WO2022148442A1 - 6-取代磷酰基喹唑啉类衍生物及其制备方法和用途 - Google Patents
6-取代磷酰基喹唑啉类衍生物及其制备方法和用途 Download PDFInfo
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- WO2022148442A1 WO2022148442A1 PCT/CN2022/070790 CN2022070790W WO2022148442A1 WO 2022148442 A1 WO2022148442 A1 WO 2022148442A1 CN 2022070790 W CN2022070790 W CN 2022070790W WO 2022148442 A1 WO2022148442 A1 WO 2022148442A1
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- alkyl
- membered
- alkoxy
- halogen
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
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Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
- C07F9/65128—Six-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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Definitions
- the present invention relates to a 6-substituted phosphoryl quinazoline derivative and its preparation method and application.
- the RAS protein is a membrane-bound protein with intrinsic GTPase activity that is activated by many extracellular stimuli, cycling between a GDP-bound (off) state and a GTP-bound (on) state. When it is in the GTP-bound (on) state, it can activate downstream pathways and promote a series of processes such as cell proliferation, differentiation, migration, and immunity.
- the RAS protein family includes three highly homologous isoforms: KRAS (Kirsten rat sarcoma virus oncogene), HRAS (Harvey rat sarcoma virus oncogene) and NRAS (Neuroblastoma ras oncogene).
- KRAS contains two alternative splicing variants: KRAS4A and KRAS4B.
- RAS family proteins have weak endogenous GTPase activity and slow nucleotide exchange rates (Hunter et al. Mol. Cancer Res. 2015, 13(9): 1325-1335).
- KRAS mutation frequency is the highest, accounting for 86% (Cox, Adrienne D. et al. Nat Rev Drug Discov. 2014, 13(11):828-851).
- KRAS-4B mutations are present in approximately 90% of pancreatic cancers, 30%-40% of colon cancers, and 15%-20% of lung cancers, and are also present in biliary tract malignancies, endometrial cancer, cervical cancer, and bladder cancer , liver cancer, myeloid leukemia and breast cancer (Liu P, et al.
- KRAS-G12D 41%
- KRAS-G12V 28%)
- KRAS-G12C 14%) mutations.
- Mutated KRAS affects its ability to bind to GTPase activating protein (GAP), thereby inhibiting GAP-induced GTP hydrolysis. With the decline of the hydrolysis capacity of GTPase, GTP gradually accumulates, and KRAS is more likely to combine with GTP, so that most of KRAS is in an activated state, which induces the occurrence and development of malignant tumors.
- GAP GTPase activating protein
- GEF GMP exchange factor
- SOS Ston of Sevenless protein
- SOS protein first discovered in Drosophila in 1992, is the GEF of RAS and Rac proteins and plays an important role in the RAS and Rac signaling pathways. Humans have two SOS homologs, SOS1 and SOS2, which are highly similar in structure and sequence, with 70% homology, but there are certain differences in biological functions.
- the SOS1 protein consists of 1300 amino acid residues, and the C-terminal contains a proline-rich domain, which can interact with growth factor receptor-bound protein 2 (Grb2) in the RAS pathway.
- Grb2 binds to SOS1 to form a complex, which can bring SOS1 to the vicinity of the RAS protein in the cell membrane.
- the interaction of SOS1 with RAS involves two domains of SOS1: the CDC25 domain and the REM domain.
- the CDC25 domain has an active site for nucleotide exchange, and the REM domain contains a site that binds RAS-GTP and leads to allosteric activation of the CDC25 domain (Pierre S, et al. Biochem Pharmacol. 2011, 82(9) : 1049-1056).
- SOS1 can convert GDP to GTP through catalytic exchange, GTP is hydrolyzed by RAS, and then activates downstream signals, causing a corresponding series of biological effects.
- Specific SOSl inhibitors inhibit the interaction of SOS1 with KRAS-GDP, thereby reducing the formation of KRAS-GTP in the activated state. Decreased levels of KRAS-GTP lead to a decrease in downstream MAPK signaling, acting in both wild-type and multiple KRAS mutant types.
- the SOS1 small-molecule inhibitor BAY-293 effectively reduces mutated KRAS and wild-type KRAS activity in tumor cells (Hillig, Roman C. et al. Proc Nat Acad Sci USA. 2019, 116(7):2551-2560).
- the SOS1 inhibitors BI-3406 and BI-1701963 developed by Boehringer Ingelheim can bind to the catalytic domain of SOS1, prevent its interaction with KRAS, reduce the formation of KRAS-GTP, and inhibit KRAS-driven proliferation of various cancer cells .
- the combination of SOS1 inhibitors and MEK inhibitors can significantly reduce KRAS signaling and enhance antitumor activity through complementary mechanisms of action (Hofmann, Marco H, et al. Cancer Discov. 2020: CD-20-0142).
- BI-3406 inhibits cytochrome P450 3A4 (CYP3A4) in a time-dependent manner, there is a potential drug-drug interaction (DDI) risk, so the development of cell-free Pigment P450 inhibition has the advantage that SOS1 inhibitors without CYP3A4 inhibition are more clinically valuable.
- BI-1701963 and its combination therapy with MEK inhibitor trametinib have both entered clinical research.
- Noonan syndrome is an autosomal dominant disorder in which SOS1 mutations occur in about 20% of NS patients, and these mutations are distributed in six domains of SOS1. Patients with SOS1 mutations exhibit phenotypic features of curly hair and ectodermal abnormalities. Mutations in the CDC25 domain directly increase the GEF activity of SOS1 and induce hyperactivation of the RAS/ERK pathway (JoséM Rojas, et al. Genes Cancer. 2011, 2(3):298-305).
- Cardiofacial skin syndrome is a type of cardiomyopathy of the renin-angiotensin system, and studies have reported mutations in SOS1 in this disease (Narumi, Yoko, et al. J Hum Genet. 2008, 53(9): 834-841.).
- Hereditary gingival fibromatosis type 1 is an autosomal dominant disorder whose etiology is associated with mutations in the proline-rich domain of SOS1 (Jang SI, et al. J Biol Chem. 2007, 282(28) : 20245-20255).
- the purpose of the present invention is to provide a 6-substituted phosphoryl quinazoline derivative, which is used as an inhibitor of the interaction between the catalytic site of SOS1 and RAS family proteins, participates in the regulation of cell proliferation, and can be used for excessive or abnormal cell proliferation treatment of disease.
- the first aspect of the present invention provides 6-substituted phosphorylquinazoline derivatives represented by formula I, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or Prodrugs:
- Z is a carbon atom or a nitrogen atom; and when Z is a nitrogen atom, R is absent ;
- R 11 and R 12 are each independently a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group; the C 1 -C 6 alkyl group or the C 1 -C 6 alkoxy group is each independently Substituted by one or more R 13 , the R 13 is a substituent selected from the following: hydroxyl, amino, nitro, halogen, cyano; when there are multiple substituents, the substituents are the same or different;
- ring B is a 4-8 membered carbocyclic ring, a 4-8 membered alkene ring or a 4-8 membered heterocyclic ring;
- R a is independently hydrogen or a substituent selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C 1 -C 6 alkyl, 3-8 membered cycloalkyl; the C 1 -C 6 The alkyl group or the 3-8 membered cycloalkyl group is independently substituted with one or more R f ; when there are multiple substituents, the R f is the same or different;
- n 1, 2, 3 or 4;
- R 2 is hydrogen or a substituent selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano,
- Y is absent or a group selected from the group consisting of:
- R 21 , R 22 , R 23 , R 24 are each independently hydrogen or a substituent selected from the group consisting of C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the 3-8 membered cycloalkyl, the 4-8 membered Heterocycloalkyl, the C 2 -C 6 alkenyl, the C 2 -C 6 alkynyl, or the C 1 -C 6 alkoxy are each independently substituted with one or more R f ; when substituted When there are multiple bases, the R f is the same or different;
- L is a group absent or selected from the group consisting of C1 - C6 alkyl, deuterated C1 - C6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C2- C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the 3-8 membered cycloalkyl, the 4-8 membered heterocycle
- the alkyl group, the C 2 -C 6 alkenyl group, the C 2 -C 6 alkynyl group, or the C 1 -C 6 alkoxy group are each independently substituted by one or more R f ; when the substituent is When more than one, the R f is the same or different;
- M is a substituent which is absent or selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, -COOC1 - C6 alkyl;
- the C 1 -C 6 alkyl group, the C 1 -C 6 alkoxy group, or the -COOC 1 -C 6 alkyl group are each independently substituted by one or more R f ; when the substituents are multiple , the R f is the same or different;
- Ring A is absent or selected from 3-15-membered cycloalkyl or 4-15-membered heterocycloalkyl, 5-15-membered aryl or 5-15-membered heteroaryl;
- R b is each independently hydrogen or a group selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 2 -C 6 amide group, C 1 -C 6 ester group, C 1 -C 6 carbonyl group; the C 1 -C 6 alkyl group, The C 1 -C 6 alkoxy group, the C 2 -C 6 amide group, the C 1 -C 6 ester group, or the C 1 -C 6 carbonyl group are each independently replaced by one or more R f Substitute; when there are multiple substituents, the R f is the same or different; n is 1, 2, 3 or 4; when R b is multiple, R b is the same or different substituents;
- R 3 is hydrogen or a substituent selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl ;
- the C 1 -C 6 alkyl group, the C 1 -C 6 alkoxy group, the 3-8 membered cycloalkyl, or the 4-8 membered heterocycloalkyl are independently replaced by one or more R f is substituted; when there are multiple substituents, the R f are the same or different;
- R 4 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl; the C 1 -C 6 alkyl, the The C 1 -C 6 alkoxy group and the 3-8 membered cycloalkyl group are independently substituted by one or more R f ; when there are multiple substituents, the R f is the same or different;
- R 5 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; said C 1 -C 6 alkyl or said C 1 -C 6 alkoxy
- the groups are independently substituted by one or more R f ; when there are multiple substituents, the R f is the same or different;
- R 6 is a 5-8 membered cycloalkyl group, or a 5-8 membered aromatic ring group, or a 5-10 membered heteroaromatic ring group; the 5-8 membered cycloalkyl group, or the 5-8 membered aromatic ring group , or a 5-10 membered heteroaryl ring optionally substituted with one or more, identical or different substituents selected from the group consisting of: hydroxy, amino, nitro, halogen, cyano, -SF 5 , C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, -SO 2 -C 1 -C 6 alkyl; the hydroxyl and amino groups are optionally substituted by C 1 -C 6 alkyl, 3-8-membered cycloalkyl or 4-10-
- the R f is a substituent selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered halocycloalkyl, 4-10 membered heterocycloalkyl, C 1 -C 6 acyl, C 1 -C 6 carbonyl, C 1 -C 6 sulfone group, C 1 -C 6 halogenated sulfone group;
- the heteroatom is selected from one or more of N, O, S and P, and the number of heteroatoms is 1-3.
- the heteroatoms are selected from one or more of N, O, S and P, and the number of heteroatoms is 1-3.
- R 2 is a C 1 -C 6 amide group, and the C 1 -C 6 amide group is substituted by one or more R f ; when there are multiple substituents, the R f is the same or different; R f is defined as described in the first aspect of the present invention.
- 6-substituted phosphoryl quinazoline derivatives shown in formula I their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or Prodrugs:
- Z is a carbon atom or a nitrogen atom; and when Z is a nitrogen atom, R does not exist ;
- R1 is R 11 and R 12 are each independently a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group; the C 1 -C 6 alkyl group or the C 1 -C 6 alkoxy group is each independently Substituted by one or more R 13 , the R 13 is a substituent selected from the following: hydroxyl, amino, nitro, halogen, cyano; when there are multiple substituents, the substituents are the same or different; Alternatively, R 11 , R 12 together with the phosphorus atom to which they are attached form a substituent Wherein, ring B is a 4-8-membered carbocyclic ring, a 4-8-membered alkene ring or a 4-8-membered heterocyclic ring; R a is independently hydrogen or a substituent selected from the following: hydroxyl, amino, nitro, halogen, cyano, C 1 -C 6 alkyl, 3-8 membered cycloalky
- R 2 is hydrogen or a substituent selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano,
- Y is absent or a group selected from the group consisting of:
- R 21 , R 22 , R 23 , R 24 are each independently hydrogen or a substituent selected from the group consisting of C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the 3-8 membered cycloalkyl, the 4-8 membered Heterocycloalkyl, the C 2 -C 6 alkenyl, the C 2 -C 6 alkynyl, or the C 1 -C 6 alkoxy are each independently substituted with one or more R f ; when substituted When there are multiple bases, the R f is the same or different;
- L is a group absent or selected from the group consisting of C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the 3-8 membered cycloalkyl, the 4-8 membered heterocycloalkyl, the C 2 -C 6
- the alkenyl group, the C 2 -C 6 alkynyl group, or the C 1 -C 6 alkoxy group are each independently substituted with one or more R f ; when there are multiple substituents, the R f is the same or different;
- M is a substituent which is absent or selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy; the C1 - C6 alkyl , or the C 1 -C 6 alkoxy groups are independently substituted by one or more R f ; when there are multiple substituents, the R f is the same or different;
- Ring A is absent or selected from 3-15-membered cycloalkyl or 4-15-membered heterocycloalkyl, 5-15-membered aryl or 5-15-membered heteroaryl;
- R b is each independently hydrogen or a group selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 2 -C 6 amide group, C 1 -C 6 ester group, C 1 -C 6 carbonyl group; the C 1 -C 6 alkyl group, The C 1 -C 6 alkoxy group, the C 2 -C 6 amide group, the C 1 -C 6 ester group, or the C 1 -C 6 carbonyl group are each independently replaced by one or more R f Substitute; when there are multiple substituents, the R f is the same or different; n is 1, 2, 3 or 4; when R b is multiple, R b is the same or different substituents;
- R 3 is hydrogen or a substituent selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl ;
- the C 1 -C 6 alkyl group, the C 1 -C 6 alkoxy group, the 3-8 membered cycloalkyl, or the 4-8 membered heterocycloalkyl are independently replaced by one or more R f is substituted; when there are multiple substituents, the R f are the same or different;
- R 4 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl; the C 1 -C 6 alkyl, the The C 1 -C 6 alkoxy group and the 3-8 membered cycloalkyl group are independently substituted by one or more R f ; when there are multiple substituents, the R f is the same or different;
- R 5 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; said C 1 -C 6 alkyl or said C 1 -C 6 alkoxy
- the groups are independently substituted by one or more R f ; when there are multiple substituents, the R f is the same or different;
- R 6 is a 5-8 membered cycloalkyl group, or a 5-8 membered aromatic ring group, or a 5-10 membered heteroaromatic ring group; the 5-8 membered cycloalkyl group, or the 5-8 membered aromatic ring group , or a 5-10 membered heteroaryl ring optionally substituted with one or more, identical or different substituents selected from the group consisting of: hydroxy, amino, nitro, halogen, cyano, -SF 5 , C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, -SO 2 -C 1 -C 6 alkyl; the hydroxyl and amino groups are optionally substituted by C 1 -C 6 alkyl, 3-8-membered cycloalkyl or 4-10-
- the R f is a substituent selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered halocycloalkyl, 4-10 membered heterocycloalkyl, C 1 -C 6 acyl, C 1 -C 6 carbonyl, C 1 -C 6 sulfone group, C 1 -C 6 halogenated sulfone group;
- the heteroatom is selected from one or more of N, O, S and P, and the number of heteroatoms is 1-3.
- 6-substituted phosphoryl quinazoline derivatives shown in the formula I are not:
- L is a group that does not exist or is selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the 3-8 membered cycloalkyl, the 4-8
- the membered heterocycloalkyl, the C 2 -C 6 alkenyl, the C 2 -C 6 alkynyl, or the C 1 -C 6 alkoxy are each independently substituted with one or more R f ; when When there are multiple substituents, the R f are the same or different;
- M is a substituent which is absent or selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy; the C1 - C6 alkyl , the C 1 -C 6 alkoxy groups are independently substituted by one or more R f ; when there are multiple substituents, the R f is the same or different;
- L is a group that is absent or selected from the group consisting of C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the 3-8 membered cycloalkyl, the 4-8 membered heterocycloalkyl, the C 2 -C 6 alkenyl group, the C 2 -C 6 alkynyl group, or the C 1 -C 6 alkoxy group are each independently substituted with one or more R f ; when there are multiple substituents, the R f the same or different;
- M is a substituent which is absent or selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, -COOC1 - C6 alkyl;
- the C 1 -C 6 alkyl group, the C 1 -C 6 alkoxy group, or the -COOC 1 -C 6 alkyl group are each independently substituted by one or more R f ; when the substituents are multiple , the R f is the same or different;
- L is a group that does not exist or is selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the 3-8 membered cycloalkyl, the 4-8
- the membered heterocycloalkyl, the C 2 -C 6 alkenyl, the C 2 -C 6 alkynyl, or the C 1 -C 6 alkoxy are each independently substituted with one or more R f ; when When there are multiple substituents, the R f are the same or different;
- M is a substituent which is absent or selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, -COOC1 - C6 alkyl;
- the C 1 -C 6 alkyl group, the C 1 -C 6 alkoxy group, or the -COOC 1 -C 6 alkyl group are each independently substituted by one or more R f ; when the substituents are multiple , the R f are the same or different.
- R 1 when Z is N or R 2 is methoxy or halogen, and R 1 is When R 11 is methyl or ethyl, R 6 is and when for , wherein R f is methyl; when for , where R f is F;
- R 1 is , R 11 and R 12 are each independently methyl, and R 2 is not halogen, methoxy or halogen-substituted methoxy;
- R 1 is , R 11 and R 12 are each independently methyl, and R 6 is not
- R a1 is a C 1 -C 6 alkyl group, a 3-8 membered cycloalkyl group, and the C 1 -C 6 membered cycloalkyl group or the 3-8 membered cycloalkyl group is independently replaced by one or more R f is substituted, when there are multiple substituents, the R f is the same or different, and the R a1 is not C 1 -C 3 alkyl,
- R 1 is , R 11 and R 12 are each independently methyl, and R 2 is not halogen, C 1 -C 6 alkoxy or halogen-substituted C 1 -C 6 alkoxy;
- R 1 is When Z is a nitrogen atom, R 1 is When R 11 and R 12 are independently methyl, and R 6 is a substituted phenyl group, the substituent is not a halogen-substituted C 1 -C 6 alkyl group;
- R 1 when Z is a carbon atom, R 1 is , R 11 and R 12 are each independently a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, and the C 1 -C 6 alkyl group or the C 1 -C 6 alkoxy group is respectively Independently substituted by one or more R 13 , the R 13 is a substituent selected from the following: hydroxyl, amino, nitro, halogen, cyano; when there are multiple substituents, the substituents are the same or different; R 2 is hydrogen or a substituent selected from the group consisting of hydroxy, amino, nitro, cyano, wherein Y is absent or a group selected from the group consisting of:
- R 1 is , R 6 is a 5-8 membered cycloalkyl group, or a 5-8 membered aromatic ring group, or a 5-10 membered heteroaryl ring group, the 5-8 membered cycloalkyl group, or the 5-8 membered aromatic ring group
- the ring group, or the 5-10 membered heteroaromatic ring group is optionally substituted with two, the same or different substituents, as defined in the first aspect of the present invention
- the 5- to 8-membered aromatic ring group in R 6 is phenyl.
- R 6 comprises:
- R 1 is Wherein, R 11 and R 12 are each independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; preferably, R 11 and R 12 are each independently methyl, ethyl, propyl, butyl base, pentyl, hexyl.
- the group is a substituent selected from:
- R a is independently hydrogen or a substituent selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C 1 -C 6 alkyl, 3-8 membered cycloalkyl; the C 1 -C 6 The alkyl group or the 3-8 membered cycloalkyl group is independently substituted with one or more R f ; when there are multiple substituents, the R f is the same or different;
- R a1 is C 1 -C 6 alkyl, 3-8 membered cycloalkyl; the C 1 -C 6 alkyl, or the 3-8 membered cycloalkyl is independently substituted by one or more R f ; When the substituents are multiple, the R f is the same or different;
- the R f is a substituent selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered halocycloalkyl, 4-10 membered heterocycloalkyl, C 1 -C 6 acyl, C 1 -C 6 carbonyl, C 1 -C 6 sulfone group, C 1 -C 6 halogenated sulfone group;
- n 1, 2, 3 or 4, preferably 1, 2 or 3.
