x Anti-Tag2-XL665在冰上下孵育3h。孵育结束后,在酶标仪EnVision(PerkinElmer,2105)上以HTRF模式测定各孔在激发波长为337nm,读取各孔在发射波长为620nm和665nm的荧光强度,使用公式Ratio=(665nm/620nm)×104算出Ratio值。通过与对照组荧光强度比值进行对比,计算化合物在各浓度下的抑制率,进而通过GraphPad Prism 8以对数浓度-抑制率进行非线性曲线拟合,得出化合物的IC50值。
测试实施例2:SOS1降解试验
在KRAS G12C突变的人非小细胞肺癌细胞NCI-H358(ATCC或中国科学院干细胞库)、KRAS G12D 突变的人肺癌细胞A-427(ATCC)、KRAS G12V突变的人结直肠腺癌细胞SW-620(ATCC)和KRAS G13D突变的人结直肠腺癌上皮细胞DLD-1(ATCC)上考察化合物对SOS1的降解作用。具体方法为:
在24孔细胞培养板每孔中铺0.95mL细胞,使细胞密度为5×105个/孔;细胞板置于5%CO
2培养箱中37℃培养过夜。然后在相应铺有细胞的孔中加入50μL稀释后的化合物溶液,使化合物的终浓度在0.03~3000nM范围内。DMSO终浓度为0.25%。给药后的细胞板置于5%CO
2培养箱中37℃培养24h后,移除24孔中细胞培养液后,用1×PBS清洗2次,细胞培养板底部贴壁的NCI-H358细胞加入180μL RIPA(强)裂解液(碧云天,P0013B),补充1mM苯甲基磺酰氟、蛋白酶抑制剂混合物(碧云天,P1008)以及蛋白酶磷酸酶抑制剂混合物(碧云天,P1045)裂解,冰上静置30min后,将每孔中的蛋白裂解液分别转移至1.5mL离心管中,15000g、4℃离心20min。离心后的细胞裂解上清液冻存于-80℃待测,用于WB方法检测SOS1蛋白降解水平。细胞裂解上清液中总蛋白浓度使用BCA蛋白质定量试剂盒(天根,PA115-02)测定。
测试实施例3:人SOS1蛋白免疫印迹试验
根据BCA检测细胞裂解液中总蛋白的浓度,用PBS和5×SDS-PAGE蛋白上样缓冲液(碧云天,P0015L)调整至0.5μg/μL,100℃水浴15min,然后置于冰上冰浴5min后,14000g、4℃离心1min,混匀作为WB的上样样品。用预制胶(凯基,KGMG010W15)做蛋白电泳,上样量为10μL(总蛋白5μg),Tris-MOPS-SDS电泳液(Adamas,P1598253)后120V 55min恒压电泳,电泳结束后,恒流250mA 65min把胶条上的蛋白转至PVDF膜上。转膜结束后将膜放入1×QuickBlock封闭液(碧云天,P0235)中室温孵育30min。封闭结束后,PVDF膜分别进行SOS1一抗(Abcam,ab140621)孵育4℃过夜,TBST缓冲液(2.4g Tris,8.8g NaCl,1.5mL Tween 20,调pH至7.4,定容至1L)洗涤膜30min(10min/次),二抗(Abcam,ab205718)室温孵育2h,TBST缓冲液洗涤膜30min(10min/次),最后用Clarity Western ECL Substrate(BIO-RAD,170-5061)孵育5min发光显色,化学发光成像系统(勤翔,ChemiScope 6200Touch)进行显色和蛋白图谱拍照。蛋白图谱通过勤翔化学发光分析软件进行灰度值分析。使用公式:灰度校正值=(目的蛋白灰度值/对应内参灰度值)×103,计算出各样品的灰度校正值。再与对照组灰度校正值对比计算降解率。进而通过GraphPad Prism 8以对数浓度-抑制率进行非线性曲线拟合,得出化合物的DC50和Dmax值。
测试实施例4:3D细胞增殖抑制试验
在KRAS G12C突变的人非小细胞肺癌细胞NCI-H358(ATCC或中国科学院干细胞库)、KRAS G12D突变的人转移胰腺腺癌细胞AsPC-1(ATCC)、KRAS G12V突变的人肺腺癌细胞NCI-H441(ATCC)和KRAS G13D突变的人结直肠腺癌上皮细胞DLD-1(ATCC)上考察化合物对3D细胞增殖的抑制作用。具体方法为:
在384孔低吸附微孔板(Corning,3657)相应微孔中用Echo声波移液系统(Labcyte,Echo 550)加入200nL化合物梯度稀释溶液,使受试化合物在反应体系中的终浓度范围为20000nM~0.008nM。然后将40μL一定密度的细胞加入对应的微孔板中。除受试化合物测试孔外,同时设置DMSO对照孔和培养基对照孔,DMSO对照孔中含有DMSO和细胞,培养基孔中只含有培养基。加样完成后盖上板盖,将测384孔低吸附微孔板放入5%二氧化碳培养箱中,37℃孵育7天。7天后取出微孔板,每孔加入40μL CTG试剂(Promega,G9683),室温孵育30分钟后在酶标仪EnVision上采用化学发光程序读数。通过细胞增殖抑制百分比计算公式:抑制率%=(DMSO对照组平均值-化合物单浓度读值)/(DMSO对照组平均值-培养基对照组平均值)×100,计算化合物在各浓度时的抑制率,进而通过GraphPad Prism 8以对数浓度-抑制率进行非线性曲线拟合,得出化合物的IC50值。
表1
表2
表1和表2中:
“-”表示未检测。
当DC
50≤50nM为A,当50nM<DC
50≤100nM时为B,当100nM<DC
50≤500nM为C,当500nM<DC
50≤1000nM为D;1000nM<DC
50≤10μM为E;
当80≤D
max(%)≤100时为A,当50≤D
max(%)<80时为B,当30≤D
max(%)<50时为C,当D
max(%)<30时为D;
当IC
50≤15nM为A,当15nM<IC
50≤30nM时为B,当30nM<IC
50≤50nM为C,当50nM<IC
50≤100nM为D,当100nM<IC
50≤1000nM为E。
实验结论:本发明化合物能够有效的与SOS1靶蛋白结合或产生抑制效果,本发明所述化合物能够有效的特异性的降解SOS1蛋白。
Claims (32)
- 一种式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐:S-L-EⅠ其中:S为能够抑制SOS1蛋白活性或与SOS1蛋白相结合的小分子化合物;L为连接链,其通过共价键连接S和E;E为E7a;其中所述E7a中:W为CH 2、CR aR b、C(S)、C(O)或SO 2;X为H 2、CH 2、O或S;Z为H 2、CH 2、O或者S;G选自氢、C 1-C 6烷基、OH、任选被R′取代的-CH 2-杂环烷基、任选被R′取代的-CH 2-苯基;Q 1、Q 2、Q 3、Q 4各自独立的为碳、氮或者氮氧化物;A为氢、C 1-C 6烷基、环烷基或卤素;R独立的选自氢、羟基、卤素、-NH 2、-N(C 1-C 6烷基) 1-2、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、-CONR′R″、-OR′、-NR′R″、-SR′、-SO 2R′、-SO 2NR′R″、-CR′R″、-CR′NR′R″、芳基、杂芳基、C 3-C 8环烷基、3-8元杂环烷基、-P(O)(OR′)R″、-P(O)R′R″、-OP(O)(OR′)R″、-Cl、-F、-Br、-I、-CF 3、-CN、-NR′SO 2NR′R″、-NR′C(O)NR′R″、-C(O)NR′C(O)R″、-NR′C(=N-CN)NR′R″、-C(=N-CN)NR′R″、-NR′C(=N-CN)R″、-NR′C(=C-NO 2)NR′R″、-SO 2NR′COR″、-NO 2、-COR′、-C(C=N-OR′)R″、-CR′=CR′R″、-CCR′、-S(C=O)(C=N-R′)R″、-SF 5或-OCF 3;R′和R″各自独立的选自键、氢、C 1-C 6烷基、环烷基、芳基、杂芳基或杂环烷基;n″为1-4的整数;
- 如权利要求1所述的式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐,其中,和/或,W为CH 2或C(O);和/或,所述E7a中,X为O;和/或,所述E7a中,Z为O;和/或,所述E7a中,G为氢;和/或,所述E7a中,Q 1为碳;和/或,所述E7a中,Q 2为碳;和/或,所述E7a中,Q 3为碳;和/或,所述E7a中,Q 4为碳;和/或,所述E7a中,A为氢;和/或,所述E7a中,R为氢。
- 如权利要求1所述的式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐,其中,E为E7a-1或E7a-2:其中所述E7a-1中:Q 1、Q 2、Q 3和Q 4各自独立的为碳或氮;W为C(O)或CH 2;A为氢、C 1-C 6烷基或卤素;R选自氢、羟基、卤素、-NH 2、-N(C 1-C 6烷基) 1-2、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基;n″为1、2、3或4;其中所述E7a-2中:W为CH 2或C(O);A为氢、甲基、Cl或F;R各自独立的选自氢、羟基、NH 2、C 1-C 6烷基或C 1-C 6烷氧基;n″为1、2、3或4;
- 如权利要求1-6中任一项所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐,所述S为S1、S1'、-X-S1'、S1”、-X-S1”、S2、S2'、-X-S2'、S2”、-X-S2”、S3、S4、S5、S5'或-X-S2”:X为O、NH或S,优选为O;其中所述S1、S1'、S1”中:R 1选自氢、卤素、-OH、-CN、-NO 2、C 1-C 6烷基巯基或-NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 1选自C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷氧基、C 3-C 6杂环烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、C 1-C 6卤代烷基、-COOH、-COOR c;所述R c为-C 1-C 6烷基、C 3-C 6烯基、C 3-C 6炔基、C 3-C 8环烷基或-C 4-C 8环烯基;R 1为-NS(O)(R d)(R e),所述C 1-C 6和R e各自独立的为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、6-10元芳基或5-10元杂芳基;R 1为-NHC(O)-(C 1-C 6烷基)、-NHC(O)-NR aR b,所述R a和R b各自独立的为氢、-C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 1为-NH-(CH 2) k-NH-C(O)-R aa,所述R aa为C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基,且k为1或者2;R 1为-NH-(CH 2) i-R f,所述i为0,1或者2且R f为4-7元杂环烷基、杂芳基、C 1-C 6烷基磺酰基;此外以上所述C 1-C 6烷基、C 1-C 6烷氧基、4-7元杂环烷基和杂芳基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-NO2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、4-7元杂环烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 1-C 6烷基磺酰基、苯基、苄基、杂芳基、-(CH 2)-杂芳基、-NHC(O)(C 1-C 6烷基)、C 3-C 8环烷氧基、苯氧基、杂芳基氧基或者-NR aR b的基团取代;所述R a和R b各自独立的选自氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 