- R 2 is hydrogen or a substituent selected from the group consisting of hydroxyl, amino, nitro, cyano, group wherein Y is absent or a group selected from the group consisting of:
- Y is
- Y is absent or a group selected from the group consisting of: L is absent or C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; M is absent or hydroxyl, cyano, halogen, C 1 -C 6 alkoxy ; Ring A is absent or selected from 5-10-membered cycloalkyl or 4-10-membered heterocycloalkyl, 5-10-membered aryl or 5-10-membered heteroaryl; R b is hydrogen or C 1 -C 6 alkyl; when R b is multiple, R b is the same or different substituents; preferably, ring A is a 4-10-membered heterocycloalkyl group or a 5-10-membered heteroaryl ring group.
- the group is a substituent selected from:
- Ring D and Ring E are each independently selected from: 3-15-membered cycloalkyl or 4-15-membered heterocycloalkyl, 5-15-membered aromatic ring or 5-15-membered heteroaryl; R b , n is defined as described in the first aspect of the present invention;
- ring D and ring E are each independently selected from: 3-10-membered cycloalkyl or 4-10-membered heterocycloalkyl, 5-8-membered aromatic ring group or 5-8-membered heteroaryl ring group;
- n is 1, 2, 3 or 4, preferably 1, 2 or 3;
- R b is each independently hydrogen or a group selected from the group consisting of halogen, C 1 -C 6 alkyl group, C 2 -C 6 amido group, C 2 -C 6 ester group, C 2 -C 6 carbonyl group; the C 1 -C 6 alkyl group, the C 2 -C 6 amido group , the C 2 -C 6 ester group, or the C 2 -C 6 carbonyl group is independently substituted by one or more R g ; when there are multiple substituents, the R g is the same or different;
- R g is a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
- R b is plural, R b is the same or different substituents.
- R 3 is hydrogen or a substituent selected from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl.
- R 4 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 3-6 membered cycloalkyl; preferably , R 4 is C 1 -C 4 alkyl; preferably, R 4 is methyl.
- R 5 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl.
- R 2 is optionally substituted by 1, 2 or 3 R f ; when there are more than one substituent R f , the substituent R f is the same or different; preferably , R f is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl.
- the 6-substituted phosphorylquinazoline derivatives represented by formula I their tautomers, stereoisomers, hydrates, solvates and pharmaceutically acceptable salts or a prodrug, which has structure Ia
- R 1 , R 2 , R 3 , R 4 , R 5 are as described in the first aspect of the present invention.
- R 61 , R 62 , R 63 , R 64 , R 65 are each independently hydrogen or a substituent selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, SF 5 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 3-8 membered halocycloalkyl, C 1 -C 6 amido , C 1 -C 4 ester group, C 1 -C 6 sulfone group, C 1 -C 6 halogenated sulfone group;
- R 61 , R 62 , R 63 , R 64 , R 65 are each independently hydrogen or are selected from the following substituents: hydroxyl, amino, nitro, halogen, cyano, SF 5 , C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 sulfone, C 1 -C 6 halosulfone.
- R 63 , R 64 , R 65 are hydrogen
- R 61 , R 62 are each independently hydrogen or are selected from the following substituents: Hydroxyl, amino, nitro, halogen, cyano, SF 5 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, 3-8 membered cycloalkyl, 4- 10-membered heterocycloalkyl, 3-8 membered halogenated cycloalkyl, C 1 -C 6 amide group, C 1 -C 4 ester group, C 1 -C 6 sulfone group, C 1 -C 6 halogenated sulfone group ;
- R 63 , R 64 , R 65 are hydrogen
- R 61 , R 62 are each independently hydrogen or are selected from the following substituents: hydroxyl, amino, nitro, halogen, cyano, SF 5 , C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 sulfone, C 1 -C 6 halogenated sulfone;
- R 63 , R 64 , R 65 are hydrogen
- R 61 , R 62 are each independently hydrogen or are selected from the following substituents: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 sulfone group, C 1 -C 6 halogenated sulfone group.
- R 63 , R 64 , R 65 are hydrogen, R 61 is hydrogen, C 1 -C 6 alkyl or halogen, R 62 is C 1 -C 6 haloalkyl; preferably, R 63 , R 64 and R 65 are hydrogen, R 61 is hydrogen, methyl or fluorine, and R 62 is trifluoromethyl or difluoromethyl.
- R 2 is hydrogen, halogen or
- Y is absent or a group selected from the group consisting of:
- R 21 , R 22 and R 23 are each independently hydrogen or C 1 -C 6 alkyl; the C 1 -C 6 alkyl is substituted by one or more R e ; when there are multiple substituents, the Re the same or different;
- L is a group absent or selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkoxy group; C 6 alkyl, the C 2 -C 6 alkenyl, the C 2 -C 6 alkynyl, or the C 1 -C 6 alkoxy are each independently substituted with one or more R e ; when substituted When there are multiple bases, the Re is the same or different;
- M is a substituent which is absent or selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy; the C1 - C6 alkyl , or the C 1 -C 6 alkoxy groups are independently substituted by one or more Re ; when there are multiple substituents, the Re is the same or different;
- Ring A is absent or selected from 5-10-membered cycloalkyl or 4-10-membered heterocycloalkyl, 5-10-membered aryl or 5-10-membered heteroaryl;
- R b is each independently hydrogen or a group selected from the group consisting of hydroxy, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the C 1 -C 6 alkoxy is independently substituted by one or more Re ; when there are multiple substituents, the Re is the same or different; n is 1, 2 or 3;
- R e is a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
- R b is plural, R b is the same or different substituents.
- R 23 is hydrogen or C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; preferably, R 23 is hydrogen or C 1 -C 3 alkyl, C 1 -C 3 haloalkyl;
- L is a group absent or selected from the following: C 1 -C 6 alkyl, C 1 -C 6 alkoxy; preferably L is a group absent or selected from the following: C 1 -C 3 alkane base, C 1 -C 3 alkoxy;
- M is a substituent absent or selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; preferably, M is a substituent absent or selected from the following: halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy;
- Ring A is absent or selected from 3-6-membered cycloalkyl or 4-10-membered heterocycloalkyl, 5-10-membered aromatic ring or 5-10-membered heteroaryl;
- the heteroatom is N;
- ring A is absent or a 3-6 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, a 5-6 membered aromatic ring group or a 5-6 membered Heteroaryl ring group; in the heterocycloalkyl group or heteroaryl ring group, the heteroatom is N;
- R b is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 halocycloalkyl, C 1 -C 6 alkoxy; Preferably R b is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
- Y is a group that is absent or selected from: R 23 is hydrogen or C 1 -C 6 alkyl; L is absent or selected from the following groups: C 1 -C 6 alkyl, C 1 -C 6 alkoxy; M is absent or selected from the following Substituents: halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
- Ring A is absent or selected from 5-10-membered cycloalkyl or 4-10-membered heterocycloalkyl, 5-10-membered aromatic ring or 5-10-membered heteroaryl; preferably, Ring A is not Exist or 5-6-membered cycloalkyl or 5-6-membered heterocycloalkyl, 5-6-membered aryl or 5-6-membered heteroaryl; in the heterocycloalkyl or heteroaryl,
- the heteroatoms are selected from N or O, and the number of heteroatoms is 1 or 2; when there are multiple heteroatoms, the heteroatoms are the same or different;
- R b is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 halocycloalkyl, C 1 -C 6 alkoxy; Preferably R b is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
- the 6-substituted phosphorylquinazoline derivatives represented by formula I their tautomers, stereoisomers, hydrates, solvates and pharmaceutically acceptable salts or a prodrug, which has structure Ie
- R2 is where Y is
- R 23 is hydrogen, and the definitions of L, M, ring A, R b and n are as described in the first aspect of the present invention.
- L is a group that is absent or selected from the group consisting of: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 alkoxy; said C 1 -C 6 alkyl, said C 2 -C 6 alkenyl, said C 2 -C 6 alkynyl, or said C 1 -
- the C 6 alkoxy groups are independently substituted by one or more R e ; when there are multiple substituents, the R e are the same or different;
- L is absent or a group selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 alkoxy; more preferably L is absent or a group selected from the group consisting of C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
- M is a substituent which is absent or selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
- the C 1 -C 6 alkyl group or the C 1 -C 6 alkoxy group is independently substituted with one or more R e ; when there are multiple substituents, the R e is the same or different;
- M is a substituent that is absent or selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; more preferably, M is a substituent that is absent or selected from the following : halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
- Ring A is absent or selected from 5-10 membered cycloalkyl or 4-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl ;
- ring A is absent or selected from 3-6 membered cycloalkyl or 4-10 membered heterocycloalkyl, 5-10 membered aromatic ring or 5-10 membered heteroaryl;
- the heteroatom is N; more preferably, ring A is absent or a 3-6 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, a 5-6 membered aromatic ring group or 5-6 membered heteroaryl ring group; in the heterocycloalkyl or heteroaryl ring group, the heteroatom is N.
- R b is independently hydrogen or a group selected from the group consisting of hydroxyl, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl group and the C 1 -C 6 alkoxy group are independently substituted by one or more R e ; when there are multiple substituents, the R e is the same or different; n is 1, 2 or 3; wherein said R e is a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; when R b is multiple, R b is the same or different substitution base;
- R b is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 halocycloalkyl, C 1 -C C 6 alkoxy; more preferably R b is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
- R 2 is
- L is a group absent or selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl group, the C 2 -C 6 alkenyl group, the C 2 -C 6 alkynyl group, or the C 1 -C 6 alkoxy group are each independently is substituted by one or more R e ; when the substituent is more than one, the R e is the same or different;
- M is a substituent which is absent or selected from the group consisting of hydroxyl, amino, nitro, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy; the C1 - C6 alkyl , or the C 1 -C 6 alkoxy groups are independently substituted by one or more Re ; when there are multiple substituents, the Re is the same or different;
- Ring A is absent or selected from 5-10-membered cycloalkyl or 4-10-membered heterocycloalkyl, 5-10-membered aryl or 5-10-membered heteroaryl;
- R b is each independently hydrogen or a group selected from the group consisting of hydroxy, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; the C 1 -C 6 alkyl, the C 1 -C 6 alkoxy is independently substituted by one or more Re ; when there are multiple substituents, the Re is the same or different; n is 1, 2 or 3;
- R e is a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
- R b is plural, R b is the same or different substituents.
- R 2 is Wherein, L is absent or selected from the following groups: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 alkoxy; preferably L is absent or selected Groups from the following: C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, C 1 -C 3 alkoxy;
- M is a substituent absent or selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; preferably, M is a substituent absent or selected from the following: halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy;
- Ring A is absent or selected from 3-6-membered cycloalkyl or 4-10-membered heterocycloalkyl, 5-10-membered aromatic ring or 5-10-membered heteroaryl;
- the heteroatom is N;
- ring A is absent or a 3-6 membered cycloalkyl group or a 5-6 membered heterocycloalkyl group, a 5-6 membered aromatic ring group or a 5-6 membered Heteroaryl ring group; in the heterocycloalkyl group or heteroaryl ring group, the heteroatom is N;
- R b is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 halocycloalkyl, C 1 -C 6 alkoxy group; preferably R b is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
- R 2 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted C 1 -C 6 alkoxy , 5-6 membered N or O-containing heterocycloalkyl substituted C 1 -C 6 alkoxy, -NH-C 1 -C 6 alkyl, -NH-C 3 -C 6 cycloalkyl, -NH -halogenated C 1 -C 6 alkyl, -NH-halo C 3 -C 6 cycloalkyl, -N(C 1 -C 6 alkyl) 2 ;
- R 2 is hydrogen or a substituent selected from the group consisting of fluorine, -NH-C 1 -C 6 alkyl, -NH-C 3 -C 6 cycloalkyl, -N(C 1 -C 6 Alkyl) 2 ; the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl is substituted by 1 or more substituents selected from the following substituents: halogen or C 1 -C 6 alkoxy; when the substituent When there are multiple, the substituents are the same or different;
- R 2 is hydrogen or a substituent selected from the group consisting of fluorine, -NH-C 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , -NH-C 3 -C 6 cycloalkyl; the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is substituted with 1 or more fluorine or 1 or more C 1 -C 6 alkoxy.
- R 2 is optionally substituted by 1, 2 or 3 R f ; when there are more than one substituent R f , the substituent R f is the same or different; preferably , R f is halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl.
- the halogen is preferably fluorine.
- the 6-substituted phosphoryl quinazoline derivatives include:
- the second aspect of the present invention provides a quinazoline derivative represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmacy, as described in the first aspect of the present invention
- the preparation method of the above acceptable salt or prodrug, the method comprises the steps:
- intermediate B-1 reacts with intermediate B-2 or B-3 to obtain intermediate B
- intermediate B reacts with intermediate B-4 to obtain the 6-substituted phosphoryl quinazoline derivative shown in formula I,
- X 1 and X 2 are each independently selected from: -OTf, -OTs, -OMs, fluorine, chlorine, bromine or iodine;
- Z is a carbon atom or a nitrogen atom; and when Z is a nitrogen atom, R is absent ;
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described in the first aspect of the present invention.
- the method further comprises one or more steps selected from the group consisting of:
- step ii) is reacted in the presence of a palladium catalyst to obtain a quinazoline derivative represented by formula I; 9-dimethylxanthene is reacted in the coexistence to obtain the quinazoline derivative shown in formula I;
- step ii) is reacted under the protection of inert gas to obtain the quinazoline derivative represented by formula I.
- the third aspect of the present invention provides an intermediate represented by formula B-5 for preparing the quinazoline derivative represented by formula I as described in the first aspect of the present invention, its tautomer, stereoisomer body, hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate has the structure:
- R 1 , R 2 , R 3 , R 4 and R 5 are as described in the first aspect of the present invention.
- an intermediate represented by formula B-6 is provided for preparing the quinazoline derivative represented by formula I as described in the first aspect of the present invention, its tautomer, stereoisomer and hydrate , solvate, pharmaceutically acceptable salt or prodrug, the intermediate has the structure:
- X 2 is selected from: -OTf, -OTs, -OMs, fluorine, chlorine, bromine or iodine;
- R 1 , R 2 , R 3 , R 4 and R 5 are as described in the first aspect of the present invention.
- the fourth aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: the quinazoline derivative represented by formula I as described in the first aspect of the present invention, its tautomer, stereoisomer Conforms, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and pharmaceutically acceptable carriers.
- a pharmaceutical composition which comprises the phosphorylquinazoline derivative represented by formula I as described in the first aspect of the present invention, its tautomer, stereoisomer, A hydrate, solvate, pharmaceutically acceptable salt or prodrug; and at least one other inhibitor of pharmacological activity.
- the other pharmacologically active inhibitor is an inhibitor of MEK and/or its mutants.
- the fifth aspect of the present invention provides the phosphorylquinazoline derivatives represented by formula I as described in the first aspect of the present invention, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically Use of an acceptable salt or prodrug, or use of the pharmaceutical composition according to the fourth aspect of the present invention, comprising: inhibiting SOS1 and RAS family proteins; and/or, preventing and/or treating SOS1 and RAS family Protein-related diseases; and/or, preparing medicines, pharmaceutical compositions or preparations for inhibiting SOS1 and RAS family proteins, and/or preventing and/or treating SOS1 and RAS family protein-related diseases; and/or, preparing medicines , such as the preparation of medicaments for the prevention and/or treatment of cancer and RAS disease.
- the use includes: inhibiting the interaction between SOS1 and RAS family proteins; and/or, preparing a drug, pharmaceutical composition or preparation for inhibiting the interaction between SOS1 and RAS family proteins.
- the diseases related to SOS1 and RAS family proteins include but are not limited to: cancer, RAS diseases; the RAS diseases include Noonan syndrome, cardiofacial skin syndrome, type 1 hereditary gingival fibromatosis, 1 Type neurofibromatosis, capillary malformation-arteriovenous malformation syndrome, Costello syndrome and Leggers syndrome; and/or, the cancer is pancreatic cancer; and/or, the RAS family protein is KRAS, such as KRAS G12C.
- a method for inhibiting SOS1 and RAS family proteins, or preventing and/or treating diseases related to SOS1 and RAS family proteins comprising the steps of: administering the first aspect of the present invention to a subject in need Quinazoline derivatives represented by formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof.
- reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
- the techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification.
- groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
- substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
- halogen alone or as part of other substituents, refers to fluorine, chlorine, bromine, iodine.
- amino means -NH2 .
- nitro means -NO2 .
- cyano means -CN
- alkyl alone or as part of other substituents, means consisting only of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond A straight or branched hydrocarbon chain group to which the remainder is attached.
- alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.
- Alkyl groups can be unsubstituted or substituted with one or more suitable substituents.
- Alkyl groups can also be isotopic isomers of naturally-abundant alkyl groups that are enriched in carbon and/or hydrogen isotopes (ie, deuterium or tritium).
- alkenyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
- alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
- C1 - C6 alkyl is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
- the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl,
- C1 - C6alkoxy alone or as part of other substituents, is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms and oxygen atoms, or expressed as C 1 -C 6 alkyl-O-.
- the definition of C1 - C6 alkyl is as described in this specification, and the oxygen atom may be attached to any carbon atom of the straight or straight chain of the C1 - C6 alkyl.
- Carbocycle refers to a cyclic alkyl group.
- mn-membered cycloalkyl or “ Cm - Cncycloalkyl” is to be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms.
- 3-15 membered cycloalkyl or “C3 - C15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which May contain 1 to 4 rings.
- 5-8 membered cycloalkyl contains 5-8 carbon atoms. Includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decalin rings. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl ring group.
- C3 - C6cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems.
- unsubstituted cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.
- 3-15 membered cycloalkyl is preferably 3-10 membered cycloalkyl; more preferably 3-8 membered cycloalkyl.
- heterocycle refers to a group in which one or more (in some embodiments 1 to 3) carbon atoms are Cycloalkyl substituted with heteroatoms such as, but not limited to, N, O, S, and P.
- mn-membered heterocycloalkyl or " Cm - Cnheterocycloalkyl” is to be understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms, wherein the heteroatoms are selected from N, O, S, P, preferably selected from N, O or S.
- 4-8 membered heterocycloalkyl or " C4 -C8 heterocycloalkyl” should be understood to mean a saturated, unsaturated or partially saturated ring having 4 to 8 atoms, wherein 1, 2 , 3, or 4 ring atoms are selected from N, O, S, P, preferably N, O or S.
- "4-10 membered heterocycloalkyl” then means a saturated, unsaturated or partially saturated ring having 4 to 10 atoms.
- a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl or heteroaryl ring group.
- heterocycloalkyl group When a prefix such as 3-8 membered or 4-10 membered is used to denote a heterocycloalkyl group, the number of carbons is also meant to include heteroatoms. Includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings.
- the term "4-15 membered heterocycloalkyl” or " C4 - C15 heterocycloalkyl” is to be understood to mean a saturated, unsaturated or partially saturated ring having 4 to 15 atoms, wherein 1, 2, 3 or 4 ring atoms selected from N, O, S, P, preferably N, O or S; preferably 4-10 membered heterocyclyl; more preferably 4-8 membered heterocycloalkyl.
- -CH2- group alone or as part of other substituents, is optionally replaced by -C(O)-; and wherein, unless stated to the contrary, a ring nitrogen atom or a ring sulfur atom is optionally oxidized to form N - oxide or S-oxide or ring nitrogen atom optionally quaternized; wherein -NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogen substituted. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other.
- heterocyclyl group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl group is monocyclic, it must not be aromatic.
- heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indoline, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 -Dioximidazolidinyl.
- C2 - C6 alkenyl alone or as part of other substituents, is understood to mean a straight or branched monovalent hydrocarbon group containing one or more double bonds and having, for example, 2, 3, 4 , 5 or 6 carbon atoms (ie, C2 - C6 alkenyl), or with 2 or 3 carbon atoms (ie, C2-C3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
- the alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -Pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-eny
- C2 - C6alkynyl alone or as part of other substituents, is understood to mean a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having, for example, 2, 3, 4 , 5 or 6 carbon atoms (ie, "C2 - C6alkynyl "), or with 2 or 3 carbon atoms (“C2-C3alkynyl”).
- the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-alkynyl, 2-methylpent-3-y
- arylcyclyl aryl ring structure, alone or as part of other substituents, includes compounds having one or more ring structures, such as monocyclic, bicyclic, tricyclic spiro or bridged compounds, and benzo-fused A combined carbocyclic moiety in which at least one ring system is aromatic.
- the aryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the aryl group.
- aromatic ring group may be used interchangeably with the terms "aromatic ring group” or "aryl group”.
- Examples of aryl groups may include phenyl, indenyl, naphthyl, and anthracenyl.
- the aryl group is optionally substituted with one or more substituents described herein.
- Representative aryl groups include phenyl, anthracenyl, fluorenyl, indenyl, phenanthrenyl and naphthyl.
- 5-15 membered aromatic ring group or " C5 - C15 aromatic ring group", alone or as part of other substituents, should be understood as a monovalent aromatic or partially aromatic group having 5 to 15 carbon atoms a monocyclic, bicyclic or tricyclic hydrocarbon ring, especially a ring with 6 carbon atoms ("C 6 aromatic ring group”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C 6 aromatic ring group”) C 9 aryl ring group”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl ring group”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
- aromatic ring group When the aromatic ring group is substituted, it may be mono- or poly-substituted. Also, the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.
- the term "5-10 membered aromatic ring group” or "C 5 -C 10 aromatic ring group” should be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or Tricyclic hydrocarbon ring; "5-8 membered aromatic ring group” or “C 5 -C 8 aromatic ring group” should be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or Tricyclic hydrocarbon ring.
- heteroarylcyclyl refers to a monocyclic or polycyclic aromatic ring system, in certain embodiments, 1 to 3 atoms in the ring system are heteroatoms, i.e., except for carbon elements other than , including but not limited to N, O, S or P. Examples are furyl, imidazolyl, indoline, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl.
- the heteroaromatic ring group can be optionally condensed with a benzene ring, and can also include monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings.
- 5-15 membered heteroaryl or " C5 - C15 heteroaryl", alone or as part of other substituents, is to be understood as having 5-15 ring atoms and including 1-5 independent
- a monovalent monocyclic, bicyclic or tricyclic aromatic ring group of heteroatoms selected from N, O and S is understood to have 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ring atoms - especially 5 or 6 or 9 or 10 carbon atoms - and it contains 1-5, preferably 1-3 - a monovalent monovalent heteroatom independently selected from N, O and S heteroatoms Cyclic, bicyclic or tricyclic aromatic ring groups, and, additionally in each case, may be benzofused.
- 5-8 membered heteroaromatic ring group is understood to have 5-8 ring atoms - in particular 5 or 6 carbon atoms - and 1-5 heteroatoms independently selected from N, O and S
- a monovalent monocyclic, bicyclic or tricyclic aromatic ring group 1-3 monovalent monovalent monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of heteroatoms independently selected from N, O and S, and, in addition, in each case may be benzo-fused .
- the heteroaryl ring group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, Thiadiazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazole or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, Isoquinolinyl, etc; Pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazin
- haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
- spirocycle refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings, which may contain one or more double bonds, but none of the rings have Fully conjugated pi electron system.
- spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
- spirocycloalkyl include:
- spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, non-limiting examples include:
- bridged ring refers to a cyclic hydrocarbon in which any two rings in a compound share two non-directly connected carbon atoms, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. according to the number of formed rings.
- Non-limiting examples include:
- acyl refers to an R-CO- group wherein R is alkyl and alkyl is as defined herein, eg "C2 - C8 acyl” refers to a group having C1 -C 7 alkyl-CO- groups, representative examples of acyl groups include (but are not limited to): CH 3 -CO-, C 2 H 5 -CO-, C 3 H 8 -CO-, or similar groups group.
- the "acyl group” includes ester groups and amide groups.
- C 1 -C 8 acyl refers to -CHO or a group having the structure C 1 -C 7 alkyl-CO-.
- ester refers to an R-CO-O- group or a -CO-OR group, where R is an alkyl group as defined herein, eg "C " 2 -C 4 ester group” refers to a group of C 1 -C 3 alkyl-CO-O- structure or a group of -CO-OC 1 -C 3 alkyl structure, and representative examples of ester groups include (but Not limited to): CH 3 COO-, C 2 H 5 COO-, C 3 H 8 COO-, (CH 3 ) 2 CHCOO-, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 8 , or similar groups group.
- C 1 -C 4 ester group refers to a group of -CO-OH, -CHO, C 1 -C 3 alkyl-CO-O- structure or a group of -CO-OC 1 -C 3 alkyl structure .
- amide refers to an R-CO-NH- group or a -CO-NH-R group, where R is an alkyl group as defined herein, eg "C 2 -C 4 amide group” refers to a group of C 1 -C 3 alkyl-CO-NH- structure or a group of -CO-NH-C 1 -C 3 alkyl structure, representative of amide group Examples include (but are not limited to): CH3CO -NH-, C2H5 - CO-NH-, C3H8-CO-NH-, ( CH3 ) 2 - CO -NH-, -CO-NH -CH3 , -CO - NHC2H5 , -CO -NH- C3H8 , or the like.
- C 1 -C 4 amide group refers to a group of the structure -CO-NH 2 , CHO-N-, C 1 -C 3 alkyl-CO-NH- or -CO-NH-C 1 -C 3 alkane group of the base structure.
- carbonyl alone or as part of other substituents, refers to the group -CO-R, wherein R is an alkyl group as defined herein above.
- R is an alkyl group as defined herein above.
- C 2 -C 6 carbonyl refers to -CO-C 1 -C 5 alkyl, representative examples include (but are not limited to): -CO-CH 3 , -CO-CH 2 CH 3 , -CO-CH 2CH2CH3 or similar .
- C 1 -C 6 carbonyl refers to -CHO or -CO-C 1 -C 5 alkyl.
- sulfone alone or as part of other substituents, refers to an R- SO2- group, wherein R is an alkyl group as defined herein, eg " C1 - C6sulfone” refers to A group having the structure of C 1 -C 5 alkyl-SO 2 -, representative examples of sulfone groups include (but are not limited to): CH 3 -SO 2 -, C 2 H 5 -SO 2 -, C 3 H 8 -SO 2 -, or a similar group.
- halosulfone refers to a R- SO2- group wherein R is alkyl substituted with one or more halo, and halo and alkyl are as defined herein above , for example "C 1 -C 6 halogenated sulfone group” refers to a group with a C 1 -C 5 alkyl-SO 2 - structure substituted by one or more halogens, representative examples include (but are not limited to): CF 3 -SO 2- .
- inert solvent includes, but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1 , 2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.
- Protected derivatives are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups).
- Suitable protecting groups for the carboxy moiety include benzyl, t-butyl, and the like, as well as isotopes and the like.
- Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
- Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
- salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- “Pharmaceutically acceptable acid addition salts” refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
- “Pharmaceutically acceptable base addition salts” refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects.
- other salts are also contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the present invention.
- amine salt refers to the product obtained by neutralizing an alkyl primary, secondary or tertiary amine with an acid.
- the acid includes the inorganic or organic acids described in this application.
- stereoisomer refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
- the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers.
- the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
- the prefixes D and L or (+) and (–) are symbols used to designate the rotation of plane polarized light by the compound, where (–) or L indicates that the compound is levorotatory.
- Compounds prefixed with (+) or D are dextrorotatory.
- tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
- the compounds of the present invention may exhibit tautomerism.
- Tautomeric compounds can exist as two or more interconvertible species.
- Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
- Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
- the ketone form predominates; in phenols, the enol form predominates.
- the present invention encompasses all tautomeric forms of the compounds.
- a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
- the medium includes a pharmaceutically acceptable carrier.
- the purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
- pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authority as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
- solvate means that a compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
- prodrug refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound.
- the prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds.
- Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- excipient refers to a pharmaceutically acceptable inert ingredient.
- classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
- treatment and other similar synonyms include the following meanings:
- the reaction temperature can be appropriately selected according to the solvent, starting materials, reagents, etc.
- the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, and the like.
- the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Under the condition of not affecting the next reaction, the target compound can also directly enter the next reaction without separation and purification.
- the reagents and raw materials used in the present invention are all commercially available.
- a 6-substituted phosphoryl quinazoline derivative shown in formula I has a significant binding inhibitory effect on the combination of the compounds in the present invention to KRAS G12C::SOS1, has a significant inhibitory effect on KRAS G12C-SOS1, has a significant inhibitory effect on the ERK phosphorylation level of DLD-1 cells, and has a significant inhibitory effect on H358 Compared with BI-3406, this compound has no inhibitory effect on cytochrome P450 3A4 (CYP3A4), and has potential The risk of drug-drug interactions is low.
- the compounds of the present invention exhibit excellent pharmacokinetic properties, and have higher safety and druggability.
- the intermediate the method has the advantages of simple operation, high yield and high purity, and can be used for the industrial production of medicine.
- Figure 1 The tumor-inhibitory ability of the test compounds at the tumor volume level
- the compounds of the present invention can be prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings given above. These methods are intended to illustrate the invention and not to limit its subject matter and the scope of the compounds claimed for these examples.
- Method, described method comprises any step in following synthetic route:
- Intermediate B-1 reacts with intermediate B-2 or B-3 to obtain intermediate B
- intermediate B reacts with intermediate B-4 to obtain the 6-substituted phosphoryl quinazoline derivative shown in formula I
- intermediate B-1 reacts with intermediate B-5 or B-6 to obtain the 6-substituted phosphorylquinazoline derivative represented by formula I.
- different synthetic routes and intermediates can be selected.
- the active group can be passed through the protective group as required. Participate in the reaction after protection, and after the completion of the reaction, deprotect the protecting group.
- protecting groups for the carboxy moiety include benzyl, t-butyl, isotopes, and the like.
- suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.
- Suitable hydroxy protecting groups include benzyl and the like.
- Other suitable protecting groups are well known to those of ordinary skill in the art.
- the intermediate B-1 can be converted into the amine salt of B-1, and then react with the intermediate B-2, B-3, B-5 or B-6, and the amine salt can be the present
- the amine salt obtained by the reaction of the pharmaceutically acceptable inorganic acid or organic acid in the invention with -NH in the intermediate B- 1 including but not limited to: ammonium hydrochloride, ammonium sulfate, ammonium nitrate, ammonium phosphate Salt.
- intermediate B reacts with intermediate B-4 in the presence of a palladium catalyst to obtain a quinazoline derivative represented by formula I, preferably 4,5-bis(diphenylphosphorus)-9 can be added , 9-dimethylxanthene (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) increases the reactivity.
- the reaction requires protection of an inert gas, and the inert gas includes but is not limited to: nitrogen, helium, neon, and argon.
- Each step of the reaction of the present invention is preferably carried out in an inert solvent, including but not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylmethylene Sulfone, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof thing.
- an inert solvent including but not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylmethylene Sulfone, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide,
- the synthetic route is as follows:
- the first step Synthesis of 1-(3-(pentafluorosulfanyl)phenyl)ethan-1-one (A1-2)
- the starting material (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylene)propane-2-sulfinamide (1.5 g, 4.3 mmol ) was added to methanol (30 mL), cooled to 0°C, NaBH 4 (744 mg, 20.1 mmol) was added to methanol in batches, warmed to room temperature, and stirred for 3 h.
- reaction solution was concentrated and purified by thin-layer preparative plate to obtain (S)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propane-2-idene Sulfamide (A1-4) (600 mg, 40.0% yield).
- the synthetic route is as follows:
- the first step the synthesis of 3-bromo-2-fluorobenzene-1-diazonium tetrafluoroborate (A2-2)
- 3-Bromo-2-fluoroaniline (10.3 g, 54.2 mmol) was added to 50% aqueous tetrafluoroboric acid solution (21 mL) at room temperature, cooled to 0°C, and stirred for 1 h.
- the second step the synthesis of (3-bromo-2-fluorophenyl) (trifluoromethyl) sulfide (A2-3)
- the third step synthesis of 1-bromo-2-fluoro-3-((trifluoromethyl)sulfonyl)benzene (A2-4)
- the fourth step synthesis of 1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethane-1-one (A2-5)
- the starting material (S,E)-N-(1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide was prepared at room temperature (1.5 g, 4.0 mmol) was added to methanol (30 mL), cooled to 0°C, NaBH 4 (744 mg, 20.1 mmol) was added to methanol in portions, warmed to room temperature, and stirred for 3 h.
- reaction solution was concentrated and purified by thin-layer preparative plate to obtain a white solid (S)-N-((R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)- 2-Methylpropane-2-sulfinamide (A2-7) (600 mg, 40.0% yield).
- the seventh step synthesis of (R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethane-1-amine hydrochloride (A2)
- the synthetic route is as follows:
- the first step the synthesis of 2-amino-4-bromo-5-iodobenzoic acid (A3-2)
- the second step the synthesis of 7-bromo-6-iodo-2-methylquinazolin-4(3H)-one (A3)
- the synthetic route is as follows:
- the first step the synthesis of methyl 2-amino-4-methoxybenzoate (B1-2)
- the second step the synthesis of methyl 2-amino-5-iodo-4-methoxybenzoate (B1-3)
- the third step the synthesis of 6-iodo-7-methoxy-2-methylquinazolin-4(3H)-one (B1-4)
- reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (3 mL), triethylamine (1.9 mmol, 0.26 mL) and (R)-1-(2-methyl-3-(trifluoromethyl)benzene) yl)ethane-1-amine hydrochloride (305 mg, 1.27 mmol), and then the reaction solution was reacted at 80° C. overnight.
- the reaction solution was cooled to room temperature, water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
- the crude product was separated and purified by column chromatography to obtain compound B1-5 (458 mg, yield 72%).
- the synthetic route is as follows:
- reaction solution was concentrated under reduced pressure to obtain the crude product, and triethylamine (0.46 mL, 3.33 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane were added to the DMSO solution of the crude product -1-amine hydrochloride (250 mg, 1.11 mmol), then reacted at 80°C overnight.
- the reaction solution was cooled to room temperature. Water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
- the crude product was separated and purified by column chromatography to obtain compound B3-1 (395 mg, yield 73%).
- the synthetic route is as follows:
- the synthetic route is as follows:
- the first step the synthesis of 2-amino-4-fluoro-5-iodobenzoic acid methyl ester (B5-2)
- the second step the synthesis of 7-fluoro-6-iodo-2-methylquinazolin-4(3H)-one
- reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (4 mL), triethylamine (0.41 mL, 2.94 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)benzene) yl)ethane-1-amine hydrochloride (240 mg, 0.99 mmol), and then the reaction solution was reacted at 80° C. overnight.
- the reaction solution was cooled to room temperature. Water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
- the crude product was separated and purified by column chromatography to obtain compound B5-4 (330 mg, yield 68%).
- Step 4 (R)-(7-Fluoro-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline- Synthesis of 6-yl)dimethylphosphine oxide (I-5)
- the synthetic route is as follows:
- the synthetic route is as follows:
- Step 2 (R)-(4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazoline Synthesis of -6-yl)dimethylphosphine oxide (I-7)
- the synthetic route is as follows:
- the first step the synthesis of methyl 2-chloro-4-hydroxy-5-iodobenzoate (B8-2)
- B8-1 (5.0g, 26.8mmol) was added to a three-necked flask, dissolved in ammonia water (100mL), cooled to 0°C, and iodine (4.45g, 26.8mmol) and potassium iodide (20.4g, 80.4mmol) were slowly added dropwise mixed aqueous solution (100 mL).
- the third step synthesis of methyl 2-chloro-5-(dimethylphosphoryl)-4-((tetrahydrofuran-3-yl)oxy)benzoate (B8-4)
- the fourth step the synthesis of 6-(dimethylphosphoryl)-2-methyl-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4(3H)-one (B8-5)
- the fifth step dimethyl(2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(( Synthesis of Tetrahydrofuran-3-yl)oxy)quinazolin-6-ylphosphine oxide (I-8)
- the reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (4 mL), triethylamine (0.41 mL, 2.94 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)benzene) yl)ethane-1-amine hydrochloride (240 mg, 0.99 mmol), and then the reaction solution was reacted at 80° C. overnight.
- the reaction solution was cooled to room temperature. Water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
- the crude product was separated and purified by column chromatography to obtain the target compound I-8 (4.1 mg, yield 1.3%).
- the synthetic route is as follows:
- the first step the synthesis of 2-chloro-5-iodo-4-(3-methoxyethoxy) benzoic acid methyl ester (B9-2)
- B9-1 (1.0g, 2.6mmol), triphenylphosphine (0.82g, 3.1mmol), ethylene glycol monomethyl ether (0.23g, 3.1mmol) and tetrahydrofuran (20mL) were added, under nitrogen protection, The temperature was lowered to 0°C and DIAD (0.63 g, 3.1 mmol) was slowly added dropwise, the temperature was maintained for 1 hour, and the temperature was raised to room temperature to react overnight. Concentration and column chromatography gave the product B9-2 (0.7 g, yield 57.2%).
- the third step Synthesis of 6-(dimethylphosphoryl)-7-(3-methoxyethoxy)-2-methylquinazolin-4(3H)-one (B9-4)
- the fourth step (R)-(7-(3-methoxyethoxy)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl) Ethyl)amino)quinazolin-6-yl)dimethylphosphine oxide (I-9)
- the reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (4 mL), triethylamine (0.41 mL, 2.94 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)benzene) yl)ethane-1-amine hydrochloride (240 mg, 0.99 mmol), and then the reaction solution was reacted at 80° C. overnight.
- the reaction solution was cooled to room temperature. Water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
- the crude product was separated and purified by column chromatography to obtain the target compound I-9 (8.2 mg, yield 2.6%).
- the synthetic route is as follows:
- the synthetic route is as follows:
- the first step the synthesis of 5-amino-2-bromoisonicotinic acid methyl ester (B11-2)
- compound B11-1 (1.6 g, 8.57 mmol) was dissolved in a hydrobromic acetic acid solution (20 mL) solution, returned to room temperature and stirred for 10 minutes. The reaction solution was reacted at 80°C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, poured into an ice-water mixture, adjusted to pH 8 with saturated sodium hydroxide solution, filtered and dried to obtain B11-2 (1.4 g, yield 71%).
- reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (4 mL), triethylamine (0.53 mL, 3.75 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)benzene) yl)ethane-1-amine hydrochloride (300 mg, 1.25 mmol), the reaction solution was reacted at 80 °C overnight.
- the reaction solution was cooled to room temperature, water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
- the target compound (R)-(7-amino-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) was obtained ) amino)quinazolin-6-yl)dimethylphosphine oxide (I-12).
- the compound I-12 is reacted with CuI and isoamyl nitrite to obtain intermediate B13-1, which is then reacted with CuCN to obtain the target compound (R)-6-(dimethylphosphoryl)-2-methyl-4-( (1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-7-carbonitrile (1-13).
- Compound I-13 is oxidized with hydrogen peroxide to obtain the target compound (R)-6-(dimethylphosphoryl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)) Phenyl)ethyl)amino)quinazoline-7-carboxamide (I-15).
- the synthetic route is as follows:
- Step 2 (R)-(7-(ethylamino)-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino ) quinazolin-6-yl) dimethyl phosphine oxide (I-16)
- the synthetic route is as follows:
- the second step (R)-(7-((2-methoxyethyl)amino)-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)) Phenyl)ethyl)amino)quinazolin-6-yl)dimethylphosphine oxide (I-17)
- the target compound (R)-1-(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) was obtained Amino)-7-(methylamino)quinazolin-6-yl)phosphane 1-oxide (I-18).
- the synthesis of compound I-19 refers to the synthesis method of compound I-16, and ethylamine is replaced with 1-amino-2-methyl-2-propanol to obtain the target compound (R)-(7-((2-hydroxy- 2-Methylpropyl)amino)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl ) dimethylphosphine oxide (I-19).
- the synthetic route is as follows:
- Step 2 (R)-(7-Bromo-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline- 6-yl)Dimethylphosphine oxide (B24-2)
- Step 2 (R)-(6-(dimethylphosphono)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) Amino) quinazolin-7-yl) tert-butyl carbamate (I-24)
- the reaction solution was stirred and reacted at 90°C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography to obtain the target compound I-24 (53.2 mg, yield 24.8%).
- the synthetic route is as follows:
- the first step (R)-(7-amino-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline- 6-yl)Dimethylphosphine oxide (B25-1)
- the crude product of the previous step was dissolved in tetrahydrofuran (10 mL), then cooled to 0 °C, triethylamine (104 mg, 1.0 mmol) and O-phenyl thiocarbonyl chloride (71.2 mg, 0.4 mmol) were added, and then the temperature was raised to room temperature The reaction was carried out for 3 hours. The reaction solution was directly used in the next step.
- the third step (R)-(7-((4,4-dimethyl-4,5-dihydrooxazol-2-yl)amino)-2-methyl-4-((1-(2 -Methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)dimethylphosphine oxide (I-25)
- the synthetic route is as follows:
- the synthetic method refers to compound I-32, and cyclobutylamine hydrochloride is replaced by 3-methylazetidine-3-ol hydrochloride.