1为-O-(CH 2) z-苯基、-O-(CH 2) z-(4-7元杂环烷基)、-O-(CH 2) z-杂芳基,所述z为0,1或2,所述苯基、杂环烷基和杂芳基任选的被选自-OH、杂环烷基或者杂环烯基取代,且能被甲基或者氧代基取代;或者R 1为或者相邻2个R 1与它们各自连接的碳原子一起形成5-7元环烷基或5-7元杂环烷基;且所述x为1、2或者3;A 1为C 4-C 12环烷基、杂环烷基、芳基或杂芳基;R 2为氢、-OH、氧代、卤素、-CN、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、-C 2-C 6炔基、-C 3-C 8环烷基、-C 3-C 8环烷氧基、-C 3-C 8卤代环烷氧基、-C 4-C 8环烯基、4-7元杂环烷基、-O-CH 2-4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、-C 1-C 6卤代烷基、-C 1-C 6卤代烷氧基、-C 1-C 6烷基磺酰基;R 2为-NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基或-C(O)C 1-C 3烷基;R 2为-C(O)NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2为-C(O)OR g,所述R g为氢或C 1-C 6烷基;R 2为-OR h;所述R h为C 1-C 6烷基;R 2为-(CH 2)NR aR b,所述R a和R b各自独立的氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;且w为1、2、3或4;所述A 2(R 3) Y为氢;或者A 2为C 4-C 12环烷基、杂环烷基、芳基或杂芳基,且R 3为氢、卤素、-OH、氧代、-CN、-NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、C 7-C 8环炔基、4-7元杂环烷基、5-10元杂环烯基、苯基、杂芳基、C 1-C 6卤代烷基;所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-C 1-C 6烷基、-C 1-C 6烷氧基、-C 1-C 6卤代烷基、苯基、杂芳基或-C(O)NR iR j的取代基取代,所述R i和R j各自独立的为氢或者C 1-C 6烷基;或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR kR l取代,所述R k和R l各自独立的为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 1-C 6烷基磺酰基、苯基、杂芳基、-CH 2-C(O)-R m、-C(O)R p或4-7元杂环烷基,且所述烷基、炔基、烯基、环烷基、苯基、杂芳基和杂环烷基各自独立的任选的被1个、2个或3个选自C 1-C 6卤代烷基、-OH、氧代基、苯基、-CN、C 1-C 6烷氧基或杂芳基取代,且所述杂芳基任选被甲基取代;且所述R m为双环杂芳基、C 1-C 6烷氧基或者-NR nR o,所述R n和R o各自独立的为氢、C 1-C 6烷基或者苯基,所述烷基任选被C 1-C 6烷氧基或者苯基取代,或者-NR nR o为4-7元氮杂环烷基,所述氮杂环烷基通过N原子连接分子其他部位,且还包含1个或者多个选自N或者O的杂原子;所述R p选自C 1-C 6烷氧基、任选被1个、2个或者3个选自-OH或者C 1-C 6烷氧基取代的C 1-C 6烷基、单环或双环杂芳基、4-7元杂环烷基或者R p为-CH 2-NR qR r,所述R q和R r各自独立的选自氢、苯基或者任选被F取代的C 1-C 6烷基;或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR sR t取代,所述-NR sR t为通过氮原子连接至分子其他部位的4-7元氮杂环烷基或者通过氮原子连接至分子其他部位的6-10元氮螺杂环烷基,且进一步包括最多两个选自N或者O的杂原子,且任选的被1个、2个或者3个选自-OH、氧代基、C 1-C 6烷基、C 1-C 6羟基烷基、-C(O)OR z的取代基取代,所述R z为C 1-C 6烷基、卤素、-N(C 1-C 6烷基) 2、-CH 2N(C 1-C 6烷基) 2、-C(O)NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;或者R 3为C(O)R v、-C(O)NH 2、-C(O)NHR v、-C(O)NR vR w、-C(O)OR v,所述R v和R w各自独立的为氢、C 1-C 4烷基、C 1-C 4卤代烷基、苯基或者-(CH 2) 2NR xR y,所述R x和R y各自独立的为氢、C 1-C 4烷基或者- (CH 2) 2N(CH 3) 2;或者R 3为-NH 2、-NHR z、-NR zR za、-NHC(O)R z、-NHC(O)O R z、-NHS(O) 2R z、4-7元杂环烷基、杂芳基、螺杂环烷基、稠杂环烷基、桥杂环烷基,所述R z和R za各自独立的为C 1-C 4烷基、C 1-C 4卤代烷基或者苯基;或者R 3为C 1-C 6烷氧基、C 1-C 6卤代烷氧基、-O(CH 2) s-C 3-C 8环烷基、-O(CH 2) s-苯基、-O(CH 2) s-杂环烷基、-O(CH 2) s-杂芳基,所述s为0、1、2或者3;或者R 3为-S(O) 2R z、-S(O) 2NH 2、-S(O) 2NHR z、-S(O) 2NR zR za,所述R z和R za各自独立的为C 1-C 4烷基、C 1-C 4卤代烷基或者苯基,所述y为0、1、2或者3;Y为0、1、2、3、4或5;L'为键、-(CH 2) k-、-O(CH 2) k-、-(CH 2) k-O-或者-O-(CH 2) k-O-,所述k为0、1、2或者3,或者L'为-CH=CH-(CH 2) n-,所述n为0、1或者2;R 4、R 5各自独立的为C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基或C 3-C 6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基或卤素取代;其中所述S2、S2'、S2”中:R 1为氢、卤素、-OH、-CN、-NO 2、C 1-C 6烷基巯基或-NR aR b;所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 1选自C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷氧基、C 3-C 6杂环烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、C 1-C 6卤代烷基、-COOH、-COOR c;所述R c为-C 1-C 6烷基、C 3-C 6烯基、C 3-C 6炔基、C 3-C 8环烷基或-C 4-C 8环烯基;R 1为-NS(O)(R d)(R e),所述R d和R e各自独立的为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基;R 1为-NHC(O)-(C 1-C 6烷基)、-NHC(O)-NR aR b,所述R a和R b各自独立的为氢、-C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 1为-NH-(CH 2) k-NH-C(O)-(C 1-C 6烷基),所述k为1或者2;R 1为-NH-(CH 2) i-R f,所述i为0、1或者2且R f为4-7元杂环烷基、杂芳基、C 1-C 6烷基磺酰基;此外以上所述C 1-C 6烷基、C 1-C 6烷氧基、4-7元杂环烷基和杂芳基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、4-7元杂环烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 1-C 6烷基磺酰基、苯基、苄基、杂芳基、-(CH 2)-杂芳基、-NHC(O)(C 1-C 6烷基)、C 3-C 8环烷氧基、苯氧基、杂芳基氧基或者-NR aR b的基团取代;所述R a和R b各自独立的选自氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 1为-O-(CH 2) z-苯基、-O-(CH 2) z-(4-7元杂环烷基)、-O-(CH 2) z-杂芳基,所述z为0,1或2,所述苯 基、杂环烷基和杂芳基任选的被选自-OH、杂环烷基或者杂环烯基取代,且能被甲基或者氧代基取代;或者R 1为或者R 1为或者相邻2个R 1与它们各自连接的碳原子一起形成5-7元环烷基或5-7元杂环烷基;且所述x为1、2、3或者4;A 1为C 4-C 12环烷基、杂环烷基、芳基或杂芳基;R 2为氢、-OH、氧代、卤素、-CN、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、-C 2-C 6炔基、-C 3-C 8环烷基、-C 3-C 8环烷氧基、-C 3-C 8卤代环烷氧基、-C 4-C 8环烯基、4-7元杂环烷基、-O-CH 2-4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、-C 1-C 6卤代烷基、-C 1-C 6卤代烷氧基、-C 1-C 6烷基磺酰基;R 2为-NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2为-C(O)NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2为-C(O)OR g,所述R g为氢或C 1-C 6烷基;R 2为-OR h;所述R h为C 1-C 6烷基;R 2为-(CH 2)NR aR b,所述R a和R b各自独立的氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;且w为1、2、3或者4;所述A 2(R 3) Y为氢;或者A 2为C 4-C 12环烷基、杂环烷基、芳基或杂芳基,且R 3为氢、卤素、-OH、氧代、-CN、-NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、C 2-C 8环炔基、4-7元杂环烷基、5-10元杂环烯基、苯基、杂芳基、C 1-C 6卤代烷基;所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-C 1-C 6烷基、-C 1-C 6烷氧基、-C 1-C 6卤代烷基、苯基、杂芳基或-C(O)NR iR j的取代基取代,所述R i和R j各自独立的为氢或者C 1-C 6烷基;或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR kR l取代,所述R k和R l各自独立的为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 1-C 6烷基磺酰基、苯基、杂芳基、-CH 2-C(O)-R m、-C(O)R p或4-7元杂环烷基,且所述烷基、炔基、烯基、环烷基、苯基、杂芳基和杂环烷基各自独立的任选的被1个、2个或3个选自C 1-C 6卤代烷基、-OH、氧代基、苯基、-CN、C 1-C 6烷氧基或杂芳基取代,且所述杂芳基任选被甲基取代;且所述R m为双环杂芳基、C 1-C 6烷氧基或者-NR nR o,所述R n和R o各自独立的为氢、C 1-C 6烷基或者苯基,所述烷基任选被C 1-C 6烷氧基或者苯基取代,或者-NR nR o为4-7元氮杂环烷基,所述氮杂环烷基通过N原子连接分子其他部位,且还包含1个或者多个选自N或者O的杂原子;所述R