- the synthetic route is as follows:
- reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (4 mL), triethylamine (303 mg, 3.0 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl) Ethan-1-amine hydrochloride (190 mg, 1.0 mmol), and then the reaction solution was reacted at 80° C. overnight.
- the reaction solution was cooled to room temperature. Water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
- Step 2 (R)-(7-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline-- 6-yl)Dimethylphosphine oxide (B27-2)
- the reaction solution was stirred and reacted at 120°C for 24 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography to obtain the target compound B27-2 (1.1 g, yield 50.0%).
- the third step (R)-(4-((1-(3-(difluoromethyl(-2-fluorophenyl)ethyl)amino)-2-methyl-7-((2,2, 2-Trifluoroethyl)amino)quinazolin-6-yl)dimethylphosphine oxide (I-27)
- the synthetic route is as follows:
- the synthetic route is as follows:
- the compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid methyl ester (2.0 g, 5.3 mmol) was dissolved in DMF (30 mL), and dimethylphosphine oxide (620 mg, 8.0 mmol) was added under nitrogen protection ), tris(dibenzylideneacetone)dipalladium (346mg, 0.38mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (438mg, 0.76mmol) and triethyl Amine (1.4 g, 14.2 mmol).
- the reaction solution was stirred at 90°C for 24 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product.
- the crude product was separated and purified by preparative chromatography to obtain the target compound (B29-3) (1.5 g, yield 86.5%).
- the compound 2-amino-4-bromo-5-(dimethylphosphoryl)-3-fluorobenzoic acid methyl ester (1.5 g, 4.6 mmol) was added to acetonitrile (20 mL), methanesulfonic acid (10 mL) was added, and heated to reflux state, react overnight, and cool to room temperature after completion of the reaction.
- the reaction solution was concentrated to dryness, the pH of the aqueous sodium hydroxide solution was adjusted to 6, the solid was collected by filtration, and dried to obtain the target compound (B29-4) (1.0 g, yield 64.9%).
- reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (10 mL), triethylamine (0.9 g, 9.0 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)benzene) yl)ethane-1-amine hydrochloride (0.7 g, 3.0 mmol), and then the reaction solution was reacted at 80° C. overnight.
- the reaction solution was cooled to room temperature. Water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
- the reaction solution was stirred and reacted at 90°C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography to obtain the target compound I-29 (59.0 mg, yield 30.6%).
- the synthetic route is as follows:
- the synthetic route is as follows:
- Step 2 (R)-6-Bromo-N7-ethyl-N4-(1-(2-fluoro - 3 -((trifluoromethyl)sulfonyl)phenyl)ethyl)-2- Synthesis of methylquinazoline-4,7-diamine (B31-2)
- the synthetic route is as follows:
- the synthetic route is as follows:
- the first step the synthesis of 6-bromo-7-(isopropylamino)-2-methylquinazolin-4(3H)-one (B33-2)
- reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (20 mL), triethylamine (4.1 mL, 29.7 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl) ) ethyl-1-amine hydrochloride (1.5 g, 6.8 mmol), and then the reaction solution was reacted at 80° C. overnight. The reaction solution was cooled to room temperature. Water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
- DMSO 20 mL
- triethylamine 4.1 mL, 29.7 mmol
- (R)-1-(3-(difluoromethyl)-2-fluorophenyl) ) ethyl-1-amine hydrochloride 1.5 g, 6.8 mmol
- the third step (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(isopropylamino)-2-methyl Quinazolin-6-yl)dimethylphosphine oxide (I-33)
- the reaction solution was stirred and reacted at 120°C for 24 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography to obtain the target compound I-33 (500 mg, yield 50.3%).
- the synthetic route is as follows:
- the synthetic method refers to compound I-30, and replaces (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with (R)-1-(3- (Trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride.
- the synthetic route is as follows:
- the first step the synthesis of 7-bromo-6-iodoquinazolin-4(3H)-one (B35-1)
- the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain a crude product.
- the crude product was prepared by reverse phase (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 33%-63%, 9min) to obtain a white solid compound (R) -(7-(Ethylamino)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)dimethylphosphine Oxidation (I-35) (8.20 mg, 21.5% yield).
- the synthetic route is as follows:
- the synthetic method refers to the third step of compound I-27, and replaces tert-butyl carbamate with 4,4,4-trifluorobutan-2-amine hydrochloride.
- the synthetic route is as follows:
- the synthetic route is as follows:
- reaction solution was concentrated under reduced pressure to obtain a crude product, to which were added DMSO (4 mL), triethylamine (303 mg, 3.0 mmol) and (R)-1-(3-(pentafluoro- ⁇ 6 -sulfanyl)phenyl) ) ethyl-1-amine hydrochloride (284 mg, 1.0 mmol), and then the reaction solution was reacted at 80° C. overnight. The reaction solution was cooled to room temperature. Water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
- Step 2 (R)-(7-Bromo-2-methyl-4-((1-(3-(pentafluoro- ⁇ 6 -sulfanyl)phenyl)ethyl)amino)quinazoline- 6-yl)Dimethylphosphine oxide (B38-2)
- the compound (R)-7-bromo-6-iodo-2-methyl-N-(1-(3-(pentafluoro- ⁇ 6 - sulfanyl)phenyl)ethyl)quinazoline-4- The amine (200 mg, 0.34 mmol) was dissolved in DMF (3 mL), and dimethylphosphine oxide (39.4 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (25 mg, 0.03 mmol), 4 was added under nitrogen protection. , 5-bis(diphenylphosphonium)-9,9-dimethylxanthene (43 mg, 0.08 mmol) and triethylamine (140 mg, 1.4 mmol). The reaction solution was stirred at 90°C for 24 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography to obtain the target compound B38-2 (100 mg, yield 54.6%).
- the reaction solution was stirred and reacted at 90°C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography to obtain the target compound I-38 (16 mg, yield 17.13%).
- the synthetic route is as follows:
- Step 2 (R)-Diethyl(7-(ethylamino)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) ) Amino) quinazolin-6-yl) phosphine oxide (I-39) synthesis
- the synthetic route is as follows:
- the third step the synthesis of 2-amino-4-bromo-3-chlorobenzoic acid (B40-4)
- the fourth step the synthesis of 2-amino-4-bromo-3-chloro-5-iodobenzoic acid (B40-5)
- the fifth step the synthesis of 7-bromo-8-chloro-6-iodo-2-methylquinazolin-4(3H)-one (B40-6)
- the sixth step the synthesis of 7-bromo-8-chloro-6-iodo-2-methylquinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (B40-7)
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic method of I-44 refers to I-27, and the third step replaces tert-butyl nitrocarbonate with cyclopropanecarboxamide.
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic method of I-47 refers to the third step of I-27, and replaces tert-butyl carbamate with 3,3-difluorocyclobutane-1-amine hydrochloride.
- the synthetic route is as follows:
- the synthetic method of I-48 refers to the third step of I-27, replacing tert-butyl carbamate with cyclopentylamine.
- the synthetic route is as follows:
- the synthetic method of 1-49 refers to 1-24, replacing tert-butyl carbamate with 1-methyl-1H-pyrazol-5-amine.
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic method of I-52 refers to the third step of I-27, replacing tert-butyl carbamate with cyclohexylamine.
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic method refers to the third step of I-27, replacing tert-butyl carbamate with cyclobutylamine.
- the synthetic route is as follows:
- the synthetic method refers to the third step of I-27, and replaces tert-butyl carbamate with (1r,3r)-3-fluorocyclobutane-1-amine.
- the synthetic route is as follows:
- the synthetic method refers to the third step of I-27, and replaces tert-butyl carbamate with (1s,3s)-3-fluorocyclobutane-1-amine.
- the synthetic route is as follows:
- the synthetic method refers to the third step of I-27, replacing tert-butyl carbamate with butyl-2-amine.
- the synthetic route is as follows:
- the third step (R)-(4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-7-(isopropylamino)-2-methyl quinazolin-6-yl)dimethylphosphine oxide (I-59)
- the synthetic route is as follows:
- the first step (R)-6-bromo-N7-(3,3-difluorocyclobutyl)-2-methyl-N4-(1-(2-methyl-3-(trifluoromethyl) Phenyl)ethyl)quinazoline-4,7-diamine
- the synthetic route is as follows:
- the synthetic method refers to the third step of I-27, replacing tert-butyl carbamate with 1-methoxypropan-2-amine.
- the synthetic route is as follows:
- the third step (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(isopropylamino)-2-methyl Quinazolin-6-yl)dimethylphosphine oxide (I-62)
- the synthetic route is as follows:
- the synthetic route is as follows:
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Abstract
一种式(I)所示的6-取代磷酰基喹唑啉类衍生物及其制备方法和用途。该6-取代磷酰基喹唑啉类衍生物具有较好的SOS1抑制作用。
Description
本申请要求申请日为2021/1/7的中国专利申请2021100192374的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种6-取代磷酰基喹唑啉类衍生物及其制备方法和用途。
RAS蛋白是一种具有固有GTP酶活性的膜结合蛋白,可被许多细胞外刺激激活,在GDP结合(关)的状态与GTP结合(开)的状态间循环。当其处于GTP结合(开)状态时能激活下游通路,促进细胞增殖、分化、迁移、免疫等一系列过程。
RAS蛋白家族包括三种高度同源的异构体:KRAS(Kirsten rat sarcoma virus oncogene)、HRAS(Harvey rat sarcoma virus oncogene)和NRAS(Neuroblastoma ras oncogene),KRAS包含2种可变剪接变异体:KRAS4A和KRAS4B。RAS家族蛋白具有较弱的内源性GTPase活性和较慢的核苷酸交换率(Hunter et al.Mol.Cancer Res.2015,13(9):1325-1335)。
RAS基因突变激活是肿瘤发生的重要原因,在所有肿瘤患者中有27%患者发生RAS突变(Hobbs GA,et al.J Cell Sci.2016,129(7):1287-1292)。其中KRAS突变频率最高,占比为86%(Cox,Adrienne D.et al.Nat Rev Drug Discov.2014,13(11):828-851)。大约90%的胰腺癌、30%-40%的结肠癌和15%-20%的肺癌中都存在KRAS-4B突变,该突变也存在于胆道恶性肿瘤、子宫内膜癌、宫颈癌、膀胱癌、肝癌、骨髓性白血病和乳腺癌中(Liu P,et al.Acta Pharm Sin B.2019,9(5):871-879)。KRAS基因突变的最常见方式是点突变,常见的有KRAS-G12D(41%)、KRAS-G12V(28%)和KRAS-G12C(14%)突变。突变的KRAS会影响其与GTP酶活化蛋白(GTPase activating protein,GAP)的结合能力,从而抑制GAP诱导的GTP水解。随着GTP酶水解能力下降,GTP逐渐积累,KRAS更易与GTP结合,进而使KRAS大多处于激活状态,诱发恶性肿瘤的发生与发展。
RAS蛋白从失活态到活化态的转变,涉及GDP的释放和GTP的结合,GDP的释放需要鸟苷酸交换因子(GMP exchange factor,GEF)的参与,如SOS(Son of Sevenless)蛋白。SOS蛋白于1992年在果蝇中首次发现,是RAS和Rac蛋白的GEF,在RAS和Rac信号通路中发挥重要作用。人类有两种SOS同源体——SOS1和SOS2,两者在结构和序列上高度相似,有70%的同源性,但在生物功能上存在一定的差异。SOS1蛋白由1300个 氨基酸残基组成,C端含有一个富含脯氨酸的结构域,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)相互作用,Grb2与SOS1相结合形成复合物后可将SOS1带至细胞膜RAS蛋白附近。SOS1与RAS的相互作用涉及SOS1的两个结构域:CDC25结构域和REM结构域。CDC25结构域具有核苷酸交换的活性位点,REM结构域包含一个能结合RAS-GTP并导致CDC25结构域变构激活的位点(Pierre S,et al.Biochem Pharmacol.2011,82(9):1049-1056)。SOS1可通过催化交换将GDP转化为GTP,GTP通过RAS发生水解,然后激活下游信号,引起相应的一系列生物学效应。
特异性SOSl抑制剂可抑制SOS1与KRAS-GDP的相互作用,从而减少活化状态的KRAS-GTP的形成。KRAS-GTP水平的减少会导致下游MAPK信号的减少,在野生型和多种KRAS突变类型中均起作用。SOS1小分子抑制剂BAY-293能有效降低肿瘤细胞中的突变的KRAS和野生型KRAS活性(Hillig,Roman C.et al.Proc Nat Acad Sci USA.2019,116(7):2551-2560)。勃林格殷格翰开发的SOS1抑制剂BI-3406和BI-1701963,能够与SOS1的催化结构域结合,阻止其与KRAS的相互作用,减少KRAS-GTP的形成,抑制KRAS驱动的多种癌症细胞增殖。SOS1抑制剂与MEK抑制剂联用,能够显著降低KRAS信号传导,并通过互补作用机制提高抗肿瘤活性(Hofmann,Marco H,et al.Cancer Discov.2020:CD-20-0142)。据勃林格殷格翰公司披露(AACR Annual Meeting,April 27
th2020)BI-3406以时间依赖性的抑制细胞色素P450 3A4(CYP3A4),存在潜在的药物药物相互作用(DDI)风险,因此开发无细胞色素P450抑制,优势是无CYP3A4抑制的SOS1抑制剂更有临床价值,BI-1701963及与MEK抑制剂曲美替尼联合疗法均已进入临床研究。
除癌症以外,SOS1基因突变和表达异常也与一些遗传性疾病的发生密切相关。努南综合征(Noonan syndrome,NS)是一种常染色体显性遗传病,在约20%的NS患者中SOS1出现突变,这些突变分布在SOS1的6个结构域。SOS1突变的患者表现出卷发和外胚层异常的表型特征。CDC25结构域中的突变可直接增加SOS1的GEF活性,诱导RAS/ERK通路的超活化(JoséM Rojas,et al.Genes Cancer.2011,2(3):298-305)。心面皮肤综合征是肾素-血管紧张素系统心肌病群的一种,有研究报道在该病中存在SOS1的突变(Narumi,Yoko,et al.J Hum Genet.2008,53(9):834-841.)。1型遗传性齿龈纤维瘤病是一种常染色体显性遗传病,其病因与SOS1的富含脯氨酸的结构域突变有关(Jang SI,et al.J Biol Chem.2007,282(28):20245-20255)。
发明内容
本发明的目的是提供一种6-取代磷酰基喹唑啉类衍生物,用作SOS1催化位点与RAS家族蛋白的相互作用的抑制剂,参与调控细胞增殖,可以用于过度或者异常细胞增殖的疾病的治疗。
本发明的第一方面,提供了式I所示6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
其中,
Z为碳原子或氮原子;且当Z为氮原子时,R
2不存在;
R
11、R
12各自独立地为C
1-C
6烷基或C
1-C
6烷氧基;所述C
1-C
6烷基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
13取代,所述R
13为选自下列的取代基:羟基、氨基、硝基、卤素、氰基;当取代基为多个时,所述的取代基相同或不同;
R
a分别独立地为氢或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、3-8元环烷基;所述C
1-C
6烷基、或所述3-8元环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
m为1、2、3或4;
R
21、R
22、R
23、R
24各自独立地为氢或选自下列的取代基:C
1-C
6烷基、3-8元环烷基、4-8元杂环烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
L为不存在或选自下列的基团:C
1-C
6烷基、氘代C
1-C
6烷基、3-8元环烷基、4-8元杂环烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基、-COOC
1-C
6烷基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、或所述-COOC
1-C
6烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
环A为不存在或选自3-15元环烷基或4-15元杂环烷基、5-15元芳环基或5-15元杂芳环基;
R
b分别独立地为氢或选自下列的基团:羟基、氨基、硝基、卤素、氰基、
C
1-C
6烷基、C
1-C
6烷氧基、C
2-C
6酰胺基、C
1-C
6酯基、C
1-C
6羰基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、所述C
2-C
6酰胺基、所述C
1-C
6酯基、或所述C
1-C
6羰基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;n为1、2、3或4;当R
b为多个时,R
b为相同或不同的取代基;
R
3为氢或选自下列的取代基:卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基、3-8元环烷基、4-8元杂环烷基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、所述3-8元环烷基、或4-8元杂环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
R
4为氢或选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6烷氧基、3-8元环烷基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、所述3-8元环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
R
5为氢或选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
R
6为5-8元环烷基、或5-8元芳环基、或5-10元杂芳环基;所述5-8元环烷基、或 所述5-8元芳环基、或5-10元杂芳环基任选地被一个或多个,相同或不同的选自下列的取代基取代:羟基、氨基、硝基、卤素、氰基、-SF
5、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、3-8元环烷基、4-10元杂环烷基、-SO
2-C
1-C
6烷基;所述羟基、氨基任选地被C
1-C
6烷基、3-8元环烷基或4-10元杂环烷基取代;其中,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、3-8元环烷基、4-10元杂环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
所述R
f为选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6烷氧基、C
1-C
6卤代烷氧基、3-8元环烷基、3-8元卤代环烷基、4-10元杂环烷基、C
1-C
6酰基、C
1-C
6羰基、C
1-C
6砜基、C
1-C
6卤代砜基;
所述杂环烷基或杂芳环基中,杂原子选自N、O、S和P中的一种或多种,杂原子数为1-3个。
在一优选实施方式中,所述4-8元杂环中,杂原子选自N、O、S和P中的一种或多种,杂原子数为1-3个。
在一优选实施方式中,R
2为C
1-C
6酰胺基,所述C
1-C
6酰胺基被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;R
f的定义如本发明第一方面所述。
在一优选实施方式中,提供了式I所示6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
其中,Z为碳原子或氮原子;且当Z为氮原子时,R
2不存在;
R
1为
R
11、R
12各自独立地为C
1-C
6烷基或C
1-C
6烷氧基;所述C
1-C
6烷基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
13取代,所述R
13为选自下列的取代基:羟基、氨基、硝基、卤素、氰基;当取代基为多个时,所述的取代基相同或不同;或者,R
11、R
12与它们连接的磷原子一起形成取代基
其中,环B为4-8元碳环、 4-8元烯环或4-8元杂环;R
a分别独立地为氢或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、3-8元环烷基;所述C
1-C
6烷基、或所述3-8元环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;m为1、2、3或4;
R
21、R
22、R
23、R
24各自独立地为氢或选自下列的取代基:C
1-C
6烷基、3-8元环烷基、4-8元杂环烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
L为不存在或选自下列的基团:C
1-C
6烷基、3-8元环烷基、4-8元杂环烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
环A为不存在或选自3-15元环烷基或4-15元杂环烷基、5-15元芳环基或5-15元杂芳环基;
R
b分别独立地为氢或选自下列的基团:羟基、氨基、硝基、卤素、氰基、
C
1-C
6烷基、C
1-C
6烷氧基、C
2-C
6酰胺基、C
1-C
6酯基、C
1-C
6羰基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、所述C
2-C
6酰胺基、所述C
1-C
6酯基、或所述C
1-C
6羰基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;n为1、2、3或4;当R
b为多个时,R
b为相同或不同的取代基;
R
3为氢或选自下列的取代基:卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基、3-8元环烷 基、4-8元杂环烷基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、所述3-8元环烷基、或4-8元杂环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
R
4为氢或选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6烷氧基、3-8元环烷基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、所述3-8元环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
R
5为氢或选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
R
6为5-8元环烷基、或5-8元芳环基、或5-10元杂芳环基;所述5-8元环烷基、或所述5-8元芳环基、或5-10元杂芳环基任选地被一个或多个,相同或不同的选自下列的取代基取代:羟基、氨基、硝基、卤素、氰基、-SF
5、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、3-8元环烷基、4-10元杂环烷基、-SO
2-C
1-C
6烷基;所述羟基、氨基任选地被C
1-C
6烷基、3-8元环烷基或4-10元杂环烷基取代;其中,所述C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、3-8元环烷基、4-10元杂环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
所述R
f为选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6烷氧基、C
1-C
6卤代烷氧基、3-8元环烷基、3-8元卤代环烷基、4-10元杂环烷基、C
1-C
6酰基、C
1-C
6羰基、C
1-C
6砜基、C
1-C
6卤代砜基;
所述杂环烷基或杂芳环基中,杂原子选自N、O、S和P中的一种或多种,杂原子数为1-3个。
在一优选实施方式中,所述式I所示6-取代磷酰基喹唑啉类衍生物不为:
(1)L为不存在或选自下列的基团:C
1-C
6烷基、氘代C
1-C
6烷基、3-8元环烷基、4-8元杂环烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
(2)L为不存在或选自下列的基团:C
1-C
6烷基、3-8元环烷基、4-8元杂环烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基、-COOC
1-C
6烷基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、或所述-COOC
1-C
6烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
(3)L为不存在或选自下列的基团:C
1-C
6烷基、氘代C
1-C
6烷基、3-8元环烷基、4-8元杂环烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基、-COOC
1-C
6烷基;所述C
1-C
6烷基、所述C
1-C
6烷氧基、或所述-COOC
1-C
6烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同。
当R
1为
时,R
a1为C
1-C
6烷基、3-8元环烷基,所述C
1-C
6烷基、或所述3-8元环烷基分别独立地被一个或多个R
f取代,当取代基为多个时,所述R
f相同或不同,所述的R
a1不为C
1-C
3烷基、
其中,m的定义如本发明第一方面中所述。
在本发明一优选实施方案中,当Z为碳原子,R
1为
时,R
11、R
12各自独立地 为C
1-C
6烷基或C
1-C
6烷氧基,所述C
1-C
6烷基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
13取代,所述R
13为选自下列的取代基:羟基、氨基、硝基、卤素、氰基;当取代基为多个时,所述的取代基相同或不同;R
2为氢或选自下列的取代基:羟基、氨基、硝基、氰基、
其中,Y为不存在或选自下列的基团:
当Z为氮原子,R
1为
时,R
6为5-8元环烷基、或5-8元芳环基、或5-10元杂芳环基,所述5-8元环烷基、或所述5-8元芳环基、或5-10元杂芳环基任选地被两个,相同或不同的取代基取代,所述取代基的定义如本发明的第一方面所述;
在本发明一优选实施方案中,R
6中5-8元芳环基为苯基。
R
a分别独立地为氢或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、3-8元环烷基;所述C
1-C
6烷基、或所述3-8元环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
R
a1为C
1-C
6烷基、3-8元环烷基;所述C
1-C
6烷基、或所述3-8元环烷基分别独立地被一个或多个R
f取代;当取代基为多个时,所述R
f相同或不同;
所述R
f为选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6烷氧基、C
1-C
6卤代烷氧基、3-8元环烷基、3-8元卤代环烷基、4-10元杂环烷基、C
1-C
6酰基、C
1-C
6羰基、C
1-C
6砜基、C
1-C
6卤代砜基;
m为1、2、3或4,较佳地为1、2或3。
在本发明一优选实施方案中,基团
中,Y为不存在或选自下列的基团:
L为不存在或C
1-C
6烷基、C
2-C
6炔基、C
1-C
6烷氧基;M为不存在或羟基、氰基、卤素、C
1-C
6烷氧基;环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;R
b为氢或C
1-C
6烷基;当R
b为多个时,R
b为相同或不同的取代基;较佳地,环A为4-10元杂环烷基或5-10元杂芳环基。
其中,Y、L、M、R
b、n、环A的定义如本发明第一方面中所述。
较佳地,环D、环E各自独立地选自:3-10元环烷基或4-10元杂环烷基、5-8元芳环基或5-8元杂芳环基;
n为1、2、3或4,较佳地为1、2或3;
R
b分别独立地为氢或选自下列的基团:卤素、
C
1-C
6烷基、C
2-C
6酰胺基、C
2-C
6酯基、C
2-C
6羰基;所述C
1-C
6烷基、所述C
2-C
6酰胺基、所述C
2-C
6酯基、或所述C
2-C
6羰基分别独立地被一个或多个R
g取代;当取代基为多个时,所述R
g相同或不同;
其中所述R
g为选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6卤代烷基;
当R
b为多个时,R
b为相同或不同的取代基。
在本发明一优选实施方案中,R
3为氢或选自下列的取代基:卤素、氰基、C
1-C
4烷基、C
1-C
4卤代烷基。
在本发明一优选实施方案中,R
4为氢或选自下列的取代基:卤素、C
1-C
4烷基、C
1-C
4卤代烷基、3-6元环烷基;较佳地,R
4为C
1-C
4烷基;较佳地,R
4为甲基。
在本发明一优选实施方案中,R
5为氢或选自下列的取代基:卤素、C
1-C
4烷基、C
1-C
4卤代烷基。
在本发明一优选实施方式中,R
2任选地被1个、2个或3个R
f取代;当取代基R
f为多个时,所述取代基R
f相同或不同;较佳地,R
f为卤素、C
1-C
3烷基、C
1-C
3卤代烷基。
在本发明一优选实施方案中,式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其具有结构Ia
或结构Ib
或结构Ic
或结构Id
在所述结构Ia、Ib、Ic或Id中,
R
1、R
2、R
3、R
4、R
5的定义如本发明第一方面中所述;
R
61、R
62、R
63、R
64、R
65各自独立地为氢或选自下列取代基:羟基、氨基、硝基、卤素、氰基、SF
5、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6烷氧基、3-8元环烷基、4-10元杂环烷基、3-8元卤代环烷基、C
1-C
6酰胺基、C
1-C
4酯基、C
1-C
6砜基、C
1-C
6卤代砜基;
较佳地,R
61、R
62、R
63、R
64、R
65各自独立地为氢或选自下列取代基:羟基、氨基、硝基、卤素、氰基、SF
5、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6砜基、C
1-C
6卤代砜基。
在本发明一优选实施方案中,在所述结构Ia、Ib、Ic或Id中,R
63、R
64、R
65为氢,R
61、R
62各自独立地为氢或选自下列取代基:羟基、氨基、硝基、卤素、氰基、SF
5、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6烷氧基、3-8元环烷基、4-10元杂环烷基、3-8元卤代环烷基、C
1-C
6酰胺基、C
1-C
4酯基、C
1-C
6砜基、C
1-C
6卤代砜基;
较佳地,R
63、R
64、R
65为氢,R
61、R
62各自独立地为氢或选自下列取代基:羟基、氨基、硝基、卤素、氰基、SF
5、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6砜基、C
1-C
6卤代砜基;
更佳地,R
63、R
64、R
65为氢,R
61、R
62各自独立地为氢或选自下列取代基:卤素、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6砜基、C
1-C
6卤代砜基。
在本发明一优选实施方案中,在所述结构Ia、Ib、Ic或Id中,R
63、R
64、R
65为氢,R
61为氢、C
1-C
6烷基或卤素,R
62为C
1-C
6卤代烷基;较佳地,R
63、R
64、R
65为氢,R
61为氢、甲基或氟,R
62为三氟甲基、二氟甲基。
R
21、R
22、R
23各自独立地为氢或C
1-C
6烷基;所述C
1-C
6烷基被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;
L为不存在或选自下列的基团:C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;
M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当 取代基为多个时,所述R
e相同或不同;
环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;
R
b分别独立地为氢或选自下列的基团:羟基、氨基、卤素、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;n为1、2或3;
其中所述R
e为选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6卤代烷基;
当R
b为多个时,R
b为相同或不同的取代基。
其中,R
23为氢或C
1-C
6烷基、C
1-C
6卤代烷基;较佳地,R
23为氢或C
1-C
3烷基、C
1-C
3卤代烷基;
L为不存在或选自下列的基团:C
1-C
6烷基、C
1-C
6烷氧基;较佳地L为不存在或选自下列的基团:C
1-C
3烷基、C
1-C
3烷氧基;
M为不存在或选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6烷氧基;较佳地,M为不存在或选自下列的取代基:卤素、C
1-C
3烷基、C
1-C
3烷氧基;
环A为不存在或选自3-6元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;较佳地,环A为不存在或3-6元环烷基或5-6元杂环烷基、5-6元芳环基或5-6元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;
R
b为氢、C
1-C
6烷基、C
1-C
6环烷基、C
1-C
6卤代烷基、C
1-C
6卤代环烷基、C
1-C
6烷氧基;较佳地R
b为氢、C
1-C
6烷基、C
1-C
6卤代烷基。
在本发明一优选实施方案中,在所述结构Ia、Ib、Ic或Id中,Y为不存在或选自下列的基团:
R
23为氢或C
1-C
6烷基;L为不存在或选自下列的基团:C
1-C
6烷基、C
1-C
6烷氧基;M为不存在或选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6烷氧基;
环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;较佳地,环A为不存在或5-6元环烷基或5-6元杂环烷基、5-6元芳环基或5-6 元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子选自N或O,杂原子数为1或2个;当杂原子为多个时,所述杂原子相同或不同;
R
b为氢、C
1-C
6烷基、C
1-C
6环烷基、C
1-C
6卤代烷基、C
1-C
6卤代环烷基、C
1-C
6烷氧基;较佳地R
b为氢、C
1-C
6烷基、C
1-C
6卤代烷基。
在本发明一优选实施方案中,式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其具有结构Ie
在所述结构Ie中,
其中,R
23为氢,L、M、环A、R
b、n的定义如本发明第一方面中所述。
在本发明一优选实施方案中,L为不存在或选自下列的基团:C
1-C
6烷基、氘代C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;
较佳地,L为不存在或选自下列的基团:C
1-C
6烷基、氘代C
1-C
6烷基、C
1-C
6烷氧基;更佳地L为不存在或选自下列的基团:C
1-C
3烷基、氘代C
1-C
3烷基、C
1-C
3烷氧基。
在本发明一优选实施方案中,M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;
较佳地,M为不存在或选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6烷氧基;更佳地,M为不存在或选自下列的取代基:卤素、C
1-C
3烷基、C
1-C
3烷氧基。
在本发明一优选实施方案中,环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;
较佳地,环A为不存在或选自3-6元环烷基或4-10元杂环烷基、5-10元芳环基或5- 10元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;更佳地,环A为不存在或3-6元环烷基或5-6元杂环烷基、5-6元芳环基或5-6元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N。
在本发明一优选实施方案中,R
b分别独立地为氢或选自下列的基团:羟基、氨基、卤素、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;n为1、2或3;其中所述R
e为选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6卤代烷基;当R
b为多个时,R
b为相同或不同的取代基;
较佳地,R
b为氢、卤素、C
1-C
6烷基、C
1-C
6环烷基、C
1-C
6卤代烷基、C
1-C
6卤代环烷基、C
1-C
6烷氧基;更佳地R
b为氢、C
1-C
6烷基、C
1-C
6卤代烷基。
其中,L为不存在或选自下列的基团:C
1-C
6烷基、氘代C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述C
2-C
6烯基、所述C
2-C
6炔基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;
M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基、或所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;
环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;
R
b分别独立地为氢或选自下列的基团:羟基、氨基、卤素、C
1-C
6烷基、C
1-C
6烷氧基;所述C
1-C
6烷基、所述C
1-C
6烷氧基分别独立地被一个或多个R
e取代;当取代基为多个时,所述R
e相同或不同;n为1、2或3;
其中所述R
e为选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6卤代烷基;
当R
b为多个时,R
b为相同或不同的取代基。
在本发明一优选实施方案中,在所述结构Ie中,R
2为
其中,L为不存在或选自下列的基团:C
1-C
6烷基、氘代C
1-C
6烷基、C
1-C
6烷氧基;较佳地L为不存在或选自下列的基团:C
1-C
3烷基、氘代C
1-C
3烷基、C
1-C
3烷氧基;
M为不存在或选自下列的取代基:卤素、C
1-C
6烷基、C
1-C
6烷氧基;较佳地,M为 不存在或选自下列的取代基:卤素、C
1-C
3烷基、C
1-C
3烷氧基;
环A为不存在或选自3-6元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;较佳地,环A为不存在或3-6元环烷基或5-6元杂环烷基、5-6元芳环基或5-6元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;
R
b为氢、卤素、C
1-C
6烷基、C
1-C
6环烷基、C
1-C
6卤代烷基、C
1-C
6卤代环烷基、C
1-C
6烷氧基;较佳地R
b为氢、C
1-C
6烷基、C
1-C
6卤代烷基。
在本发明一优选实施方案中,R
2为氢或选自下列的取代基:卤素、C
1-C
6烷氧基、C
1-C
6烷氧基取代的C
1-C
6烷氧基、5-6元含N或O的杂环烷基取代的C
1-C
6烷氧基、-NH-C
1-C
6烷基、-NH-C
3-C
6环烷基、-NH-卤代C
1-C
6烷基、-NH-卤代C
3-C
6环烷基、-N(C
1-C
6烷基)
2;
较佳地;R
2为氢或选自下组的取代基:氟、-NH-C
1-C
6烷基、-NH-C
3-C
6环烷基、-N(C
1-C
6烷基)
2;所述C
1-C
6烷基、C
3-C
6环烷基被1个或多个选自下列取代基取代:卤素或C
1-C
6烷氧基;当取代基为多个时,所述取代基相同或不同;
更佳地,R
2为氢或选自下组的取代基:氟、-NH-C
1-C
6烷基、-N(C
1-C
6烷基)
2、-NH-C
3-C
6环烷基;所述C
1-C
6烷基或C
3-C
6环烷基被1个或多个氟或者1个或多个C
1-C
6烷氧基取代。
在本发明一优选实施方式中,R
2任选地被1个、2个或3个R
f取代;当取代基R
f为多个时,所述取代基R
f相同或不同;较佳地,R
f为卤素、C
1-C
3烷基、C
1-C
3卤代烷基。
在本发明一优选实施方案中,所述卤素优选为氟。
在本发明一优选实施方案中,所述6-取代磷酰基喹唑啉类衍生物包括:
本发明第二方面,提供了一种如本发明第一方面所述的如式I所示的喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的制备方法,所述方法包括步骤:
i)中间体B-1与中间体B-2或B-3反应得到中间体B,
ii)中间体B与中间体B-4反应得到式I所示的6-取代磷酰基喹唑啉类衍生物,
iii)中间体B-1与中间体B-5或B-6反应得到式I所示的6-取代磷酰基喹唑啉类衍生物,
其中,X
1、X
2各自独立地选自:-OTf、-OTs、-OMs、氟、氯、溴或碘;
Z为碳原子或氮原子;且当Z为氮原子时,R
2不存在;
R
1、R
2、R
3、R
4、R
5、R
6的定义如本发明第一方面所述。
在本发明一优选实施方案中,所述方法还包括选自下组的一种或多种步骤:
iv)中间体B-1转化为B-1的胺盐后,再与中间体B-2、B-3、B-5或B-6反应;
v)所述步骤ii)在钯催化剂存在下反应,得到式I所示喹唑啉衍生物;或者,所述步骤ii)在钯催化剂和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽共同存在下反应,得到式I所示喹唑啉衍生物;
vi)所述步骤ii)在惰性气体保护条件下反应,得到式I所示喹唑啉衍生物。
本发明第三方面,提供一种如式B-5所示中间体,用于制备如本发明第一方面所述式I所示喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,所述中间体具有结构:
其中,R
1、R
2、R
3、R
4、R
5的定义如本发明第一方面所述。
另外,提供一种如式B-6所示中间体,用于制备如本发明第一方面所述式I所示喹 唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,所述中间体具有结构:
其中,X
2选自:-OTf、-OTs、-OMs、氟、氯、溴或碘;
R
1、R
2、R
3、R
4、R
5的定义如本发明第一方面所述。
本发明第四方面,提供一种药物组合物,所述的药物组合物包括:如本发明第一方面中所述的式I所示喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药;和药学上可接受的载体。另外,提供了一种药物组合物,所述药物组合物包括如本发明第一方面中所述的式I所示磷酰基喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药;和至少一种其他药理学活性抑制剂。较佳地,所述其他药理学活性抑制剂为MEK及/或其突变体的抑制剂。
本发明第五方面,提供了如本发明第一方面中所述的式I所示磷酰基喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途,或本发明第四方面所述的药物组合物的用途,所述用途包括:抑制SOS1与RAS家族蛋白;和/或,预防和/或治疗SOS1与RAS家族蛋白相关的疾病;和/或,制备用于抑制SOS1与RAS家族蛋白,和/或预防和/或治疗SOS1与RAS家族蛋白相关的疾病的药物、药物组合物或制剂;和/或,制备药物,例如制备用于预防和/或治疗癌症、RAS病的药物。
较佳地,所述用途包括:抑制SOS1与RAS家族蛋白的相互作用;和/或,制备用于抑制SOS1与RAS家族蛋白的相互作用的药物、药物组合物或制剂。
较佳地,所述SOS1与RAS家族蛋白相关的疾病包括但不限于:癌症、RAS病;所述RAS病包括努南综合征、心面皮肤综合征、1型遗传性齿龈纤维瘤病、1型神经纤维瘤病、毛细血管畸形-动静脉畸形综合征、科斯特洛综合症和莱格斯综合征;和/或,所述的癌症为胰腺癌;和/或,所述的RAS家族蛋白为KRAS,例如KRAS G12C。
在本发明第六方面,提供一种抑制SOS1与RAS家族蛋白,或预防和/或治疗SOS1与RAS家族蛋白相关的疾病的方法,包括步骤:给需要的对象施用本发明第一方面所述的式I所示喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得 明显,或通过本发明的实践了解到。
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义,以本章的定义为准。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本发明主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,CH
2O等同于OCH
2。如本文所用,
表示基团的连接位点。如本文所用,“R
1”、“R1”和“R
1”的含义相同,可相互替换。对于R
2等其它其他符号,类似定义的含义相同。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围,当该数值范围被理解为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“1~6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。
在本申请中,在单独或作为其他取代基一部分时,术语“卤素”是指氟、氯、溴、碘。
如本文所用,在单独或作为其他取代基一部分时,术语“氨基”表示-NH
2。
如本文所用,在单独或作为其他取代基一部分时,术语“硝基”表示-NO
2。
如本文所用,在单独或作为其他取代基一部分时,术语“氰基”表示-CN。
如本文所用,在单独或作为其他取代基一部分时,术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基,叔丁基,戊基,异戊基,新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。如本文所用,术语“烯基”表示无支链或支链的单价烃链,其含有一个或多个碳-碳双键。如本文所用,术语“炔基”是指无支链或支链的一价烃链,其含有一个或多个碳-碳三键。
在单独或作为其他取代基一部分时,术语“C
1-C
6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2或3个碳原子(“C
1-C
3烷基”),例如甲基、乙基、正丙基或异丙基。
在单独或作为其他取代基一部分时,术语“C
1-C
6烷氧基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基和氧原子组成,或者表示为C
1-C
6烷基-O-。C
1-C
6烷基的定义如本说明书中所述,氧原子可以连接在C
1-C
6烷基的直链或直链的任何一个碳原子上。包括但不限于:甲氧基(CH
3-O-)、乙氧基(C
2H
5-O-)、丙氧基(C
3H
7-O-)、丁氧基(C
4H
9-O-)、戊氧基(C
5H
11-O-)、己氧基(C
6H
13-O-)。
在单独或作为其他取代基一部分时,术语“碳环”、“烯环”、“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“C
m-C
n环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如,“3-15元环烷基”或者“C
3-C
15环烷基”是指含有3至15,3至9,3至6或3至5个碳原子的环状烷基,它可能包含1至4个环。“5-8元环烷基”则含有5-8个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基,环丁基,环戊基,环己基和金刚烷基,或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中,环烷基可以是与芳环基或杂芳环基稠合的环烷基。术语“C
3-C
6环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~6个碳原子,包括稠合或桥接的多环系统。例如环丙基、环丁基、环戊基、环己基。未取代的环烷基的实例包括但不限于环丙烯基,环丁烯基,环戊烯基,环己烯基和环己二烯基。在一些实施方案中,3-15元环烷基优选3-10元环烷基;更优选3-8元环烷基。
在单独或作为其他取代基一部分时,术语“杂环”、“杂环烷基”或“杂环基”是指其中一个或多个(在一些实施方案中为1至3个)碳原子被杂原子取代的环烷基,所述杂原子例如但不限于N、O、S和P。术语“m-n元杂环烷基”或者“C
m-C
n杂环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的环,其中杂环原子选自N、O、S、P,优选地选自N、O或S。例如,术语“4-8元杂环烷基”或者“C
4-C
8杂环烷基”应理解为表示具有4至8个原子的饱和、不饱和或部分饱和的环,其中1、2、3、或4个环原子选自N、O、S、P,优选地选自N、O或S。“4-10元杂环烷基”则是表示具有4至10个原子的饱和、不饱和或部分饱和的环。在一些实施方案中,杂环烷基可以是与芳环基或杂芳环基稠合的杂环烷基。当诸如3-8元或4-10元的前缀用于表示杂环烷基时,碳的数目也意味着包括杂原子。包括单环、二环、三环、螺环或桥环。术语“4-15元杂环烷基”或者“C