p选自C 1-C 6烷氧基、任选被1个、2个或者3个选自-OH或者C 1-C 6烷氧基取代的C 1-C 6烷基、单环或双环杂芳基、4-7元杂环烷基或者R p为-CH 2-NR qR r,所述R q和R r各自独立的选自氢、苯基或者任选被F取代的C 1-C 6烷基;或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR sR t取代,所述-NR sR t为通过氮原子连接至分子其他部位的4-7元氮杂环烷基或者通过氮原子连接至分子其他部位的6-10元氮螺杂环烷基,且进一步包括最多两个选自N或者O的杂原子,且任选的被1个、2个或者3个选自-OH、氧代基、C 1-C 6烷基、C 1-C 6羟基烷基、-C(O)OR z的取代基取代,所述R z为C 1-C 6烷基、卤素、-N(C 1-C 6烷基) 2、-CH 2N(C 1-C 6烷基) 2、-C(O)NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;或者R 3为C(O)R v、-C(O)NH 2、-C(O)NHR v、-C(O)NR vR w、-C(O)OR v,所述R v和R w各自独立的为氢、C 1-C 4烷基、C 1-C 4卤代烷基、苯基或者-(CH 2) 2NR xR y,所述R x和R y各自独立的为氢、C 1-C 4烷基或者-(CH 2) 2NH(CH 3) 2;或者R 3为-NH 2、-NHR z、-NR zR za、-NHC(O)R z、-NHC(O)O R z、-NHS(O) 2R z、4-7元杂环烷基、杂芳基、螺杂环烷基、稠杂环烷基、桥杂环烷基,所述R z和R za各自独立的为C 1-C 4烷基、C 1-C 4卤代烷基或者苯基;或者R 3为C 1-C 6烷氧基、C 1-C 6卤代烷氧基、-O(CH 2) s-C 3-C 8环烷基、-O(CH 2) s-苯基、-O(CH 2) s-杂环烷基、-O(CH 2) s-杂芳基,所述s为0、1、2或者3;或者R 3为-S(O) 2R z、-S(O) 2NH 2、-S(O) 2NHR z、-S(O) 2NR zR za,所述R z和R za各自独立的为C 1-C 4烷基、C 1-C 4卤代烷基或者苯基;Y为0、1、2、3、4或5;L'为键、-(CH 2) k-、-O(CH 2) k-、-(CH 2) k-O-或者-O-(CH 2) k-O-,所述k为0、1、2或者3,或者L'为-CH=CH-(CH 2) n-,所述n为0、1或者2;R 4、R 5各自独立的为C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基或C 3-C 6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基或卤素取代;T和V都为N,或者T为C,V为N,或者T为N,V为C;其中所述S3中:Q 1和Q 2各自独立的CH或者N;Q 3、Q 4和Q 7各自独立的为C或者N,所述Q 3和Q 4至少有一个为C,所述Q 3、Q 4和Q 7不全部为N;Q 5为CH、N、NH、O或者S;Q 6为CH、N、NH、N(C 1-C 6烷基)、N(C 1-C 6杂烷基)、N(3-7元环烷基)、N(3-7元杂环)、O或者S;所述Q 1、Q 2、Q 3、Q 4、Q 5、Q 6和Q 7中至少有一个为N、NH、O或者S;R 1选自氢、C 1-C 6烷基、C 1-C 6烷氧基、卤素、-NHR 1a、-OR 1a、C 3-C 6环烷基、C 3-C 6环烷氧基或者-CN;所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基和C 3-C 6环烷氧基任选的被选自卤素、-NHR 1a或-OR 1a的取代基取代;所述R 1a为氢、C 1-C 6烷基、3-6元杂环或者C 1-C 6卤代烷基;L 2选自键、-C(O)-、-C(O)O-、-C(O)NH(CH 2) o-、-S(O) 2-、-S(O)-、-S(=O)(=NH)-、-S(=O)[=N(C 1-C 6烷基)]-、-N(C 1-C 6烷基)-、-C(O)(CH 2) p-、-(CH 2) p-或者O;所述o为0、1或者2;所述p为1至6的整数;R 2选自氢、卤素、-CN、-NO 2、C 1-C 6烷基巯基、C 2-C 6炔基、C 1-C 6烷基、C 2-C 6烯基、-NR 2bR 2c、-OR 2a、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基;所述C 1-C 6烷基、C 2-C 6烯基、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基和5-10元杂芳基各自独立的任选的被选自C 1-C 6烷基、C 1-C 6卤代烷基、-OH、-OR 2a、氧代基、卤素、-C(O)R 2a、-C(O)OR 2a、-C(O)NR 2bR 2c、-CN、-NR 2bR 2c、3-6元环烷基、3-7元杂环烷基、6-10元芳基或5-10元杂芳基的取代基取代;所述R 2a为氢、C 1-C 6烷基、C 1-C 6卤代烷基、3-7元杂环烷基、或者-(CH 2) rOCH 3,所述r为1、2或者3;所述R 2b为氢或C 1-C 6烷基;所述R 2c为氢或C 1-C 6烷基;R 2为-NHC(O)-(C 1-C 6烷基)、-NHC(O)-NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2为-NH-(CH 2) k-NH-C(O)-(C 1-C 6烷基),所述k为1或者2;R 2为-NH-(CH 2) i-R f,所述i为0,1或者2且R f为4-7元杂环烷基、杂芳基、C 1-C 6烷基磺酰基;R 3和R 4各自独立的为氢、C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 6环烷氧基;所述R 3和R 4至少有一个不为氢,或者所述R 3和R 4和其所连接的原子一起形成3-6元环烷基;所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基或卤素取代;A为任选取代的6-元芳基或者任选取代的5-6元杂芳基;其中所述S4中:Q 1为CH或者N;Q 4为CH、C或者N;每个Q 2各自独立的为C-R 1或者N,所述Q 2其中一个为N另一个Q 2为C-R 1;每个Q 3和Q 5分子独立的为C(R QC) 2、NR QN、C(O)、O、S或者SO 2,所述R QC各自独立的为氢、F、Cl、Br、或者6-10元芳基,所述R QN各自独立的为氢、C 1-C 6烷基或者6-10元芳基;所述Q 1、Q 2、Q 3、Q 4、和Q 5至少有一个是N、NR QN、O或者SO 2;m为0、1、2或者3;n为0、1、2或者3;且当m为0时,n不是0;R 1选自氢、C 1-C 6烷基、卤素、-C(O)NHR 1a、-NHR 1a、-OR 1a、环丙基、氮杂环丁烷或者-CN;所述C 1-C 6烷基和氮杂环丁烷任选的被选自卤素、R 1a、-NHR 1a或-OR 1a的取代基取代;所述R 1a为氢、C 1-C 6烷基、环丙基、3-6元杂环或者C 1-C 6卤代烷基;L 2选自键、-C(O)-、-C(O)O-、-C(O)NH(CH 2) o-、-S(O) 2-、-S(O)-、-S(=O)(=NH)-、-S(=O)[=N(C 1-C 6烷基)]-、-N(C 1-C 6烷基)-、-C(O)(CH 2) p-、-(CH 2) p-或者O;所述o为0、1或者2;所述p为1至6的整数;R 2选自氢、C 1-C 6烷基、-NR 2bR 2c、-OR 2a、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基;所述C 1-C 6烷基、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基和5-10元杂芳基各自独立的任选的被选自C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6羟基烷基、C 1-C 6甲氧基烷基、-OH、-OR 2a、氧代基、卤素、=N、-C(O)R 2a、-C(O)OR 2a、-C(O)NR 2bR 2c、-S(O) 2R 2a、-CN、-NR 2bR 2c、3-6元环烷基、3-7元杂环烷基、6-10元芳基或5-10元杂芳基的取代基取代;所述R 2a为氢、C 1-C 6烷基、C 1-C 6卤代烷基、3-7元杂环烷基、或者-(CH 2) rOCH 3,所述r为1、2或者3;所述R 2b为氢或C 1-C 6烷基;所述R 2c为氢或C 1-C 6烷基;R 3和R 4各自独立的为氢、任选被卤素、-OH取代的C 1-C 6烷基,所述R 3和R 4至少有一个为氢,或者所述R 3和R 4和其所连接的原子一起形成3-6元环烷基;A为任选取代的6-元芳基或者任选取代的5-6元杂芳基;其中所述S5、S5'中:所述R 1为氢或R a1;R a1选自C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 1-C 6炔基、C 3-C 10环烷基、C 4-C 10环烯基、3-10元杂环烷基、C 6-C 10元芳基或者5-10元杂芳基,所述C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 1-C 6炔基、C 3-C 10环烷基、C 4-C 10环烯基、3-10元杂环烷基、C 6-C 10元芳基和5-10元杂芳基任选的被1个或多个相同的或者不同的R b1和/或R c1取代;每个R b1各自独立的为-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-C 4烷基)C(O)R c1、-NHC(O)OR c1或者-N(C 1-C 4烷基)C(O)OR c1;每个R c1各自独立的为氢、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 4-C 10环烯基、3-10元杂环烷基、C 6-C 10芳基或者5-10元杂芳基;所述C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 4-C 10环烯基、3-10元杂环烷基、C 6-C 10芳基和5-10元杂芳基各自独立的任选的被1个或者多个相同的或者不同的R d1和/或R e1;每个R d1各自的独立为-OR e1、-NR e1R e1、卤素、-CN、-C(O)R e1、-C(O)OR e1、-C(O)NR e1R e1、-S(O)2R e1、-S(O) 2NR e1R e1、-NHC(O)R e1、-N(C 1-C 4烷基)C(O)R e1、-NHC(O)OR e1或者-N(C 1-C 4烷基)C(O)OR e1;每个R e1各自独立的为氢、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 4-C 10环烯基、3-10元杂环烷基、C 6-C 10芳基或者5-10元杂芳基;R 2选自氢、C 1-C 4烷基、C 3-C 6环烷基、3-6元杂环烷基或者卤素;环A选自C 6-C 10芳基、5-10元杂芳基或者9-10元双杂环烷基;p为1、2或3;每个R 4各自独立的为氢、羟基、氧代、卤素、氰基、C 1-C 4烷基、-NH 2、C 1-C 4卤代烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4羟基烷基、羟基-C 1-C 4卤代烷基、C 3-C 6环烷基、C 3-C 6环烷氧基、3-6元杂环烷基、C 3-C 6羟基环烷基,被3-6元杂环烷基取代的C 1-C 4卤代烷基,被羟基、卤素、-NH 2、-S(O) 2-(C 1-C 4烷基)或者氧代基取代的3-6元杂环烷基,且氧代基仅在非芳香环上取代;R 4为-NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 4为-C(O)NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 4为-C(O)OR g,所述R g为氢或C 1-C 6烷基;R 4为-OR h;所述R h为C 1-C 6烷基;或者,R 4为-(CH 2)NR aR b,所述R a和R b各自独立的氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 3和R 5各自独立的为氢、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基或C 3-C 6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基或卤素取代。