4-C
15杂环烷基”应理解为表示具有4至15个原子的饱和、不饱和或部分饱和的环,其中1、2、3或4个环原子选自N、O、S、P,优选地选自N、O或S;优选4-10元杂环基;更优选4-8元杂环烷基。
在单独或作为其他取代基一部分时,其中-CH
2-基团任选被-C(O)-代替;及其中除非另有相反说明,环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化;其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代;及环任选被一个或多个卤素取代。应该理解的是,当杂环基中S原子和O原子的总数超过1时,这些杂原子不彼此相邻。若所述杂环基为二环或三环,则至少一个环可任选为杂芳族环或芳族环,条件是至少一个环是非杂芳族的。若所述杂环基为单环,则其一定不是芳族 的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。
在单独或作为其他取代基一部分时,术语“C
2-C
6烯基”应理解为表示直连或支链的一价烃基,其包含一个或多个双键并且具有例如2、3、4、5或6个碳原子(即,C
2-C
6烯基),或具有2或3个碳原子(即,C
2-C
3烯基)。应理解,在所述烯基包含多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
在单独或作为其他取代基一部分时,术语“C
2-C
6炔基”应理解为表示直连或支链的一价烃基,其包含一个或多个三键并且具有例如2、3、4、5或6个碳原子(即,“C
2-C
6炔基”),或具有2或3个碳原子(“C
2-C
3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地,所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
在单独或作为其他取代基一部分时,术语“芳环基”芳基环结构包括具有一个或多 个环结构的化合物,例如单环,双环、三环螺环或桥环化合物,以及苯并稠合的碳环部分,其中至少一个环体系是芳香族的。芳基基团通常,但不必须地通过芳基基团的芳香性环与母体分子连接。术语“芳环基”可以和术语“芳香环基”或“芳基”交换使用。芳基基团的实例可以包括苯基、茚基、萘基和蒽基。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。代表性的芳基包括苯基,蒽基,芴基,茚基,菲基和萘基。
在单独或作为其他取代基一部分时,术语“5-15元芳环基”或者“C
5-C
15芳环基”应理解为具有5~15个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,特别是具有6个碳原子的环(“C
6芳环基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C
9芳环基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C
10芳环基”),例如四氢化萘基、二氢萘基或萘基。当芳环基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为邻位、对位或间位取代。同样的,术语“5-10元芳环基”或者“C
5-C
10芳环基”,应理解为具有5~10个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环;“5-8元芳环基”或者“C
5-C
8芳环基”应理解为具有5~8个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环。
在单独或作为其他取代基一部分时,术语“杂芳环基”是指单环或多环芳环系统,在某些实施方案中,环系统中1至3个原子是杂原子,即除碳以外的元素,包括但不限于N,O、S或P。例如呋喃基,咪唑基,二氢吲哚基,吡咯烷基,嘧啶基,四唑基,噻吩基,吡啶基,吡咯基,N-甲基吡咯基,喹啉基和异喹啉基。杂芳环基可任选与苯环稠合,也可以是包括单环、二环、三环、螺环或桥环。
在单独或作为其他取代基一部分时,术语“5-15元杂芳环基”或者“C
5-C
15杂芳环基”应理解为具有5~15个环原子且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团,应理解为具有5、6、7、8、9、10、11、12、13、14或15个环原子——特别是5或6或9或10个碳原子——且其包含1-5个,优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团,并且,另外在每一种情况下可为苯并稠合的。“5-8元杂芳环基”则应理解为具有5-8个环原子——特别是5或6个碳原子——且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团。优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团,并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳环基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪 基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
在单独或作为其他取代基一部分时,“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw,其中v=1至3,w=1至(2v+1))。卤代烷基的实例包括,但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
在单独或作为其他取代基一部分时,术语“螺环”指单环之间共用一个碳原子(称螺原子)的多环基团,其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、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。螺环烷基的非限制性实例包括:
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基,非限制性实例包括:
术语“桥环”是指化合物中的任意两个环共用两不直接相连的碳原子的环烃,根据组成环的数目分为二环烃、三环烃、四环烃等。非限制性实例包括:
在单独或作为其他取代基一部分时,术语“酰基”是指R-CO-基团,其中R为烷基,烷基为如上本文所定义,例如“C
2-C
8酰基”指具有C
1-C
7烷基-CO-结构的基团,酰基的代表性示例包括(但不限于):CH
3-CO-、C
2H
5-CO-、C
3H
8-CO-,或类似基团。在一些实施方案中,所述“酰基”包括酯基和酰胺基。“C
1-C
8酰基”指-CHO或具有C
1-C
7烷基-CO-结构的基团。
在单独或作为其他取代基一部分时,术语“酯基”指具R-CO-O-基团或-CO-O-R基团,其中R为烷基,烷基为如上本文所定义,例如“C
2-C
4酯基”是指C
1-C
3烷基-CO-O-结构的 基团或者-CO-O-C
1-C
3烷基结构的基团,酯基的代表性示例包括(但不限于):CH
3COO-、C
2H
5COO-、C
3H
8COO-、(CH
3)
2CHCOO-、-COOCH
3、-COOC
2H
5、-COOC
3H
8,或类似基团。“C
1-C
4酯基”是指-CO-O-H、-CHO、C
1-C
3烷基-CO-O-结构的基团或者-CO-O-C
1-C
3烷基结构的基团。
在单独或作为其他取代基一部分时,术语“酰胺基”指具R-CO-NH-基团或-CO-NH-R基团,其中R为烷基,烷基为如上本文所定义,例如“C
2-C
4酰胺基”是指C
1-C
3烷基-CO-NH-结构的基团或者-CO-NH-C
1-C
3烷基结构的基团,酰胺基的代表性示例包括(但不限于):CH
3CO-NH-、C
2H
5-CO-NH-、C
3H
8-CO-NH-、(CH
3)
2-CO-NH-、-CO-NH-CH
3、-CO-NHC
2H
5、-CO-NH-C
3H
8,或类似基团。“C
1-C
4酰胺基”是指-CO-NH
2、CHO-N-、C
1-C
3烷基-CO-NH-结构的基团或者-CO-NH-C
1-C
3烷基结构的基团。
在单独或作为其他取代基一部分时,术语“羰基”是指-CO-R基团,其中R为烷基,烷基为如上本文所定义。例如“C
2-C
6羰基”是指-CO-C
1-C
5烷基,代表性示例包括(但不限于):-CO-CH
3、-CO-CH
2CH
3、-CO-CH
2CH
2CH
3或类似基团。“C
1-C
6羰基”是指-CHO或-CO-C
1-C
5烷基。
在单独或作为其他取代基一部分时,术语“砜基”是指R-SO
2-基团,其中R为烷基,烷基为如上本文所定义,例如“C
1-C
6砜基”指具有C
1-C
5烷基-SO
2-结构的基团,砜基的代表性示例包括(但不限于):CH
3-SO
2-、C
2H
5-SO
2-、C
3H
8-SO
2-,或类似基团。
在单独或作为其他取代基一部分时,术语“卤代砜基”是指R-SO
2-基团,其中R为被一个或多个卤素取代的烷基,卤素和烷基为如上本文所定义,例如“C
1-C
6卤代砜基”指具有C
1-C
5被一个或多个卤素取代的烷基-SO
2-结构的基团,代表性示例包括(但不限于):CF
3-SO
2-。
术语“惰性溶剂”包括但不限于:甲苯、苯、水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃二氯甲烷、三氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环,或其组合物。
本文提供的化合物,包括可用于制备本文提供的化合物的中间体,其含有反应性官能团(例如但不限于羧基,羟基和氨基部分),还包括其保护的衍生物。“受保护的衍生物”是其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物。合适的羧基部分保护基包括苄基,叔丁基等,以及同位素等。合适的氨基和酰氨基保护基包括乙酰基,三氟乙酰基,叔丁氧基羰基,苄氧基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团是本领域普通技术人员所熟知的。
在本申请中,“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不 发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳环基”表示芳环基被取代或未被取代,且该描述同时包括被取代的芳环基与未被取代的芳环基。
在本申请中,术语“盐”或“药学上可接受的盐”,包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外,本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“胺盐”是指用酸中和烷基伯胺、仲胺或叔胺得到的产物。所述酸包括本申请中所述的无机酸或有机酸。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在,例如作为纯旋光异构体,或作为异构体混合物,如作为外消旋和非对映异构体混合物,这取决于不对称碳原子的数量。当描述具有光学活性的化合物时,使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号,其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。
当将本发明式中与手性碳的键描写直成线时,应当理解为,手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在,尝试分离单一互变异构体时通常产生一种混合物,其理 化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如,在很多脂族醛和酮如乙醛中,酮型占优势;而在酚中,烯醇型占优势。本发明包含化合物的所有互变异构形式。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂,当溶剂为水时,则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备,该修饰可以按常规的操作或者在体内被除去,而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物,当本发明化合物的前药被施予哺乳动物个体时,前药被割裂而分别形成游离的羟基、游离的氨基。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氘(
2H),氚(
3H),碘-125(
125I)或C-14(
14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性,即通过增加流动性和/或粘着性使制剂更适于直接压缩。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
各步骤的反应,反应温度可因溶剂、起始原料、试剂等适宜选择,反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后,目标化合物可按常用方法自反应体系中进行分离、提纯等步骤,如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下,目标化合物也可不经过分离、纯化直接进入下一步反应。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
本发明人经过广泛而深入地研究,意外地开发了一种6-取代磷酰基喹唑啉类衍生物或其药学上可接受的盐及制备方法和用途。
提供了一种式I所示6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,所述式I化合物对本发明中的化合物对KRAS G12C::SOS1结合具有显著的结合抑制作用,对KRAS G12C-SOS1具有显著的抑制作用,对DLD-1细胞ERK磷酸化水平显示显著的抑制作用,对H358细胞3D增殖显示较好的抑制作用,对LO2细胞毒性较小,并表现出较为优良的肝代谢稳定性;相比于BI-3406,该类化合物对细胞色素P450 3A4(CYP3A4)无抑制,潜在的药物药物相互作用风险低。本发明所述化合物表现出优良的药代动力学性质,具备更高的安全性和成药性。
提供了一种制备I所示6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的方法及中间体,所述方法操作简单、收率高、纯度高,可用于医药工业化生产。
图1测试化合物在瘤体积水平的抑瘤能力
以下结合具体实施例,进一步说明本发明。需理解,以下的描述仅为本发明的最优选实施方式,而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上,下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件,本领域技术人员可以对本发明的技术方案作出非本质的改动,这样的改动应当被视为包括于本发明的保护范围之中的。
本发明所述的化合物可以通过下文所述的合成方法制备,其中通式的取代基具有上文给出的含义。这些方法旨在说明本发明而不是限制其主题和对于这些实施例所要求保护的化合物的范围。如本发明第一方面所述的如式I所示的喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的制备方法,所述方法包括以下合成路线中的任一步骤:
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
中间体B-1与中间体B-2或B-3反应得到中间体B,中间体B再与中间体B-4反应得到式I所示的6-取代磷酰基喹唑啉类衍生物,或者中间体B-1与中间体B-5或B-6反应得到式I所示的6-取代磷酰基喹唑啉类衍生物。根据式I化合物中各个基团的不同,可以选择不同的合成路线和中间体,当取代基中存在活性基团(例如羧基、氨基、羟基等)时,可以根据需要将活性基团通过保护基进行保护后再参与反应,在反应完成后,去保护所述保护基。其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物为本发明所述式I化合物的“受保护的衍生物”。例如,合适的羧基部分保护基包括苄基,叔丁基、同位素等。合适的氨基和酰氨基保护基包括乙酰基、三氟乙酰基、叔丁氧基羰基、苄氧基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团 是本领域普通技术人员所熟知的。
在一些实施方式中,中间体B-1可以转化为B-1的胺盐后,再与中间体B-2、B-3、B-5或B-6反应,所述胺盐可以是本发明所述的药学上可接受的无机酸或有机酸与中间体B-1中的-NH
2反应得到的胺盐,包括但不限于:盐酸胺盐、硫酸胺盐、硝酸胺盐、磷酸胺盐。
在一些实施方式中,中间体B与中间体B-4反应在钯催化剂存在下反应得到式I所示喹唑啉衍生物,优选地可以加入4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)提高反应活性。优选地,所述反应需要惰性气体保护,所述惰性气体包括但不限于:氮气、氦气、氖气、氩气。
本发明各步反应优选地在惰性溶剂中进行,所述惰性溶剂包括但不限于:甲苯、苯、水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃二氯甲烷、三氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环,或其组合物。
下列中间体的制备可以参考专利WO2019122129A1合成。
(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐
(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐
(R)-1-(3-(二氟甲基)-2-甲基苯基)乙烷-1-胺盐酸盐
中间体A1:中间体A1的制备
合成路线如下所示:
第一步:1-(3-(五氟硫烷基)苯基)乙烷-1-酮(A1-2)的合成
室温下将化合物3-溴-(五氟硫烷基)苯(3.00g,10.6mmol)加入到二氧六环(100mL)中,加入二三苯基膦二氯化钯(744mg,1.06mmol),三丁基(1-乙氧基乙烯)锡(4.20g,11.7mmol),N
2保护下加热至90℃,搅拌14h。冷却至室温,加入2N盐酸(100mL),搅拌4h。用乙酸乙酯(200mL×3)萃取,分液,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=8:1)得1-(3-(五氟硫烷基)苯基)乙烷-1-酮(A1-2)(2.4g,收率89%)。
LC-MS,M/Z(ESI):247.0[M+H]
+。
第二步:(S,E)-2-甲基-N-(1-(3-(五氟硫烷基)苯基)亚乙基)丙烷-2-亚硫酰胺(A1-3)的合成
室温下将化合物1-(3-(五氟硫烷基)苯基)乙烷-1-酮(1.0g,4.06mmol)加入到THF(150mL)中,加入(S)-叔丁基亚磺酰胺(492mg,4.06mmol),钛酸四乙酯(1.14g,5.0mmol),加热至70℃,搅拌16h。冷却至室温,加入水(100mL)稀释,用乙酸乙酯(100mL×3)萃取,分液,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱分离纯化(石 油醚:乙酸乙酯(V/V)=4:1)得(S,E)-2-甲基-N-(1-(3-(五氟硫烷基)苯基)亚乙基)丙烷-2-亚硫酰胺(A1-3)(1.42g,产率100%)。
LC-MS,M/Z(ESI):350.2[M+H]
+。
第三步:(S)-2-甲基-N-((R)-1-(3-(五氟硫烷基)苯基)乙基)丙烷-2-亚硫酰胺(A1-4)的合成
室温下,原料(S,E)-2-甲基-N-(1-(3-(五氟硫烷基)苯基)亚乙基)丙烷-2-亚硫酰胺(1.5g,4.3mmol)加入到甲醇(30mL)中,冷却至0℃,将NaBH
4(744mg,20.1mmol)分批加入到甲醇中,升至室温,搅拌3h。反应液浓缩,经薄层制备板纯化得(S)-2-甲基-N-((R)-1-(3-(五氟硫烷基)苯基)乙基)丙烷-2-亚硫酰胺(A1-4)(600mg,产率40.0%)。
LC-MS,M/Z(ESI):352.1[M+H]
+。
第四步:(R)-1-(3-(五氟硫烷基)苯基)乙烷-1-胺盐酸盐(A1)的合成
室温下将原料(S)-2-甲基-N-((R)-1-(3-(五氟硫烷基)苯基)乙基)丙烷-2-亚硫酰胺(600mg,1.70mmol)加入到4mol/L的盐酸二氧六环溶液(10mL)中,搅拌4h。反应液浓缩,加入甲基叔丁基醚(20mL),搅拌1h,过滤,得(R)-1-(3-(五氟硫烷基)苯基)乙烷-1-胺盐酸盐(A1)(350mg,72.7%)。
LC-MS,M/Z(ESI):248.2[M+H]
+。
中间体A2:中间体A2的制备
合成路线如下所示:
第一步:3-溴-2-氟苯-1-重氮四氟硼酸盐(A2-2)的合成
室温下将3-溴-2-氟苯胺(10.3g,54.2mmol)加入到50%四氟硼酸水溶液(21mL)中,冷却至0℃,搅拌1h。0℃下滴加亚硝酸钠(3.8g,55mmol)溶于水(6mL)的溶液,低温下继续搅拌1h。过滤,干燥得黄色固体3-溴-2-氟苯-1-重氮四氟硼酸盐(A2-2)(13.0g,收率83.2%)。
第二步:(3-溴-2-氟苯基)(三氟甲基)硫醚(A2-3)的合成
室温下将3-溴-2-氟苯-1-重氮四氟硼酸盐(13g,45.1mmol),加入到乙腈(130mL)中,加入碳酸铯(30g,91.0mmol),硫氰酸钠(5.5g,67.9mmol),硫氰酸亚铜(2.8g,23.0mmol),搅拌0.5h,加入三氟甲基三甲基硅(12.8g,90mmol),搅拌16h。过滤,得化合物A2-3溶液。
LC-MS,M/Z(ESI):274.9[M+H]
+。
第三步:1-溴-2-氟-3-((三氟甲基)磺酰基)苯(A2-4)的合成
室温下将上一步化合物A2-3溶液加入到乙腈(200mL)、四氯化碳(200mL)和水(400mL)中,加入三氯化钌(9.3g,45.0mmol),高碘酸钠(28.8g,134.5mmol),搅拌16h。加入水(800mL)稀释,用DCM(400mL×3)萃取,分液,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=10:1)得无色液体1-溴-2-氟-3-((三氟甲基)磺酰基)苯(A2-4)(6.5g,收率46.9%)。
LC-MS,M/Z(ESI):306.9[M+H]
+。
第四步:1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙烷-1-酮(A2-5)的合成
室温下将化合物1-溴-2-氟-3-((三氟甲基)磺酰基)苯(6.5g,21.2mmol)加入到二氧六环(150mL)中,加入二三苯基膦二氯化钯(1.5g,2.12mmol),三丁基(1-乙氧基乙烯)锡(11.5g,31.7mmol),N
2保护下加热至90℃,搅拌14h。冷却至室温,加入2N盐酸(100mL),搅拌4h。用乙酸乙酯(200mL×3)萃取,分液,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=10:1)得1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙烷-1-酮(A2-5)(5.0g,收率87.7%)。
LC-MS,M/Z(ESI):271.0[M+H]
+。
第五步:(S,E)-N-(1-(2-氟-3-((三氟甲基)磺酰基)苯基)亚乙基)-2-甲基丙烷-2-亚磺胺(A2-6)的合成
室温下,将化合物1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙烷-1-酮(2.7g,10.0mmol)加入到THF(150mL)中,加入(S)-叔丁基亚磺酰胺(1.82g,15.0mmol),钛酸四乙酯(4.56g,20.0mmol),加热至70℃,搅拌16h。冷却至室温,加入水(300mL)稀释,用乙酸乙酯(200mL×3)萃取,分液,合并有机相,有机相用无水硫酸钠干燥,过滤,浓缩,残留物用 硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=4:1)得白色固体(S,E)-N-(1-(2-氟-3-((三氟甲基)磺酰基)苯基)亚乙基)-2-甲基丙烷-2-亚磺胺(A2-6)(4.0g,产率100%)。
LC-MS,M/Z(ESI):374.1[M+H]
+。
第六步:(S)-N-((R)-1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)-2-甲基丙烷-2-亚磺胺(A2-7)的合成
室温下将原料(S,E)-N-(1-(2-氟-3-((三氟甲基)磺酰基)苯基)亚乙基)-2-甲基丙烷-2-亚磺胺(1.5g,4.0mmol)加入到甲醇(30mL)中,冷却至0℃,将NaBH
4(744mg,20.1mmol)分批加入到甲醇中,升至室温,搅拌3h。反应液浓缩,经薄层制备板纯化得白色固体(S)-N-((R)-1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)-2-甲基丙烷-2-亚磺胺(A2-7)(600mg,产率40.0%)。
LC-MS,M/Z(ESI):376.1[M+H]
+。
第七步:(R)-1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙烷-1-胺盐酸盐(A2)的合成
室温下将原料(S)-N-((R)-1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)-2-甲基丙烷-2-亚磺胺(250mg,0.67mmol)加入到4mol/L的盐酸二氧六环溶液(1mL)中,搅拌4h。反应液浓缩,加入甲基叔丁基醚(20mL),搅拌1h,过滤,得白色固体(R)-1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙烷-1-胺盐酸盐(A2)(163mg,收率79.6%)。
LC-MS,M/Z(ESI):272.2[M+H]
+。
中间体A3:中间体A3的制备
合成路线如下所示:
第一步:2-氨基-4-溴-5-碘苯甲酸(A3-2)的合成
在25℃下,将碘代丁二酰亚胺(343g,1.53mol)加入到2-氨基-4-溴苯甲酸(300g,1.39mol)的N,N-二甲基甲酰胺(1.50L)溶液中,反应液在70℃下搅拌12小时。反应完成后,将反应液倒入冰水(3.00L)中,然后过滤,滤饼干燥得到黄色固体2-氨基-4-溴-5-碘苯甲酸(A3-2)(410g,粗品)。
LC-MS,M/Z(ESI):342.0[M+H]
+。
第二步:7-溴-6-碘-2-甲基喹唑啉-4(3H)-酮(A3)的合成
在室温下,将2-氨基-4-溴-5-碘苯甲酸(410g,1.20mol)溶解在醋酸酐(2.00L)中,混合液在140℃下搅拌12小时后浓缩得到棕色固体,将固体溶解在氨水(7.14L)中,混合液在80℃下搅拌5小时。反应完成后,将反应液过滤,滤饼用水洗涤后干燥得到灰色固体7-溴-6-碘-2-甲基喹唑啉-4(3H)-酮(A3)(253g,收率54.9%)。
1H NMR(400MHz,DMSO-d
6)δ12.33(br s,1H),8.45(s,1H),7.89(s,1H),2.33(s,3H)
LC-MS,M/Z(ESI):366.1[M+H]
+。
中间体A4的合成参考专利WO2018115380
实施例1:化合物I-1的制备
合成路线如下所示:
第一步:2-氨基-4-甲氧基苯甲酸甲酯(B1-2)的合成
在5℃下,向化合物B1-1(5g,29.91mmol)的甲醇(60mL)溶液中滴加氯化亚砜(299mmol,21.7mL),然后反应液在70℃反应12小时。将反应液减压浓缩得到粗品,粗品用乙酸乙酯打浆纯化,过滤得到化合物B1-2(4.34g,收率80%)。
第二步:2-氨基-5-碘-4-甲氧基苯甲酸甲酯(B1-3)的合成
在室温下,向化合物B1-2(4g,22.1mmol)的DMF(60mL)溶液中加入N-碘代丁二酰亚胺(5.22g,23.2mmol),然后室温反应12小时。将反应液减压浓缩得到粗品,粗品用乙酸乙酯打浆纯化,过滤,得到化合物B1-3(4.41g,收率65%)。
第三步:6-碘-7-甲氧基-2-甲基喹唑啉-4(3H)-酮(B1-4)的合成
向化合物B1-3(3g,9.8mmol)的乙腈(30mL)溶液中加入甲磺酸(5.1mL),然后反应液在100℃反应过夜。将反应液减压浓缩得到粗品,粗品用饱和氢氧化钠溶液调节pH至8,过滤并干燥,得到化合物B1-4(1.92g,收率62%)。
第四步:(R)-6-碘-7-甲氧基-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B1-5)的合成
向化合物B1-4(400mg,1.27mmol)的二氯甲烷(8mL)溶液中加入2,4,6-三异丙基苯磺酰氯(424mg,1.40mmol),4-二甲氨基吡啶(16mg,0.13mmol),三乙胺(0.53mL,3.81mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(3mL)、三乙胺(1.9mmol,0.26mL)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(305mg,1.27mmol),然后反应液80℃反应过夜。反应液冷却至室温,向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B1-5(458mg,收率72%)。
第五步:(R)-(7-甲氧基-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-1)的合成
将化合物B1-5(120mg,0.24mmol)溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(27mg,0.35mmol)、三(二亚苄基丙酮)二钯(17.6mg,0.0192mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(22.2mg,0.0384mmol)和三乙胺(0.1mL,0.72mmol)。反应液在90℃下反应6小时,反应完全后,将反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-1(81mg,收率75%)。
1H NMR(400MHz,DMSO):δ8.96(d,1H),8.75(d,1H),7.85(d,1H),7.56-7.51(m,1H),7.36-7.32(m,1H),7.08(d,1H),5.74-5.70(m,1H),3.94(s,2H),3.32(s,3H),3.30(s,2H), 2.63(s,2H),2.32(s,2H),1.71(d,2H),1.67(d,2H),1.55(d,2H),1.50-1.46(m,1H).