- 如权利要求7所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐,所述S为S1a、S1a'、-X-S1a'、S1a”、-X-S1a”、S2a、S2a'、-X-S2a'、S2a”、-X-S2a”、S3a、S4a、S5a、S5a'或-X-S5a':X为O、NH或S,优选为O;其中所述S1a、S1a'、S1a”中:R 1选自氢、-OCH 3、-OCH 2CH 3、 -CH 2OH、-C(O)OH、-C(O)OCH 3、-Br、-OCH(CH 3) 2、-O(CH 2) 2CH(CH 3) 2、-O(CH 2) 3CH 3、-O(CH 2) 2OCH 3、 -O(CH 2)-苯基、-N=S(O)(CH 3) 2、-CH 3、环丙基、-N(CH 3) 2、-NHCH 3、-NH 2、 -C(CH 3) 2-OH、 -NH(CH 2)-NH-C(O)CH 3、-NH(CH 2)-吗啡啉、-NH-C(O)CH 3、-NH-C(O)NHCH 3、-NH-C(O)-N(CH 3) 2、硝基、-NH-S(O) 2CH 3、-N=S(O)(CH 3) 2、羟基、-O-(CH 2) 2-S(O) 2CH 3、-F、 环丙氧基、环丁氧基、环戊氧基、环己氧基、氮杂环丁烷基、氮杂环戊烷基、哌啶基、哌嗪基、氧杂环丁烷、氧杂环戊烷基、氧杂环己烷基、硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、氮杂环丁烷氧基、氮杂环戊烷氧基、哌啶基氧基、哌嗪基氧基、氧杂环丁烷氧基、氧杂环戊烷氧基、氧杂环己烷氧基、硫杂环丁烷氧基、硫杂环戊烷氧基、硫杂环己烷氧基、-OCH 2CH 2CH 3、-OCH 2CH 2CH 2N(CH 3) 2、-OCH 2CH 2CH 2OH、 -OCH 2CH 2NC(O)CH 3、-OCH 2CH 2N(CH 3) 2、-OCH 2CH 2OH、 -SCH 3、-N(CH 3) 2、x为1或者2;R 2选自:氢、羟基、氧代基、氰基、环丙基、1,1-二甲基环丙基、-C(=CH 2)CH 3、-C(CH 3)(=CH 2)CH 3、-CH=CH(CH 2) 2CH 3、-CH=CHCH 3、-CH=CH-环丙基、-C(O)NH 2、-C(O)OCH 3、-S(O) 2CH 3、-OCH 3、-CH 2NH 2、三氟甲基、甲基、三氟甲氧基、卤素(F、Cl、Br)、-NH 2、-NHC(O)CH 3、-NHCH 2CH 3或-NHCH(CH 3) 2;w为1、2或者3;R 3选自-C(O)NH(CH 2) 2CH 3、-C(O)N(CH 3) 2、-C(O)NH 2、-C(O)NH(CH 2) 2N(CH 3) 2、-CH 2C(O)NH 2、氢、-F、-Cl、-Br、氰基、-CF 3、-CH 3、-CH 2CH 3、-CH=CH 2、-CH 2CN、-CH(CH 3)-NH 2、-CH=CH-CN、-C(O)-OH、-C(O)OCH 3、-C(O)CH 3、-C(CH 3) 2-C(O)-OCH 3、-C(CH 3) 2-CN、氧代基、羟基、环丙基、环丁基、环戊基、-NH 2、-NH-C(O)CH 3、-NH-S(O) 2CH 3、-NH-C(O)OC(CH 3) 3、 -S(O) 2CH 3、-S(O) 2NCH 3、-S(O) 2NH 2、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCF 3、 -OCH 2环丙基、-OCH 3、-O(CH 2) 3CH 3、-OCH 2苯基、-O-苯基、-(CH 2)-OH、-(CH 2) 2-OH、-(CH 2)-OCH 3、-(CH 2)-OCH 2CH 3、-CH(OH)-CH 2-苯基、-CH(OH)-CH 2CH 3、-CH(OH)-CH 2CH 2CH 3、-CH(OH)-CH 2CH 2CH 2CH 3、-CH(OH)-CH(CH 3) 2、-CH(OH)-苯基、-CH(OH)-CN、-CH(OH)-CH 2-OH、-CH(OH)-CF 3、-CH(OH)-(CH 2) 2-苯基、*-CH(OH)-C≡CH、-CH(NH 2)-CH 2-C(O)OH、-CH 2-NH-S(O) 2-CH 3、-CH 2-NH-(CH 2) 3CH 3、-CH 2-NH-CH 3、-CH 2-N(CH 3) 2、-CH 2-NH-CH 2CH 3、-CH(CH 3)-NH 2、-CH 2-NH 2、-CH 2CH 2-NH 2、-CH 2NH-CH 2-苯基、-CH 2N(CH 2CH 3) 2、-CH 2NH-环丙基、-CH 2NH-环丁基、-CH 2NH-环戊基、-CH 2NH-吡啶基、-CH 2NH-苯基、-CH 2NH-(CH 2) 2-OH、-CH 2N(CH 3)-(CH 2) 2-OH、-CH 2NH-CH 2-CN、-CH 2N(CH 3)-CH 2-CN、-CH 2N(CH 3)-CH 2-CF 3、-CH 2N(CH 3)-CH 2-CF 2H、-CH 2NH-CH 2-CF 2H、-CH 2NH-(CH 2) 2-OCH 3、-CH 2NH-C(O)-OC(CH 3) 3、-CH 2CH 2NH-C(O)-OC(CH 3) 3、-CH 2NH-C(O)-CH 2NOH、-CH 2NH-C(O)-CH 2OCH 3、-CH(CH 3)NH-C(O)-OC(CH 3) 3、-CH 2NH-C(O)-CH 3、 CH 2NHCH 2-C(O)-NH 2、-CH 2NHCH 2-C(O)-(CH 3) 2、-CH 2NHCH 2-C(O)-OCH 3、-CH 2NHCH 2-C(O)-NHCH 3、-CH 2NHCH 2-C(O)-NH(CH 2) 2-OCH 3、-CH 2NHCH 2-C(O)-NHCH 2-苯基、 -CH 2NHCH 2-C(O)-NH-苯基、 -CH 2NH-C(O)-CH 2NH-苯基、 或-CH 2NH-C(O)-CH 2NH-CH 2CF 3;y为1或者2;L'为键、-(CH 2) k-或者-O(CH 2) k-,所述k为1或者2,或者L'为-CH=CH-(CH 2) n-,所述n为0、1或者2;其中所述S2a、S2a'、S2a”中:T和V都为N,或者T为C,V为N,或者T为N,V为C;R 1选自氢、-OCH 3、-OCH 2CH 3、 -CH 2OH、-C(O)OH、-C(O)OCH 3、-Br、-OCH(CH 3) 2、-O(CH 2) 2CH(CH 3) 2、-O(CH 2) 3CH 3、-O(CH 2) 2OCH 3、 -O(CH 2) z-苯基、-N=S(O)(CH 3) 2、-CH 3、环 丙基、-N(CH 3) 2、-NHCH 3、-NH 2、 -C(CH 3) 2-OH、 -NH(CH 2)-NH-C(O)CH 3、-NH(CH 2)-吗啡啉、-NH-C(O)CH 3、-NH-C(O)NHCH 3、-NH-C(O)-N(CH 3) 2、硝基、-NH-S(O) 2CH 3、-N=S(O)(CH 3) 2、羟基、-O-(CH 2) 2-S(O) 2CH 3、-F、 环丙氧基、环丁氧基、环戊氧基、环己氧基、氮杂环丁烷基、氮杂环戊烷基、哌啶基、哌嗪基、氧杂环丁烷、氧杂环戊烷基、氧杂环己烷基、硫杂环丁烷基、硫杂环戊烷基、硫杂环己烷基、氮杂环丁烷氧基、氮杂环戊烷氧基、哌啶基氧基、哌嗪基氧基、氧杂环丁烷氧基、氧杂环戊烷氧基、氧杂环己烷氧基、硫杂环丁烷氧基、硫杂环戊烷氧基、硫杂环己烷氧基、-OCH 2CH 2CH 3、-OCH 2CH 2CH 2N(CH 3) 2、-OCH 2CH 2CH 2OH、 -OCH 2CH 2NC(O)CH 3、-OCH 2CH 2N(CH 3) 2、-OCH 2CH 2OH、 -SCH 3、-N(CH 3) 2、z为1或者2;x为1或者2;R 2选自:氢、羟基、氧代基、氰基、环丙基、1,1-二甲基环丙基、-C(=CH 2)CH 3、-C(CH 3)(=CH 2)CH 3、-CH=CH(CH 2) 2CH 3、-CH=CHCH 3、-CH=CH-环丙基、-C(O)NH 2、三氟甲基、甲基、三氟甲氧基、-C(O)OCH 3、-S(O) 2CH 3、-OCH 3、-CH 2NH 2或卤素(F、Cl、Br);w为1、2或者3;R 3选自-C(O)NH(CH 2) 2CH 3、-C(O)N(CH 3) 2、-C(O)NH 2、-C(O)NH(CH 2) 2N(CH 3) 2、-CH 2C(O)NH 2、氢、-F、-Cl、-Br、氰基、-CF 3、-CH 3、-CH 2CH 3、-CH=CH 2、-CH 2CN、-CH(CH 3)-NH 2、-CH=CH-CN、-C(O)-OH、-C(O)OCH 3、-C(O)CH 3、-C(CH 3) 2-C(O)-OCH 3、-C(CH 3) 2-CN、氧代基、羟基、环丙基、环丁基、环戊基、-NH 2、-NH-C(O)CH 3、-NH-S(O) 2CH 3、-NH-C(O)OC(CH 3) 3、 -S(O) 2CH 3、-S(O) 2NCH 3、-S(O) 2NH 2、-OCH 2CH 3、-O(CH 2) 2CH 3、-OCF 3、 -OCH 2环丙基、-OCH 3、-O(CH 2) 3CH 3、-OCH 2苯基、-O-苯基、-(CH 2)-OH、-(CH 2) 2-OH、-(CH 2)-OCH 3、-(CH 2)-OCH 2CH 3、-CH(OH)-CH 2-苯基、-CH(OH)-CH 2CH 3、-CH(OH)-CH 2CH 2CH 3、-CH(OH)-CH 2CH 2CH 2CH 3、-CH(OH)-CH(CH 3) 2、-CH(OH)-苯基、-CH(OH)-CN、-CH(OH)-CH 2-OH、-CH(OH)-CF 3、-CH(OH)-(CH 2) 2-苯基、*-CH(OH)-C≡CH、-CH(NH 2)-CH 2-C(O)OH、-CH 2-NH-S(O) 2-CH 3、-CH 2-NH-(CH 2) 3CH 3、-CH 2-NH-CH 3、-CH 2-N(CH 3) 2、-CH 2-NH-CH 2CH 3、-CH(CH 3)-NH 2、-CH 2-NH 2、-CH 2CH 2-NH 2、-CH 2NH-CH 2-苯基、-CH 2N(CH 2CH 3) 2、-CH 2NH-环丙基、-CH 2NH-环丁基、-CH 2NH-环戊基、-CH 2NH-吡啶基、-CH 2NH-苯基、-CH 2NH-(CH 2) 2-OH、-CH 2N(CH 3)-(CH 2) 2-OH、-CH 2NH-CH 2-CN、-CH 2N(CH 3)-CH 2-CN、-CH 2N(CH 3)-CH 2-CF 3、-CH 2N(CH 3)-CH 2-CF 2H、-CH 2NH-CH 2-CF 2H、-CH 2NH-(CH 2) 2-OCH 3、 -CH 2NH-C(O)-OC(CH 3) 3、-CH 2CH 2NH-C(O)-OC(CH 3) 3、-CH 2NH-C(O)-CH 2NOH、-CH 2NH-C(O)-CH 2OCH 3、-CH(CH 3)NH-C(O)-OC(CH 3) 3、-CH 2NH-C(O)-CH 3、 CH 2NHCH 2-C(O)-NH 2、-CH 2NHCH 2-C(O)-(CH 3) 2、-CH 2NHCH 2-C(O)-OCH 3、-CH 2NHCH 2-C(O)-NHCH 3、- CH 2NHCH 2-C(O)-NH(CH 2) 2-OCH 3、-CH 2NHCH 2-C(O)-NHCH 2-苯基、 -CH 2NHCH 2-C(O)-NH-苯基、 -CH 2NH-C(O)-CH 2NH-苯基、 或-CH 2NH-C(O)-CH 2NH-CH 2CF 3;Y为1或者2;L'为键、-(CH 2)k-或者-O(CH 2) k-,所述k为1或者2,或者L'为-CH=CH-(CH 2) n-,所述n为0或者1;其中所述S3a中:Q 1和Q 2各自独立的CH或者N;Q 3和Q 4各自独立的为C或者N,所述Q 3和Q 4至少有一个为C;Q 6为CH、N、NH、O或者S;Q 5为CH、N、NH、O或者S;所述Q 1、Q 2、Q 3、Q 4、Q 5和Q 6中至少有一个为N、NH、O或者S;R 1选自氢、C 1-C 6烷基、卤素、-OR 1a、环丙基或者-CN;所述R 1a为氢或C 1-C 6烷基;L 2选自键、-C(O)-、-C(O)O-、-C(O)NH(CH 2) o-、-S(O) 2-、-C(O)(CH 2) p-、-(CH 2) p-或者O;所述o为0、1或者2;所述p为1至6的整数;R 2选自氢、-(CH 2) qCH 3、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基;所述q为1至5的整数;所述3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基和5-10元杂芳基各自独立的任选的被选自C 1-C 6烷基、-OH、卤素、-C(O)R 2a、-C(O)NR 2bR 2c的取代基取代;所述R 2a为C 1-C 6烷基或者-(CH 2) rOCH 3,所述r为1、2或者3;所述R 2b为氢或C 1-C 6烷基;所述R 2c为氢或C 1-C 6烷基;R 3和R 4各自独立的为氢或C 1-C 6烷基,所述R 3和R 4至少有一个不为氢,或者所述R 3和R 4和其所连接的原子一起形成3-6元环烷基;A为任选取代的苯基或者任选取代的5-6元杂芳基;其中所述S4a中:Q 1为CH或者N;Q 4为CH、C或者N;每个Q 2各自独立的为CR 1或者N;每个Q 3和Q 5分子独立的为C(R QC) 2、NR QN、C(O)、O、S或者SO 2,所述R QC各自独立的为氢、F、Cl、Br、或者6-10元芳基,所述R QN各自独立的为氢、C 1-C 6烷基或者6-10元芳基;所述Q 1、Q 2、Q 3、Q 4、和Q 5至少有一个是N、NR QN、O或者SO 2;R 1选自氢、C 1-C 6烷基、卤素、环丙基、氰基或-OR 1a,所述R 1a为氢或C 1-C 6烷基;L 2选自键、-C(O)-、-C(O)O-、-C(O)NH(CH 2) o-、-S(O) 2-、-C(O)(CH 2) p-、-(CH 2) p-或者O;所述o为0、1或者2;所述p为1至6的整数;R 2选自氢、-(CH 2) qCH 3、3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基;所述q为1至5的倍数;所述3-14元环烷基、3-14元环烯基、3-14元杂环烷基、6-10元芳基、5-10元杂芳基各自独立的任选的被选自C 1-C 6烷基、羟基、卤素、-C(O)R 2a或-C(O)NR 2bR 2c的基团取代;所述R 2a选自C 1-C 6烷基或-(CH 2) rOCH 3;所述r为1、2或者3;所述R 2b和R 2c各自独立的为氢或C 1-C 6烷基;R 3和R 4各自独立的为氢或C 1-C 6烷基,所述R 3和R 4至少有一个为氢,或者所述R 3和R 4和其所连接的原子一起形成3-6元环烷基;A为任选取代的6-元芳基或者任选取代的5-6元杂芳基;其中,所述S5a、S5a'中,R 1、R 2、R 3、R 4、环A和p如权利要求7中的S5中所定义和描述。
- 如权利要求1-6中任一项所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐,所述S为S6、S6'、-X-S6'、S6”、S6”'、-X-S6”'、S6a、S6a”、S6c、S6c”、-X-S6c或-X-S6c”,优选为S6c:其中,X为O、NH或者S,优选为O;其中所述S6、S6'、S6”、S6”'、S6a、S6a”、S6c、S6c”中:R 2选自氢、卤素、-OH、-CN、-NO 2、C 1-C 6烷基巯基或-NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2选自C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷氧基、C 3-C 6杂环烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、C 1-C 6卤代烷基、-COOH、-COOR c;所述R c为-C 1-C 6烷基、C 3-C 6烯基、C 3-C 6炔基、C 3-C 8环烷基或-C 4-C 8环烯基;R 2为-NS(O)(R d)(R e),所述R d和R e各自独立的为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、6-10元芳基或5-10元杂芳基;R 2为-NHC(O)-(C 1-C 6烷基)、-NHC(O)-NR aR b,所述R a和R b各自独立的为氢、-C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2为-NH-(CH 2) k-NH-C(O)-R aa,所述R aa为C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基,且k为1或者2;R 2为-NH-(CH 2) i-R f,所述i为0,1或者2且R f为4-7元杂环烷基、杂芳基、C 1-C 6烷基磺酰基;此外以上所述C 1-C 6烷基、C 1-C 6烷氧基、4-7元杂环烷基和杂芳基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、4-7元杂环烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 1-C 6烷基磺酰基、苯基、苄基、杂芳基、-(CH 2)-杂芳基、-NHC(O)(C 1-C 6烷基)、C 3-C 8环烷氧基、苯氧基、杂芳基氧基或者-NR aR b的基团取代;所述R a和R b各自独立的选自氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2为-O-(CH 2) z-苯基、-O-(CH 2) z-(4-7元杂环烷基)、-O-(CH 2) z-杂芳基,所述z为0,1或2,所述苯基、杂环烷基和杂芳基任选的被选自-OH、杂环烷基或者杂环烯基取代,且能被甲基或者氧代基取代;或者R 2为R 1为氢或-OR A;R A为氢、C 3-C 10环烷基或3-10元杂环烷基;所述C 3-C 10环烷基和3-10元杂环烷基任选被1个或者多个相同或不同的R a1和/或R c1取代;每个R a1各自独立的为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基各自独立的任选的被1个或者多个相同或不同的R b1和/或R c1取代;每个R b1各自独立的为-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-C 4烷基)C(O)R c1、氧代基所取代,且所述氧代基仅在非芳香环取代;每个R c1各自独立的为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10杂芳基;或者R 1选自C 3-C 10环烷基、C 3-C 10环烯基、C 6-C 10芳基、3-10元杂环烷基或5-10元杂芳基;所述C 3-C 10环烷基、C 3-C 10环烯基、C 6-C 10芳基、3-10元杂环烷基或5-10元杂芳基任选的被1个或多个R a2和/或R b2取代;每个R a2各自独立的选自C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R c2和/或R b2取代;每个R b2各自独立的选自-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-C 4烷基)C(O)R c2、-NHC(O)OR c2、氧代基、=NH,且所述氧代基、=NH仅在非芳香环上取代;每个R c2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R d2和/或R e2取代;每个R d2各自独立的为-OR e2、-NR e2R e2、卤素、-CN、-C(O)R e2、-C(O)OR e2、-C(O)NR e2R e2、-S(O) 2R e2、-S(O) 2NR e2R e2、-NHC(O)R e2、-N(C 1-C 4烷基)C(O)R e2、氧代基,所述氧代基仅在非芳香环上取代;每个R e2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R f2和/或R g2取代;每个R f2各自独立的选自-OR g2、-NR g2R g2、卤素、-CN、-C(O)R g2、-C(O)OR g2、-C(O)NR g2R g2、-S(O) 2R g2、-S(O) 2NR g2R g2、-NHC(O)R g2、-N(C 1-C 4烷基)C(O)R g2、氧代基,所述氧代基仅在非芳香环上取代;每个R g2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;或R 1选自C 2-C 4烷基、C 2-C 4烯基;所述C 2-C 4烷基和C 2-C 4烯基任选的R b3取代;R b3选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3或者-C(O)N(C 1-C 4烷基)OR c3;每个R c3各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、 3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R d3和/或R e3取代;每个R d3各自独立的选自-OR e3、-NR e3R e3、卤素、-CN、-C(O)R e3、-C(O)OR e3、-C(O)NR e3R e3、-S(O) 2R e3、-S(O) 2NR e3R e3、-NHC(O)R e3、-N(C 1-C 4烷基)C(O)R e3、氧代基,所述氧代基仅在非芳香环上取代;每个R e3各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;R 3选自氢、C 1-C 4烷基、-O(C 1-C 4烷基)、-NH 2、-NH(C 1-C 4烷基)、-N(C 1-C 4烷基) 2或者卤素;R 5选自氢、羟基或者-NHR’;R’选自氢、C 1-C 3烷基和-C(O)C 1-C 3烷基;R 4选自C 1-C 4烷基、羟基、氧代、氰基、C 1-C 4烷氧基、C 1-C 4卤代烷基、C 1-C 4羟基烷基、羟基-C 1-C 4卤代烷基、C 2-C 6烯基、-C 2-C 6炔基、C 3-C 6环烷氧基、C 3-C 6环烷基、3-6元杂环烷基、3-6元羟基杂环烷基、卤素或者-SO 2-C 1-C 4烷基;R 6选自氢、C 1-C 4烷基或者卤素;或者R 4、R 6与它们连接的碳原子一起形成任选取代的C 5-C 6环烷基和5-6元杂环烷基,所述5-6元杂环烷基中的杂原子选自包含1、2、3或4个独立选自-NH、-O-、-S-和N的杂原子或杂原子团;R 7、R 8各自独立的为C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基或C 3-C 6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基或卤素取代。