LC-MS m/z=452.4[M+H]
+。
实施例2:化合物I-2的制备
(R)-二乙基(7-甲氧基-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧化膦(I-2)的合成
将化合物B1-5(100mg,0.2mmol)溶于DMF(3mL),在氮气保护下加入氧化二乙基膦(31mg,0.29mmol)、三(二亚苄基丙酮)二钯(0.016mmol,14.7mg)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(0.032mmol,18.5mg)和三乙胺(0.08mL,0.6mmol)。反应液在90℃下反应。反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-2(75mg,收率78%)。
1H NMR(400MHz,CDCl
3):δ8.38(d,1H),7.62-7.52(m,1H),7.28-7.24(m,1H),7.10(d,1H),6.34(d,1H),5.87-5.80(m,1H),3.92(s,3H),2.63(d,3H),2.52(s,3H),2.14-1.96(m,4H),1.64-1.60(m,4H),1.13-1.06(m,6H).
LC-MS m/z=480.4[M+H]
+。
实施例3:化合物I-3的制备
合成路线如下:
第一步:(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-碘-7-甲氧基-2-甲基喹唑啉-4-胺(B3-1)的合成
向化合物B1-4(350mg,1.11mmol)的二氯甲烷(9mL)溶液中加入2,4,6-三异丙基苯磺酰氯(368mg,1.22mmol),4-二甲氨基吡啶(13.4mg,0.11mmol),三乙胺(0.46mL,3.33mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品的DMSO溶液加入三乙胺(0.46mL,3.33mmol)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(250mg,1.11mmol),然后80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B3-1(395mg,收率73%)。
第二步:(R)-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)二甲基氧化膦(I-3)的合成
将化合物B3-1(150mg,0.31mmol)溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(35mg,0.45mmol)、三(二亚苄基丙酮)二钯(22.7mg,0.0248mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(28.7mg,0.05mmol)和三乙胺(0.13mL,0.93mmol)。反应液在90℃下搅拌反应。反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-3(111mg,收率82%)。
1H NMR(400MHz,CDCl
3):δ8.46(d,1H),7.54-7.46(m,2H),7.18(t,1H),7.12(d,1H),7.06-6.79(m,1H),6.41(d,1H),5.86-5.79(m,1H),3.97(s,3H),2.51(s,3H),1.82(s,3H),1.77(s,3H),1.65(d,2H),1.63-1.59(m,1H).
LC-MS m/z=438.2[M+H]
+。
实施例4:化合物I-4的制备
合成路线如下:
步骤1:(R)-6-溴-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B4-2)的合成
将化合物B4-1(200mg,0.78mmol)溶于DMF(3mL),加入N,N-二异丙基乙胺(0.39mL,2.34mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(187mg,0.82mmol)。微波100℃反应1小时。反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B4-2(297mg,收率90%)。
第二步:(R)-二甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧化膦(I-4)的合成
将化合物B4-2(150mg,0.35mmol)溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(40mg,0.51mmol)、三(二亚苄基丙酮)二钯(25.6mg,0.028mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(32.4mg,0.056mmol)和三乙胺(0.15mL,1.05mmol)。反应液在120℃下搅拌反应,反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物 I-4(103mg,收率70%)。
1H NMR(400MHz,CDCl
3):δ8.57(d,1H),7.79-7.76(m,1H),7.66-7.61(m,1H),7.55-7.50(m,2H),7.19(t,1H),6.65(d,1H),5.87-5.80(m,1H),2.61(s,2H),2.54(s,2H),2.03(s,2H),1.80(s,3H),1.77(s,3H),1.61(d,3H)。
LC-MS m/z=422.3[M+H]
+。
实施例5:化合物I-5的制备
合成路线如下:
第一步:2-氨基-4-氟-5-碘苯甲酸甲酯(B5-2)的合成
在室温下,向化合物B5-1(3.0g,17.75mmol)的DMF(30mL)溶液中加入N-碘代丁二酰亚胺(4.19g,18.64mmol),然后室温反应12小时。将反应液倒入搅拌中的水,用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B5-2(3.72g,收率71%)。
第二步:7-氟-6-碘-2-甲基喹唑啉-4(3H)-酮的合成
向化合物B5-2(3.0g,10.14mmol)的乙腈(30mL)溶液中加入甲磺酸(5.3mL),然后反应液在100℃反应过夜。将反应液减压浓缩得到粗品,粗品用饱和氢氧化钠溶液调节pH至8,过滤并干燥,得到化合物B5-3(2.0g,收率65%)。
第三步:(R)-7-氟-6-碘-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B5-4)的合成
向化合物B5-3(300mg,0.99mmol)的二氯甲烷(8mL)溶液中加入2,4,6-三异丙基苯磺酰氯(332mg,1.1mmol),4-二甲氨基吡啶(12mg,0.1mmol),三乙胺(0.41mL,2.97mmol),然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(4mL)、三乙胺(0.41mL,2.94mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(240mg,0.99mmol),然后反应液80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B5-4(330mg,收率68%)。
第四步:(R)-(7-氟-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-5)的合成
将化合物B5-4(120mg,0.245mmol)溶于DMF(3.0mL),在氮气保护下加入二甲基氧化膦(27.7mg,0.356mmol)、三(二亚苄基丙酮)二钯(18mg,0.0196mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(22.7mg,0.0392mmol)和三乙胺(0.1mL,0.735mmol)。反应液在90℃反应,反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-5(81mg,收率75%)。
1H NMR(400MHz,CDCl
3):δ8.50-8.45(m,1H),7.60-7.53(m,2H),7.39-7.35(m,1H),7.27-7.23(m,1H),6.53(d,1H),5.87-5.81(m,1H),2.61(s,2H),2.53(s,2H),1.86(s,3H),1.82(s,6H),1.62(d,2H)。
LC-MS m/z=440.2[M+H]
+。
实施例6:化合物I-6的制备
合成路线如下:
第一步:(R)-6-碘-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B6-1)的合成
将化合物B4-2(100mg,0.24mmol)溶于1,4-二氧六环(3mL),在氮气保护下加入碘化亚铜(6mg,0.0315mmol)、碘化钾(209mg,1.26mmol)和N,N'-二甲基乙二胺(5.5mg,0.063mmol)。反应液在110℃下搅拌24小时。反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B6-1(100mg,收率90%)。
第二步:(R)-二乙基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基) 氧化膦(I-6)的合成
将化合物B6-1(100mg,0.21mmol)、溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(24mg,0.31mmol)、三(二亚苄基丙酮)二钯(15.4mg,0.0168mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(19.4mg,0.034mmol)和三乙胺(0.09mL,0.63mmol)。反应液在120℃下搅拌过夜。反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-6(66mg,收率70%)。
1H NMR(400MHz,CDCl
3):δ8.48(d,1H),7.78-7.75(m,1H),7.61-7.52(m,1H),7.24-7.22(m,1H),6.53(d,1H),5.88-5.81(m,1H),2.64(s,3H),2.54(s,3H),2.12-1.78(m,5H),1.65(d,2H),1.24-1.08(m,8H)。
LC-MS m/z=450.2[M+H]
+。
实施例7:化合物I-7的制备
合成路线如下:
第一步:(R)-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-6-碘-7-甲氧基-2-甲基喹唑啉-4-胺(B7-1)的合成
向化合物B1-4(350mg,1.11mmol)的二氯甲烷(9mL)溶液中加入2,4,6-三异丙基苯磺酰氯(368mg,1.22mmol),4-二甲氨基吡啶(13.4mg,0.11mmol),三乙胺(0.46mL,3.33mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品的DMSO溶液加入三乙胺(0.46mL,3.33mmol)和(R)-1-(3-(二氟甲基)-2-甲基苯基)乙烷-1-胺盐酸盐(250mg,1.11mmol),然后80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B7-1(395mg,收率73%)。
步骤2:(R)-(4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)二甲基氧化膦(I-7)的合成
将化合物B7-1(150mg,0.31mmol)溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(35mg,0.45mmol)、三(二亚苄基丙酮)二钯(22.7mg,0.0248mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(28.7mg,0.05mmol)和三乙胺(0.13mL,0.93mmol)。反应液在90℃下搅拌反应4h。反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-7(111mg,收率82%)。
1H NMR(400MHz,CDCl
3):δ8.48(d,1H),7.68-7.38(m,3H),7.20-6.79(m,3H),6.43(d,1H),5.86-5.79(m,1H),3.97(s,3H),2.48(s,3H),1.82(s,3H),1.79(s,3H),1.67-1.59(m,5H)。
LC-MS m/z=434.0[M+H]
+。
实施例8:化合物I-8的制备
合成路线如下所示:
第一步:2-氯-4-羟基-5-碘苯甲酸甲酯(B8-2)的合成
在三口瓶中加入B8-1(5.0g,26.8mmol),溶解到氨水(100mL)中,降温至0℃,慢慢滴加碘(4.45g,26.8mmol)和碘化钾(20.4g,80.4mmol)的混合水溶液(100mL)。滴加完毕后,升至室温反应两小时,稀盐酸调节pH值至5,乙酸乙酯(50mL*3)萃取,干燥浓缩得粗品,柱层析分离(石油醚:乙酸乙酯(V/V)=10:1~1:1)得产物B8-2(6.0g,收率71.7%)。
第二步:2-氯-5-碘-4-((四氢呋喃-3-基)氧基)苯甲酸甲酯(B8-3)的合成
在三口瓶中加入B8-2(1.0g,2.6mmol),三苯基膦(0.82g,3.1mmol),3-羟基四氢呋喃(0.23g,3.1mmol)和四氢呋喃(20mL),氮气保护,降温至0℃慢慢滴加DIAD(0.63g,3.1mmol),保持温度1小时,升温至室温反应过夜。浓缩,柱层析得产物B8-3(0.7g,收率57.2%)。
第三步:2-氯-5-(二甲基磷酰基)-4-((四氢呋喃-3-基)氧基)苯甲酸甲酯(B8-4)的合成
将化合物B8-3(0.5g,1.3mmol)溶于DMF(3.0mL),在氮气保护下加入二甲基氧化膦(122mg,1.6mmol)、三(二亚苄基丙酮)二钯(95mg,0.1mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(120mg,0.21mmol)和三乙胺(200mg,2.0mmol)。反应液在90℃反应,反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到B8-4(0.3g,收率69.0%)。
第四步:6-(二甲基磷酰基)-2-甲基-7-((四氢呋喃-3-基)氧基)喹唑啉-4(3H)-酮(B8-5)的合成
将化合物B8-4(300mg,0.9mmol)溶于DMF(3.0mL),在氮气保护下加入CuI(17.1mg,0.09mmol)、L-脯氨酸(10.4mg,0.09mmol)、盐酸乙脒(128mg,1.35mmol)和碳酸钾(186mg,1.35mmol)。反应液在90℃微波反应15小时,反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B8-5(200mg,收率68.8%)。
第五步:二甲基(2-甲基-4-(((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7-((四氢呋喃-3-基)氧基)喹唑啉-6-基氧化膦(I-8)的合成
向化合物B8-5(200mg,0.6mmol)的二氯甲烷(8mL)溶液中加入2,4,6-三异丙基苯磺酰氯(226mg,0.74mmol),4-二甲氨基吡啶(12mg,0.1mmol),三乙胺(0.41mL 2.97mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(4mL)、 三乙胺(0.41mL,2.94mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(240mg,0.99mmol),然后反应液80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-8(4.1mg,收率1.3%)。
LC-MS m/z=508.3[M+H]
+。
1H NMR(400MHz,DMSO-d6):δ8.94(d,1H),8.76(d,1H),7.82(d,1H),7.49(d,1H),7.33(t,1H),7.04(d,1H),5.71-5.67(m,1H),5.28(b,1H),3.87-3.85(m,2H),3.53-3.50(m,2H),2.60(s,3H),2.29(s,3H),2.12-1.92(m,2H),1.68-1.64(dd,6H),1.52(d,3H)。
实施例9:化合物I-9的制备
合成路线如下所示:
第一步:2-氯-5-碘-4-(3-甲氧基乙氧基)苯甲酸甲酯(B9-2)的合成
在三口瓶中加入B9-1(1.0g,2.6mmol),三苯基膦(0.82g,3.1mmol),乙二醇单甲醚(0.23g,3.1mmol)和四氢呋喃(20mL),氮气保护,降温至0℃慢慢滴加DIAD(0.63g,3.1mmol),保持温度1小时,升温至室温反应过夜。浓缩,柱层析得产物B9-2(0.7g,收率57.2%)。
第二步:2-氯-5-(二甲基磷酰基)-4-(3-甲氧基乙氧基)苯甲酸甲酯(B9-3)的合成
将化合物B9-2(0.5g,1.3mmol)溶于DMF(3.0mL),在氮气保护下加入二甲基氧化膦(122mg,1.6mmol)、三(二亚苄基丙酮)二钯(95mg,0.1mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(120mg,0.21mmol)和三乙胺(200mg,2.0mmol)。反应液在90℃反应,反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到B9-3(0.3g,收率69.0%)。
第三步:6-(二甲基磷酰基)-7-(3-甲氧基乙氧基)-2-甲基喹唑啉-4(3H)-酮(B9-4)的合成
将化合物B9-3(300mg,0.9mmol)溶于DMF(3.0mL),在氮气保护下加入CuI(17.1mg,0.09mmol)、L-脯氨酸(10.4mg,0.09mmol)、盐酸乙脒(128mg,1.35mmol)和碳酸钾(186mg,1.35mmol)。反应液在90℃微波反应15小时,反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到化合物B9-4(200mg,收率68.8%)。
第四步:(R)-(7-(3-甲氧基乙氧基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-9)
向化合物B9-4(200mg,0.6mmol)的二氯甲烷(8mL)溶液中加入2,4,6-三异丙基苯磺酰氯(226mg,0.74mmol),4-二甲氨基吡啶(12mg,0.1mmol),三乙胺(0.41mL 2.97mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(4mL)、三乙胺(0.41mL,2.94mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(240mg,0.99mmol),然后反应液80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-9(8.2mg,收率2.6%)。
LC-MS m/z=496.2[M+H]
+。
1H NMR(400MHz,CDCl
3):δ8.40(d,1H),7.55(dd,2H),7.05(d,1H),6.27(d,1H),5.82(m,1H),4.24(t,2H),3.77(t,2H),3.41(s,3H),2.61(s,3H),2.51(s,3H),1.83(dd,6H),1.59(d,3H)。
实施例10:化合物I-10的制备
(R)-二甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7-(甲基氨基)喹唑啉-6-基)氧化膦(I-10)
合成路线如下所示:
将化合物I-5(200mg,0.6mmol)加入到微波管中,加入甲胺醇溶液(3mL,30%)。然后60℃微波反应液30min。反应完毕后浓缩至干,粗品经制备板分离纯化,得到目标化合物I-10(25.5mg,收率2.6%)。
LC-MS m/z=451.2[M+H]
+。
1H NMR(400MHz,CDCl
3):δ7.95(d,1H),7.75(d,1H),7.51(d,1H),7.19(t,1H),6.74(d,1H),5.90-5.85(m,1H),2.81(d,3H),2.59(s,3H),2.50(s,3H),1.93(dd,6H),1.69(d,3H)。
实施例11:化合物I-11的制备
合成路线如下所示:
第一步:5-氨基-2-溴异烟酸甲酯(B11-2)的合成
在4℃下,将化合物B11-1(1.6g,8.57mmol)溶于氢溴酸醋酸溶液(20mL)溶液,恢复至室温搅拌10分钟。反应液在80℃反应过夜。反应完全后,将反应液冷却至室温后,倒入冰水混合物中,用饱和氢氧化钠溶液调节pH至8,过滤并干燥,得到B11-2(1.4g,收率71%)。
第二步:6-溴-2-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮(B11-3)的合成
向B11-2(1.4g,6.06mmol)的乙腈(15mL)溶液中加入甲磺酸(3.1mL),然后反应液在100℃反应过夜。将反应液减压浓缩得到粗品,粗品用饱和氢氧化钠溶液调节pH至8,过滤并干燥,用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=100:1-20:1),得到B11-3(0.8g,收率55%)。
第三步:(R)-6-溴-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶基[3,4-d]嘧啶-4-胺(B11-4)的合成
向B11-3(5mL)溶液中加入2,4,6-三异丙基苯磺酰氯(455mg,1.5mmol),4-二甲氨基吡啶(15mg,0.125mmol),三乙胺(0.53mL,3.75mmol),室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(4mL)、三乙胺(0.53mL,3.75mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(300mg,1.25mmol),反应液80℃反应过夜。反应液冷却至室温,向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=100:1-20:1),得到B11-4(200mg,收率38%)。
第四步:(R)-二甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)吡啶基[3,4-d]嘧啶-6-基)氧化膦(I-11)的合成
将B11-4溶于DMF(4mL),在氮气保护下加入二甲基氧化膦(54mg,0.68mmol)、三(二亚苄基丙酮)二钯(35mg,0.0378mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(44mg,0.0752mmol)和三乙胺(0.2mL,1.41mmol)。反应液在120℃反应24小时,反应完全后,反应液直接浓缩得到粗品。粗品经用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=100:1-15:1),得到目标化合物I-11(90mg,收率45%)。
1H NMR(400MHz,CDCl
3):δ9.15(s,1H),8.71(d,1H),7.60(d,1H),7.53(d,1H),7.29(d,1H),7.23(t,1H),5.88-5.81(m,1H),2.62(s,3H),2.58(s,3H),1.83(d,3H),1.79(d,3H),1.64(d,3H)。
LC-MS m/z=423.20[M+H]
+。
实施例12:化合物I-12的制备
参照化合物B25-1的合成方法得到目标化合物(R)-(7-氨基-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-12)。
化合物I-12:LC-MS m/z=437.2[M+H]
+。
实施例13:化合物I-13的制备
将化合物I-12与CuI和亚硝酸异戊酯反应得到中间体B13-1,再与CuCN反应得到目标化合物(R)-6-(二甲基磷酰基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-7-腈(I-13)。
化合物I-13:LC-MS m/z=447.2[M+H]
+。
实施例14:化合物I-14的制备
化合物I-14:LC-MS m/z=479.2[M+H]
+。
实施例15:化合物I-15的制备
化合物I-13经双氧水氧化后得到目标化合物(R)-6-(二甲基磷酰基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-7-甲酰胺(I-15)。
化合物I-15:LC-MS m/z=465.2[M+H]
+。
实施例16:化合物I-16的制备
合成路线如下所示:
第一步:(R)-6-溴-N
7-乙基-2-甲基-N
4-(1-(2-(3-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺(B16-1)的合成
在单口瓶中加入化合物B12-5(0.5g,1.1mmol),碳酸铯(553mg,1.7mmol),DMA(2mL)和乙胺的四氢呋喃溶液(1mL),体系被加热至150℃,保持温度12小时,反应完毕后,浓缩,柱层析得产物B16-1(0.4g,收率75.7%)。
第二步:(R)-(7-(乙胺基)-(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-16)
将化合物B16-1(400mg,0.86mmol)溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(101mg,1.3mmol)、三(二亚苄基丙酮)二钯(63mg,0.069mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(80mg,0.14mmol)和三乙胺(260mg,2.6mmol)。反应液在120℃下搅拌反应24小时。反应完全后,反应液直接浓缩得到粗品。粗品经柱层析分离纯化,得到目标化合物I-16(112mg,收率28.2%)。
1H NMR(400MHz,CDCl
3):δ8.91(b,1H),8.49(b,1H),7.95(d,1H),7.42(d,1H),7.07(t,1H),6.82(d,1H),5.91(m,1H),3.02(m,2H),2.59(s,3H),2.53(s,3H),2.02(d,6H),1.74(d,3H),1.16(t,3H)。
LC-MS m/z=465.2[M+H]
+。
实施例17:化合物I-17的制备
合成路线如下所示:
第一步:(R)-6-溴-N
7-(甲氧基乙基)-2-甲基-N
4-(1-(2-(3-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺(B17-1)的合成
在单口瓶中加入化合物B12-5(0.5g,1.1mmol),碳酸铯(553mg,1.7mmol),DMA(2mL)和2-甲氧基乙-1-胺(128mg,1.7mmol),体系被加热至150℃,保持温度12小时,反应完毕后,浓缩,柱层析得产物B17-1(0.3g,收率53.4%)。
第二步:(R)-(7-((2-甲氧基乙基)氨基)-(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-17)
将化合物B17-1(300mg,0.6mmol)溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(70mg,0.9mmol)、三(二亚苄基丙酮)二钯(44mg,0.048mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(55.5mg,0.096mmol)和三乙胺(260mg,2.6mmol)。反应液在120℃下搅拌反应24小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物I-17(144mg,收率48.2%)。
1H NMR(400MHz,CDCl
3):δ8.42(b,1H),8.11(b,1H),7.78(d,1H),7.47(d,1H),7.14(t,1H),6.75(d,1H),5.86(m,1H),3.53(t,2H),3.31(s,3H),3.23(q,2H),2.59(s,3H),2.49(s,3H),1.93(q,6H),1.68(d,3H)。
LC-MS m/z=495.2[M+H]
+。
实施例18:化合物I-18的制备
参照化合物I-16的合成方法,得到目标化合物(R)-1-(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7-(甲基氨基)喹唑啉-6-基)膦烷1-氧化物(I-18)。
化合物I-18:LC-MS m/z=477.2[M+H]
+。
实施例19:化合物I-19的制备
化合物I-19的合成参照化合物I-16的合成方法,将乙胺换为1-氨基-2-甲基-2-丙醇,得到目标化合物(R)-(7-((2-羟基-2-甲基丙基)氨基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-19)。
化合物I-19:LC-MS m/z=509.2[M+H]
+。
1H NMR(400MHz,CDCl3)δ8.16(d,1H),8.11(d,1H),7.91(d,1H),7.69(d,1H),7.50(d,1H),7.32(t,1H),6.47(d,1H),5.69-5.63(t,1H),4.46(d,1H),2.58(s,3H),2.20(s,3H),1.86-1.76(m,6H),1.51(d,3H),1.14-1.05(m,9H).