- 如权利要求9所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐,其中,R 1为氢或-OR A;R A为氢;R 2为氢、C 1-C 4烷基或者-O(C 1-C 4烷基),所述-O(C 1-C 4烷基)任选的被-O(C 1-C 4烷基)取代;R 3为氢;R 5为氢或者-NHR’;R’选自氢、C 1-C 3烷基和-C(O)C 1-C 3烷基;R 4为C 1-C 4卤代烷基;R 6为氢或者卤素;R 7为C 1-C 6烷基;R 8为C 1-C 6烷基。
- 如权利要求1-6中任一项所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐,其中所述S为S7;其中所述S7中:R 2选自氢、卤素、-OH、-CN、-NO 2、C 1-C 6烷基巯基或-NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2选自C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷氧基、C 3-C 6杂环烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、4-7元杂环烷基、5-10元杂环烯烃基、螺杂环烷基、稠杂环烷基、桥杂环烷基、苯基、杂芳基、C 1-C 6卤代烷基、-COOH、-COOR c;所述R c为-C 1-C 6烷基、C 3-C 6烯基、C 3-C 6炔基、C 3-C 8环烷基或-C 4-C 8环烯基;R 2为-NS(O)(R d)(R e),所述R d和R e各自独立的为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、6-10元芳基或5-10元杂芳基;R 2为-NHC(O)-(C 1-C 6烷基)、-NHC(O)-NR aR b,所述R a和R b各自独立的为氢、-C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2为-NH-(CH 2) k-NH-C(O)-R aa,所述R aa为C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基,且k为1或者2;R 2为-NH-(CH 2) i-R f,所述i为0,1或者2且R f为4-7元杂环烷基、杂芳基、C 1-C 6烷基磺酰基;此外以上所述C 1-C 6烷基、C 1-C 6烷氧基、4-7元杂环烷基和杂芳基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、4-7元杂环烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 1-C 6烷基磺酰基、苯基、苄基、杂芳基、-(CH 2)-杂芳基、-NHC(O)(C 1-C 6烷基)、C 3-C 8环烷氧基、苯氧基、杂芳基氧基或者-NR aR b的基团取代;所述R a和R b各自独立的选自氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;R 2为-O-(CH 2) z-苯基、-O-(CH 2) z-(4-7元杂环烷基)、-O-(CH 2) z-杂芳基,所述z为0,1或2,所述苯基、杂环烷基和杂芳基任选的被选自-OH、杂环烷基或者杂环烯基取代,且能被甲基或者氧代基取代;或者R 2为R 1为氢或-OR A;R A为氢、C 3-C 10环烷基或3-10元杂环烷基;所述C 3-C 10环烷基和3-10元杂环烷基任选被1个或者多个相同或不同的R a1和/或R c1取代;每个R a1各自独立的为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基各自独立的任选的被1个或者多个相同或不同的R b1和/或R c1取代;每个R b1各自独立的为-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-C 4烷基)C(O)R c1、氧代基所取代,且所述氧代基仅在非芳香环取代;每个R c1各自独立的为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10杂芳基;或者R 1选自C 3-C 10环烷基、C 3-C 10环烯基、C 6-C 10芳基、3-10元杂环烷基或5-10元杂芳基;所述C 3-C 10环烷基、C 3-C 10环烯基、C 6-C 10芳基、3-10元杂环烷基或5-10元杂芳基任选的被1个或多个R a2和/或R b2取代;每个R a2各自独立的选自C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R c2和/或R b2取代;每个R b2各自独立的选自-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-C 4烷基)C(O)R c2、-NHC(O)OR c2、氧代基、=NH,且所述氧代基、=NH仅在非芳香环上取代;每个R c2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R d2和/或R e2取代;每个R d2各自独立的为-OR e2、-NR e2R e2、卤素、-CN、-C(O)R e2、-C(O)OR e2、-C(O)NR e2R e2、-S(O) 2R e2、-S(O) 2NR e2R e2、-NHC(O)R e2、-N(C 1-C 4烷基)C(O)R e2、氧代基,所述氧代基仅在非芳香环上取代;每个R e2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R f2和/或R g2取代;每个R f2各自独立的选自-OR g2、-NR g2R g2、卤素、-CN、-C(O)R g2、-C(O)OR g2、-C(O)NR g2R g2、-S(O) 2R g2、-S(O) 2NR g2R g2、-NHC(O)R g2、-N(C 1-C 4烷基)C(O)R g2、氧代基,所述氧代基仅在非芳香环上取代;每个R g2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;或R 1选自C 2-C 4烷基、C 2-C 4烯基;所述C 2-C 4烷基和C 2-C 4烯基任选的R b3取代;R b3选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3或者-C(O)N(C 1-C 4烷基)OR c3;每个R c3各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R d3和/或R e3取代;每个R d3各自独立的选自-OR e3、-NR e3R e3、卤素、-CN、-C(O)R e3、-C(O)OR e3、-C(O)NR e3R e3、-S(O) 2R e3、-S(O) 2NR e3R e3、-NHC(O)R e3、-N(C 1-C 4烷基)C(O)R e3、氧代基,所述氧代基仅在非芳香环上取代;每个R e3各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;R 4选自氢、C 1-C 4烷基、-O(C 1-C 4烷基)、-NH 2、-NH(C 1-C 4烷基)、-N(C 1-C 4烷基) 2或者卤素;所述A 2(R 3) Y为氢;或者A 2为C 4-C 12环烷基、杂环烷基、芳基或杂芳基,且R 3为氢、卤素、-OH、氧代、-CN、-NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、C 7-C 8环炔基、4-7元杂环烷基、5-10元杂环烯基、苯基、杂芳基、C 1-C 6卤代烷基;所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被1 个、2个或者3个选自卤素、-OH、氧代、-CN、-C 1-C 6烷基、-C 1-C 6烷氧基、-C 1-C 6卤代烷基、苯基、杂芳基或-C(O)NR iR j的取代基取代,所述R i和R j各自独立的为氢或者C 1-C 6烷基;或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR kR l取代,所述R k和R l各自独立的为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 1-C 6烷基磺酰基、苯基、杂芳基、-CH 2-C(O)-R m、-C(O)R p或4-7元杂环烷基,且所述烷基、炔基、烯基、环烷基、苯基、杂芳基和杂环烷基各自独立的任选的被1个、2个或3个选自C 1-C 6卤代烷基、-OH、氧代基、苯基、-CN、C 1-C 6烷氧基或杂芳基的取代基取代,且所述杂芳基任选被甲基取代;且所述R m为双环杂芳基、C 1-C 6烷氧基或者-NR nR o,所述R n和R o各自独立的为氢、C 1-C 6烷基或者苯基,所述烷基任选被C 1-C 6烷氧基或者苯基取代,或者-NR nR o为4-7元氮杂环烷基,所述氮杂环烷基通过N原子连接分子其他部位,且还包含1个或者多个选自N或者O的杂原子;所述R p选自C 1-C 6烷氧基、任选被1个、2个或者3个选自-OH或者C 1-C 6烷氧基取代的C 1-C 6烷基、单环或双环杂芳基、4-7元杂环烷基或者R p为-CH 2-NR qR r,所述R q和R r各自独立的选自氢、苯基或者任选被F取代的C 1-C 6烷基;或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR sR t取代,所述-NR sR t为通过氮原子连接至分子其他部位的4-7元氮杂环烷基或者通过氮原子连接至分子其他部位的6-10元氮螺杂环烷基,且进一步包括最多两个选自N或者O的杂原子,且任选的被1个、2个或者3个选自-OH、氧代基、C 1-C 6烷基、C 1-C 6羟基烷基、-C(O)OR z的取代基取代,所述R z为C 1-C 6烷基、卤素、-N(C 1-C 6烷基) 2、-CH 2N(C 1-C 6烷基) 2、-C(O)NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;或者R 3为C(O)R v、-C(O)NH 2、-C(O)NHR v、-C(O)NR vR w、-C(O)OR v,所述R v和R w各自独立的为氢、C 1-C 4烷基、C 1-C 4卤代烷基、苯基或者-(CH 2) 2NR xR y,所述R x和R y各自独立的为氢、C 1-C 4烷基或者-(CH 2) 2N(CH 3) 2;或者R 3为-NH 2、-NHR z、-NR zR za、-NHC(O)R z、-NHC(O)O R z、-NHS(O) 2R z、4-7元杂环烷基、杂芳基、螺杂环烷基、稠杂环烷基、桥杂环烷基,所述R z和R za各自独立的为C 1-C 4烷基、C 1-C 4卤代烷基或者苯基;或者R 3为C 1-C 6烷氧基、C 1-C 6卤代烷氧基、-O(CH 2) s-C 3-C 8环烷基、-O(CH 2) s-苯基、-O(CH 2) s-杂环烷基、-O(CH 2) s-杂芳基,所述s为0、1、2或者3;或者R 3为-S(O) 2R z、-S(O) 2NH 2、-S(O) 2NHR z、-S(O) 2NR zR za,所述R z和R za各自独立的为C 1-C 4烷基、C 1-C 4卤代烷基或者苯基;Y为0、1、2、3、4或5;L'为键、-(CH 2) k-或者-O(CH 2) k-,所述k为0、1、2或者3,或者L'为-CH=CH-(CH 2) n,所述n为0、1或者2;R 7、R 8各自独立的为C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基或C 3-C 6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基或卤素取代。
- 如权利要求13所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐,其中,所述S7中,R 1为氢或-OR A;R A为氢、C 3-C 10环烷基或3-10元杂环烷基;所述C 3-C 10环烷基和3-10元杂环烷基任选被1个或者多个相同或不同的R a1和/或R c1取代;每个R a1各自独立的为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基各自独立的任选的被1个或者多个相同或不同的R b1和/或R c1取代;每个R b1各自独立的为-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-C 4烷基)C(O)R c1、氧代基所取代,且所述氧代基仅在非芳香环取代;每个R c1各自独立的为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10杂芳基;或者R 1选自C 3-C 10环烷基、C 3-C 10环烯基、C 6-C 10芳基、3-10元杂环烷基或5-10元杂芳基;所述C 3- C 10环烷基、C 3-C 10环烯基、C 6-C 10芳基、3-10元杂环烷基或5-10元杂芳基任选的被1个或多个R a2和/或R b2取代;每个R a2各自独立的选自C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R c2和/或R b2取代;每个R b2各自独立的选自-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-C 4烷基)C(O)R c2、-NHC(O)OR c2、氧代基、=NH,且所述氧代基、=NH仅在非芳香环上取代;每个R c2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R d2和/或R e2取代;每个R d2各自独立的为-OR e2、-NR e2R e2、卤素、-CN、-C(O)R e2、-C(O)OR e2、-C(O)NR e2R e2、-S(O) 2R e2、-S(O) 2NR e2R e2、-NHC(O)R e2、-N(C 1-C 4烷基)C(O)R e2、氧代基,所述氧代基仅在非芳香环上取代;每个R e2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R f2和/或R g2取代;每个R f2各自独立的选自-OR g2、-NR g2R g2、卤素、-CN、-C(O)R g2、-C(O)OR g2、-C(O)NR g2R g2、-S(O) 2R g2、-S(O) 2NR g2R g2、-NHC(O)R g2、-N(C 1-C 4烷基)C(O)R g2、氧代基,所述氧代基仅在非芳香环上取代;每个R g2各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;或R 1选自C 2-C 4烷基、C 2-C 4烯基;所述C 2-C 4烷基和C 2-C 4烯基任选的R b3取代;R b3选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3或者-C(O)N(C 1-C 4烷基)OR c3;每个R c3各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基任选被1个或者多个R d3和/或R e3取代;每个R d3各自独立的选自-OR e3、-NR e3R e3、卤素、-CN、-C(O)R e3、-C(O)OR e3、-C(O)NR e3R e3、-S(O) 2R e3、-S(O) 2NR e3R e3、-NHC(O)R e3、-N(C 1-C 4烷基)C(O)R e3、氧代基,所述氧代基仅在非芳香环上取代;每个R e3各自独立的选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基、C 6-C 10芳基、3-10元杂环烷基或者5-10元杂芳基;R 2选自氢、C 1-C 4烷基、-O(C 1-C 4烷基)、-NH 2、-NH(C 1-C 4烷基)、-N(C 1-C 4烷基) 2或者卤素;R 4选自氢、C 1-C 4烷基、-O(C 1-C 4烷基)、-NH 2、-NH(C 1-C 4烷基)、-N(C 1-C 4烷基) 2或者卤素;所述A 2(R 3) Y为氢;或者A 2为C 4-C 12环烷基、杂环烷基、芳基或杂芳基,且R 3为氢、卤素、-OH、氧代、-CN、-NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 4-C 8环烯基、C 7-C 8环炔基、4-7元杂环烷基、5-10元杂环烯基、苯基、杂芳基、C 1-C 6卤代烷基;所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被1个、2个或者3个选自卤素、-OH、氧代、-CN、-C 1-C 6烷基、-C 1-C 6烷氧基、-C 1-C 6卤代烷基、苯基、杂芳基或-C(O)NR iR j的取代基取代,所述R i和R j各自独立的为氢或者C 1-C 6烷基;或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR kR l取代,所述R k和R l各自独立的为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 1-C 6烷基磺酰基、苯基、杂芳基、-CH 2-C(O)-R m、-C(O)R p或4-7元杂环烷基,且所述烷基、炔基、烯基、环烷基、苯基、杂芳基和杂环烷基各自独立的任选的被1个、2个或3个选自C 1-C 6卤代烷基、-OH、氧代基、苯基、-CN、C 1-C 6烷氧基或杂芳基的取代基取代,且所述杂芳基任选被甲基取代;且所述R m为双环杂芳基、C 1-C 6烷氧基或者-NR nR o,所述R n和R o各自独立的为氢、C 1-C 6烷基或者苯基,所述烷基任选被C 1-C 6烷氧基或者苯基取代,或者-NR nR o为4-7元氮杂环烷基,所述氮杂环烷基通过N原子连接分子其他部位,且还包含1个或者多个选自N或者O的杂原子;所述R p选自C 1-C 6烷氧基、任选被1个、2个或者3个 选自-OH或者C 1-C 6烷氧基取代的C 1-C 6烷基、单环或双环杂芳基、4-7元杂环烷基或者R p为-CH 2-NR qR r,所述R q和R r各自独立的选自氢、苯基或者任选被F取代的C 1-C 6烷基;或者所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烯基、环炔基和杂环烯基任选的被-NR sR t取代,所述-NR sR t为通过氮原子连接至分子其他部位的4-7元氮杂环烷基或者通过氮原子连接至分子其他部位的6-10元氮螺杂环烷基,且进一步包括最多两个选自N或者O的杂原子,且任选的被1个、2个或者3个选自-OH、氧代基、C 1-C 6烷基、C 1-C 6羟基烷基、-C(O)OR z的取代基取代,所述R z为C 1-C 6烷基、卤素、-N(C 1-C 6烷基) 2、-CH 2N(C 1-C 6烷基) 2、-C(O)NR aR b,所述R a和R b各自独立的为氢、C 1-C 6烷基、C 3-C 8杂环烷基或C 3-C 8环烷基;或者R 3为C(O)R v、-C(O)NH 2、-C(O)NHR v、-C(O)NR vR w、-C(O)OR v,所述R v和R w各自独立的为氢、C 1-C 4烷基、C 1-C 4卤代烷基、苯基或者-(CH 2) 2NR xR y,所述R x和R y各自独立的为氢、C 1-C 4烷基或者-(CH 2) 2N(CH 3) 2;或者R 3为-NH 2、-NHR z、-NR zR za、-NHC(O)R z、-NHC(O)O R z、-NHS(O) 2R z、4-7元杂环烷基、杂芳基、螺杂环烷基、稠杂环烷基、桥杂环烷基,所述R z和R za各自独立的为C 1-C 4烷基、C 1-C 4卤代烷基或者苯基;或者R 3为C 1-C 6烷氧基、C 1-C 6卤代烷氧基、-O(CH 2) s-C 3-C 8环烷基、-O(CH 2) s-苯基、-O(CH 2) s-杂环烷基、-O(CH 2) s-杂芳基,所述s为0、1、2或者3;或者R 3为-S(O) 2R z、-S(O) 2NH 2、-S(O) 2NHR z、-S(O) 2NR zR za,所述R z和R za各自独立的为C 1-C 4烷基、C 1-C 4卤代烷基或者苯基;Y为0、1、2、3、4或5;L'为键、-(CH 2) k-或者-O(CH 2) k-,所述k为0、1、2或者3,或者L'为-CH=CH-(CH 2) n,所述n为0、1或者2;R 7、R 8各自独立的为C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基或C 3-C 6环烷氧基,所述烷基、烷氧基、环烷基和环烷氧基任选的被氰基、羟基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基或卤素取代。
- 如权利要求13所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐,其中,所述S7中,R 1为氢;和/或,所述S7中,R 2为氢、C 1-C 4烷基或者-O(C 1-C 4烷基),所述-O(C 1-C 4烷基)任选的被-O(C 1-C 4烷基)取代;和/或,所述S7中,R 4为氢;和/或,所述S7中,R 3为氢、卤素或C 1-C 6烷基,所述烷基任选被-NR kR l取代;所述R k和R l各自独立的为氢或C 1-C 6烷基;和/或,所述S7中,A 2为芳基;和/或,所述S7中,Y为0、1、2或3;和/或,所述S7中,L'为键;和/或,所述S7中,R 7为C 1-C 6烷基;和/或,所述S7中,R 8为C 1-C 6烷基;
- 如权利要求15所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐,其中,所述S7中,R 2为-O(C 1-C 4烷基),例如-OCH 3;和/或,所述S7中,R 3为氢、F、Cl、甲基或乙基,所述甲基和乙基被-NR kR l取代;所述R k为甲基或乙基,R l为氢、甲基或乙基;例如,R 3为氢、Cl、-CH 2NHCH 3或-CH 2N(CH 3) 2;和/或,所述S7中,A 2为苯基;和/或,所述S7中,R 7为甲基;和/或,所述S7中,R 8为甲基。
- 如权利要求1-18中任一项所述式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐,其特征在于,所述L为-(CH 2) j-,所述-(CH 2) j-中的1个或多个亚甲基任选的被选自-NR 3’-、-O-、-CR 1’R 2’-、-C(O)-、-S(O)-、-S(O) 2-、-C(O)O-、-OC(O)-、-C(O)NR 3’-、-NR 3’C(O)-、-S(O) 2NR 3’-、-NR 3’S(O) 2-、亚乙烯基、亚乙炔基、苯基、8-10元双环亚芳基、3-7元饱和或部分不饱和的亚环烷基、5-11元的饱和或部分不饱和的亚螺环烷基、5-11元的饱和或部分不饱和的亚稠环烷基、8-10元双环饱和或部分不饱和的亚环烷基、具有1-2个独立地选自氮、氧或硫杂原子的4-7元饱和或部分不饱和的亚杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的5-11元饱和或部分不饱和的亚螺杂环烷基、具有1-2个独立的选自氮、氧或硫杂原子的5-11元饱和或部分不饱和的亚稠杂环烷基、具有1-2个独立地选自氮、氧或硫杂原子的8-10元双环饱和或部分不饱和的亚杂环烷基、具有1-4个独立地选自 氮、氧或硫杂原子的5-6元亚杂芳基、或具有1-5个选自氮、氧或硫杂原子的8-10元双环杂芳基的基团替代,所述亚乙烯基、亚乙炔基、亚环烷基、亚杂环烷基、苯基、亚螺杂环烷基、亚稠杂环烷基、亚螺环烷基、亚稠环烷基、亚杂芳基各自独立的任选的被1个或多个选自卤素、氧代、-NR 3’R 4’、-OR 3’、硝基、-CN、C 1-C 6烷基、C 3-C 10环烷基、C 3-C 10杂环烷基的取代基取代,所述烷基、环烷基、杂环烷基任选被1个或多个选自卤素、-OH、-NH 2、-CN、C 1-C 4烷基、C 3-C 6环烷基的取代基取代,R 1’、R 2’各自独立为卤素、-OH、-NH 2、C 1-C 4烷基、C 1-C 4氯代烷基、C 1-C 4羟基烷基、-O(C 1-C 4烷基)、-NH(C 1-C 4烷基)、-NH(C 1-C 4烷基)、C 3-C 6环烷基、-O(C 3-C 6环烷基)、-NH(C 3-C 6环烷基)、C 3-C 6杂环烷基、-O(C 3-C 6杂环烷基)、-NH(C 3-C 6环烷基);R 3’、R 4’各自独立的为氢、氘、C 1-C 4烷基、C 3-C 6环烷基、C 3-C 6杂环烷基,j为2、3、4、5、6、7、8、9、10、11或12;优选地,所述L为-(CH 2) j-,所述-(CH 2) j-中的1个、2个、3个4个或者5个亚甲基任选的被选自-NH-、-NCH 3-、-O-、-C(CH 3) 2-、-CHF-、-CHCF 3-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH 3-、-NHC(O)-、-NCH 3C(O)-、亚乙烯基、亚乙炔基、亚环丙基、亚环丁基、亚环戊基、亚环己基、亚氧杂环丙基、亚氧杂环丁基、亚氧杂环戊基、亚氧杂环己基、亚氮杂环丙基、亚氮杂环丁基、亚氮杂环戊基、亚哌啶基、亚哌嗪基、亚吗啉基、亚高吗啉基、亚苯基、亚吡咯基、亚噻吩基、亚呋喃基、亚咪唑基、亚吡唑基、亚三唑基、亚四唑基、亚噁唑基、亚异噁唑基、亚噻唑基、亚异噻唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、 的基团替代,且所述替代基团任选的被1个或多个选自卤素、氧代、-NR 3’R 4’、-OR 3’、C 1-C 4烷基的取代基取代,所述烷基任选被1个或多个选自卤素、-OH、-NH 2的取代基取代,R 3’、R 4’各自独立的为氢、氘、C 1-C 4烷基,j为2、3、4、5、6、7、8、9或者10;
- 如权利要求1-18中任一项所述的式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐,所述L为LA:其中所述LA中:环A为键、C 3-C 12亚环烷基或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基,所述亚环烷基和亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6羟基烷基或-O-(C 1-C 6烷基)的取代基取代;环B为键、C 3-C 12亚环烷基或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基,所述亚环烷基和亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6羟基烷基或-O-(C 1-C 6烷基)的取代基取代;环C为C 3-C 12亚环烷基或含有1-2个选自N、O或S杂原子的3-12元亚杂环烷基,所述亚环烷基和亚杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6羟基烷基或-O-(C 1-C 6烷基)的取代基取代;X”为键、-NH-、-NCH 3-、-O-、-C(CH 3) 2-、-S-、-C=C-、-C≡C-、-CHF-、-CHCF 3-、-C(O)-、-S(O)-、-S(O) 2-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH 3-、-NHC(O)-、-NCH 3C(O)-或-C(O)CH 2O-;L 3为-(CH 2) k,所述L 3中的一个或两个亚甲基任选的被选自-O-、-NH-、-C≡C-、-N(C 1-C 6烷基)-、-N(C 1-C 6卤代烷基)-、-C(O)-、-N(C 1-C 6羟基烷基)-或-N(C 3-C 8环烷基)-替代,k为0、1、2、3、4、5、6或7;X”'为键、-NH-、-NCH 3-、-O-、-C(CH 3) 2-、-S-、-C=C-、-C≡C-、-CHF-、-CHCF 3-、-C(O)-、-S(O)-、-S(O) 2-、-C(O)O-、-OC(O)-、-C(O)NH-、-C(O)NCH 3-、-CH 2NCH 3-、-NHC(O)-或-NCH 3C(O)-。
- 如权利要求21所述的式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐,所述LA中环A为3-6元饱和的亚环烷基;环B含有1个或者2个氮杂原子的的4-7元饱和的单环亚杂环烷基;环C为含有1个或者2个氮杂原子的的4-7元饱和的单环亚杂环烷基、含有1个或者2个氮杂原子的的7-11元的亚螺杂环烷基或者亚稠杂环烷基;X”为键或-C(O)-;L 3为-(CH 2) k,k为1、2、3、4或者5。
- 如权利要求21所述的式Ⅰ化合物、或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐,其中,所述LA为LA-2或LA-4:X”'为-C(O)-;L 3为-(CH 2) k-,其中所述L 3中包含的一个或两个CH 2各自独立地任选的被-O-、-NH-或-N(C 1-C 6烷基)-替代;k为1、2、3或4;X”为键或-C(O)-;X”'为键;环B为键;L 3为-(CH 2) k-,其中所述L 3中包含的一个或两个CH 2各自独立地任选的被-O-、-NH-或-N(C 1-C 6烷基)-替代;k为1、2、3或4;X”为键。
- 和/或,所述LA-2中,L 3为-(CH 2) k-,其中所述L 3中包含的一个CH 2任选的被-O-替代;k为2、3或4;和/或,所述LA-4中,L 3为-(CH 2) k-,其中所述L 3中包含的一个CH 2任选的被-O-替代;k为2、3或4;
- 一种药物组合物,其包含权利要求1-26任一项所述化合物,或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药或其药学上可接受的盐,以及药学上可接受的载体、稀释剂或赋形剂。
- 一种权利要求1-26任一项所述化合物,和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐或权利要求27所述的药物组合物在制备用于治疗和/或预防SOS1介导的疾病或病症、或由SOS1与Ras或者SOS1与Rac相互作用所引起的疾病或病症、或癌症的药物中的应用。
- 如权利要求28中所述的应用,其中所述癌症选自:心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、黏液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤组;肺:支气管癌(鳞状细胞癌、未分化小细胞癌、未分化大细胞癌、腺癌)、肺泡癌(细支气管癌)、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤;胃肠道食管(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌肿瘤、血管活性肠肽瘤)、小肠(腺癌、淋巴瘤、类癌肿瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛腺瘤、错构瘤、平滑肌瘤);泌尿生殖系统:肾(腺癌、肾母细胞瘤、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎瘤、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤);肝:肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤;胆道:胆囊癌、壶腹癌、胆管癌;骨:骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、软骨瘤(骨软骨外生骨病)、良性软骨瘤、成软骨瘤、软骨黏液纤维瘤、骨样骨瘤和巨细胞瘤;神经系统:颅骨(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形骨炎)、脑膜(脑膜瘤、脑膜肉瘤、胶质瘤)、大脑(星形细胞瘤、髓母细胞瘤、胶质瘤、室管膜瘤、生发细胞瘤(松果体瘤)、多形胶质母细胞瘤、少突胶质母细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、胶质瘤、肉瘤);妇科:子宫(子宫内膜癌(浆液性囊腺癌、粘液性囊腺癌、未分类癌)、颗粒-鞘膜细胞瘤、支持间质细胞瘤、无生殖细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑素瘤)、阴道(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎型横纹肌肉瘤)、输卵管(癌);血液学:血液(髓系白血病(急性和慢性)、急性淋巴母细胞白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤);皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、银屑病;肾上腺:成神经细胞瘤。
- 如权利要求28中所述的应用,其中,所述癌症为胰腺癌、肺癌、结肠直肠癌、胆管上皮癌、多发性骨髓瘤、黑色素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、子宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞性白血病、肝细胞癌、乳腺癌、卵巢癌、前列腺癌、成胶质细胞瘤、肾癌或肉瘤。
- 一种权利要求1-26任一项所述化合物,和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐或权利要求27所述的药物组合物在制备治疗和/预防1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多雀斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征和遗传性牙龈纤维瘤病药物的应用。
- 一种权利要求1-26任一项所述化合物,和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐或权利要求27所述的药物组合物在制备用于治疗和/或预防KRAS介导的疾病或病症的药物中的应用,所述的KRAS优选为突变型KRAS,所述突变型KRAS优选为KRAS G12C、KRAS G12D、KRAS G13D和KRAS G12V中的一种或多种。
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