实施例20:化合物I-20的制备
中间体B13-1依次与CO、格氏试剂MeMgBr反应得到目标化合物(R)-(7-(2-羟基丙-2-基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基膦氧化物(I-20)。
化合物I-20:LC-MS m/z=480.2[M+H]
+。
实施例21:化合物I-21的制备
中间体B13-1与4-氨基-1-甲基-1H-吡唑反应得到目标化合物(R)-二甲基(2-甲基-7-((1-甲基-1H-吡唑-4-基)氨基)-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧化膦(I-21)。
化合物I-21:LC-MS m/z=517.2[M+H]
+。
实施例22:化合物I-22的制备
中间体B13-1与三氟乙胺反应得到目标化合物(R)-二甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)-7-((2,2,2-三氟乙基)氨基)喹唑啉-6-基)氧化膦(I-22)。
化合物I-22:LC-MS m/z=519.2[M+H]
+。
实施例23:化合物I-23的制备
中间体B13-1与环丙胺反应得到目标化合物(R)-(7-(环丙基氨基)-2-甲基-4-((1-(2-甲 基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-23)。
化合物I-23:LC-MS m/z=477.2[M+H]
+。
1H NMR(400MHz,DMSO-d6)δ8.21-8.13(m,3H),7.69(d,1H),7.50(d,1H),7.33(t,1H),6.84(t,1H),5.71-5.64(m,1H),2.58(s,3H),2.40(s,1H),2.23(s,3H),1.80(d,6H),1.52(d,3H),0.76(d,2H),0.38(s,2H)
实施例24:目标化合物I-24的制备
合成路线如下所示:
第一步:(R)-7-溴-6-碘-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B24-1)
向化合物7-溴-6-碘-2-甲基喹唑啉-4(3H)-酮(365mg,1.0mmol)的二氯甲烷(8mL)溶液中加入2,4,6-三异丙基苯磺酰氯(363mg,1.2mmol),4-二甲氨基吡啶(12mg,0.1mmol),三乙胺(303mg,3.0mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(4mL)、三乙胺(303mg,3.0mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(240mg,1.0mmol),然后反应液80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物(R)-7-溴-6-碘-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(220mg,收率40%)。
第二步:(R)-(7-溴-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(B24-2)
将化合物(R)-7-溴-6-碘-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(2.6g,4.7mmol)溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(553mg,7.1mmol)、三(二亚苄基丙酮)二钯(346mg,0.38mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(438mg,0.76mmol)和三乙胺(1.4g,14.2mmol)。反应液在120℃下搅拌反应24小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物(1.0g,收率42.3%)。
第二步:(R)-(6-(二甲基膦酰基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-7-基)氨基甲酸叔丁酯(I-24)
将化合物(R)-(7-溴-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(200mg,0.4mmol)溶于1,4-二氧六环(2mL)和甲苯(2mL),在氮气保护下加入氨基甲酸叔丁酯(94mg,0.8mmol)、醋酸钯(9mg,0.04mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(46.3mg,0.08mmol)和碳酸铯(261mg,0.8mmol)。反应液在90℃下搅拌反应12小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物I-24(53.2mg,收率24.8%)。
1H NMR(400MHz,CDCl
3)δ11.26(s,1H),8.47(d,1H),8.31(s,1H),7.72(d,1H),7.53(d,1H),7.35(t,1H),5.70(t,1H),2.59(s,3H),2.30(s,3H),1.91(dd,6H),1.56(d,3H),1.45(s,9H).
LC-MS m/z=537.2[M+H]
+。
实施例25:目标化合物I-25的制备
合成路线如下所示:
第一步:(R)-(7-氨基-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(B25-1)
将化合物(R)-(6-(二甲基膦酰基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-7-基)氨基甲酸叔丁酯(200mg,0.4mmol)溶于1,4-二氧六环/HCl(4M,5mL),室温下搅拌反应1小时。反应完全后,反应液直接浓缩得到粗品。直接用于下一步。
第二步:O-苯基(R)-(6-(二甲基磷酰基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-7-基)氨基甲硫酸酯(B25-2)
将上一步的粗品溶入四氢呋喃(10mL)中,然后降温至0℃,加入三乙胺(104mg,1.0mmol)和O-苯基硫代碳酰氯(71.2mg,0.4mmol),然后升温至室温反应3小时。反应液直接用于下一步。
第三步:(R)-(7-((4,4-二甲基-4,5-二氢恶唑-2-基)氨基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-25)
向上一步的反应液中加入2-氨基-2-甲基丙-1-醇(46mg,0.5mmol),升温至50℃搅拌过夜,浓缩,制备色谱纯化得化合物I-25(25mg,收率13.6%)。
1H NMR(400MHz,DMSO)δ8.8(d,1H),7.83(d,2H),7.52(d,1H),7.35(t,1H),7.2(b,1H),5.76-5.72(m,1H),4.18(s,1H),2.8(b,1H),2.59(s,3H),2.34(s,3H),1.70(d,6H),1.56(d,3H),1.27(s,6H).
LC-MS m/z=534.2[M+H]
+。
实施例26:目标化合物I-26的制备
合成路线如下所示:
合成方法参考化合物I-32,将环丁胺盐酸盐替换为3-甲基氮杂环丁烷-3-醇盐酸盐。
1H NMR(400MHz,CDCl3)δ7.69(b,3H),7.52(d,1H),7.22(d,1H),5.81(t,1H),3.30(d,1H),3.18(s,2H),2.88(d,1H),2.58(s,3H),2.52(s,3H),1.91-1.88(dd,6H),1.67(d,3H),1.11(s,3H).
LC-MS m/z=507.2[M+H]
+。
实施例27:目标化合物I-27的制备
合成路线如下所示:
第一步:(R)-7-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-碘-2-甲基喹唑啉-4-胺(B27-1)
向化合物7-溴-6-碘-2-甲基喹唑啉-4(3H)-酮(365mg,1.0mmol)的二氯甲烷(8mL)溶液中加入2,4,6-三异丙基苯磺酰氯(363mg,1.2mmol),4-二甲氨基吡啶(12mg,0.1mmol),三乙胺(303mg,3.0mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(4mL)、三乙胺(303mg,3.0mmol)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺盐酸盐(190mg,1.0mmol),然后反应液80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物(R)-7-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-碘-2-甲基喹唑啉-4-胺(236mg,收率44%)。
第二步:(R)-(7-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉--6-基)二甲基氧化膦(B27-2)
将化合物(R)-7-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-碘-2-甲基喹唑啉-4-胺(2.46g,4.6mmol)溶于DMF(30mL),在氮气保护下加入二甲基氧化膦(553mg,7.1mmol)、三(二亚苄基丙酮)二钯(346mg,0.38mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(438mg,0.76mmol)和三乙胺(1.4g,14.2mmol)。反应液在120℃下搅拌反应24小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物B27-2(1.1g,收率50.0%)。
第三步:(R)-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(二甲基磷酰基)-2-甲基喹唑啉-7-基)氨基甲酸叔丁酯(B27-3)
将(R)–(7-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(300mg,0.705mmol)溶解在2mL二氧六环中,加入氨基甲酸叔丁酯(165mg,1.41mmol),醋酸钯(15.83mg,0.071mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(82mg,0.141mmol),碳酸铯(460mg,1.41mmol),氮气置换三次后90℃搅拌12小时。加入10mL水,用乙酸乙酯(10mL*3)萃取,合并有机相,用无水硫酸钠干燥,过滤浓缩,浓缩物经过柱层析(二氯甲烷:甲醇(V:V)=50:1至20:1)分离纯化得(R)-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(二甲基磷酰基)-2-甲基喹唑啉-7-基)氨基甲酸叔丁酯(220mg,收率59.6%)。
LC-MS,M/Z(ESI):523.2[M+H]
+。
第二步:(R)-(7-氨基-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(B27-4)
将(R)-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(二甲基磷酰基)-2-甲基喹唑啉-7-基)氨基甲酸叔丁酯(220mg,0.421mmol)溶解在5mL二氧六环中,加入4M盐酸二氧六环(5mL),室温搅拌1h,旋干得(R)-(7-氨基-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(193mg,收率100%)。
LC-MS,M/Z(ESI):423.2[M+H]
+。
第三步:(R)-(4-((1-(3-(二氟甲基(-2-氟苯基)乙基)氨基)-2-甲基-7-((2,2,2-三氟乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-27)
将磷酸钾(2.51mg,0.012mmol),18-冠-6(6.26mg,0.024mmol)溶解在四氢呋喃(2mL)中,加入(R)-(7-氨基-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(50mg,0.118mmol),三氟乙酸(62.1mg,0.545mmol),苯基硅烷(102mg,0.947mmol),80℃搅拌12小时。加入10mL水,用乙酸乙酯(10mL*3)萃取,合并有机相,用无水硫酸钠干燥,过滤浓缩,浓缩物经过柱层析(二氯甲烷:甲醇(V:V)=50:1至20:1)分离纯化得(R)-(4-((1-(3-(二氟甲基(-2-氟苯基)乙基)氨基)-2-甲基-7-((2,2,2-三氟乙基)氨基)喹唑啉-6-基)二甲基氧化膦(30mg,收率50.2%)。
1H NMR(400m Hz,CD3Cl)δ8.04-8.07(m,1H),7.50-7.55(m,2H),7.46(d,1H),7.21-7.26(m,1H),6.91(t,1H),6.90(s,1H),5.77-5.83(m,1H),5.71-5.75(m,1H),3.82-3.90(m,2H),2.50(s,3H),1.87-1.92(q,6H),1.70(d,3H).
LC-MS,M/Z(ESI):505.1[M+H]
+。
实施例28:目标化合物I-28的制备
合成路线如下所示:
合成方法参考I-32,将环丁胺盐酸盐替换为环丙甲胺。
1H NMR(400MHz,CDCl3)δ7.56(t,2H),7.40(t,2H),6.71(d,1H),5.88-5.81(m,1H),5.52(b,1H),3.01(t,2H),2.58(s,3H),2.47(s,3H),1.88-1.83(dd,6H),1.61(d,3H),1.17-1.11(m,1H),0.57(t,2H),0.27(t,2H).
LC-MS m/z=491.3[M+H]
+。
实施例29:目标化合物I-29的制备
合成路线如下所示:
第一步:2-氨基-4-溴-3-氟-5-碘苯甲酸甲酯(B29-2)
化合物2-氨基-4-溴-3-氟-5-碘苯甲酸(B29-1)的合成参考专利CN111499634。将2-氨基-4-溴-3-氟-5-碘苯甲酸(2.0g,5.6mmol)加入到无水二氯甲烷(30mL)中,然后加入甲醇(0.3g,9.4mmol),HATU(2.6g,6.7mmol)和三乙胺(1.7g,16.8mmol),室温搅拌2小时。加入水(20mL)洗涤,二氯甲烷相无水硫酸钠干燥,有机相浓缩。柱层析得产物(B29-2)(2.0g,收率96.2%)。
第二步:2-氨基-4-溴-5-(二甲基磷酰基)-3-氟苯甲酸甲酯(B29-3)
将化合物2-氨基-4-溴-3-氟-5-碘苯甲酸甲酯(2.0g,5.3mmol)溶于DMF(30mL),在氮气保护下加入二甲基氧化膦(620mg,8.0mmol)、三(二亚苄基丙酮)二钯(346mg,0.38mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(438mg,0.76mmol)和三乙胺(1.4g,14.2mmol)。反应液在90℃下搅拌反应24小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物(B29-3)(1.5g,收率86.5%)。
第三步:(7-溴-8-氟-4-羟基-2-甲基喹唑啉-6-基)二甲基氧化磷(B29-4)
将化合物2-氨基-4-溴-5-(二甲基磷酰基)-3-氟苯甲酸甲酯(1.5g,4.6mmol)加入乙腈(20mL)中,加入甲磺酸(10mL),加热至回流状态,反应过夜,反应完毕后冷却至室温。反应液浓缩至干,氢氧化钠水溶液调节pH至6,过滤收集固体,干燥得目标化合物(B29-4)(1.0g,收率64.9%)。
第四步:(R)-(7-溴-8-氟-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化磷(B29-5)
向化合物(7-溴-8-氟-4-羟基-2-甲基喹唑啉-6-基)二甲基氧化磷(1.0g,3.0mmol)的二氯甲烷(20mL)溶液中加入2,4,6-三异丙基苯磺酰氯(1.1g,3.6mmol),4-二甲氨基吡啶(36mg,0.3mmol),三乙胺(0.9g,9.0mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(10mL)、三乙胺(0.9g,9.0mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(0.7g,3.0mmol),然后反应液80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物(R)-(7-溴-8-氟-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化磷(300mg,收率19.3%)。
第五步:(R)-(7-(乙基氨基)-8-氟-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化磷(I-29)
将化合物(R)-(7-溴-8-氟-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化磷(207mg,0.4mmol)溶于1,4-二氧六环(2mL)和甲苯(2mL),在氮气保护下加入乙胺四氢呋喃溶液(94mg,0.8mmol)、碘化亚铜(7.6mg,0.04mmol)、L-脯氨酸(9.2mg,0.08mmol)和碳酸铯(261mg,0.8mmol)。反应液在90℃下搅拌反应12小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物I-29(59.0mg,收率30.6%)。
1H NMR(400MHz,DMSO)δ8.35(d,1H),8.01(d,1H),7.73(t,1H),7.69(d,1H),7.52(d,1H),7.34(t,1H),5.71-5.66(m,1H),3.39(q,2H),2.58(s,3H),2.26(s,3H),1.85(d,6H),1.53(d,3H),1.13(t,3H).
LC-MS m/z=483.3[M+H]
+。
实施例30:化合物I-30的合成
合成路线如下所示:
第一步:(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-氟-2-甲基喹唑啉-4-胺(B30-1)的合成
在单口瓶中加入化合物6-溴-4-氯-7-氟-2-甲基喹唑啉(1.0g,3.68mmol),(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺盐酸盐(0.69g,3.68mmol),N,N-2-异丙基乙胺(1.64g,12.7mmol),加入乙醇(10mL),100℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=5:1)得(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-氟-2-甲基喹唑啉-4-胺(B30-1)黄色固体(1.1g,收率70.8%)。
第二步:(R)-6-溴-N
4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N
7-乙基-2-甲基喹唑啉-4,7-二胺(B30-2)的合成
在封管中加入化合物(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-氟-2-甲基喹唑啉-4-胺(0.5g,1.2mmol),乙胺/四氢呋喃溶液(2M,3mL),加入N,N-2-甲基乙酰胺(5mL),160℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得(R)-6-溴-N
4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N
7-乙基-2-甲基喹唑啉-4,7-二胺(B30-2)浅黄色油状物(0.3g,收率56.7%)。
第三步:(R)-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-(乙基氨基)-2-甲基喹唑啉-6-基)二甲基氧化磷(I-30)的合成
在单口瓶中,加入化合物(R)-6-溴-N
4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N
7-乙基-2-甲基喹唑啉-4,7-二胺(0.3g,0.66mmol),二甲基氧化膦(0.26g,3.3mmol),三(二亚苄基丙酮)二钯(0.09g,0.1mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.12g,0.20mmol),三乙胺(0.20g,3.97mmol),加入N,N-2-甲基乙酰胺(5mL),140℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得(R)-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-(乙基氨基)-2-甲基喹唑啉-6-基)二甲基氧化磷(I-30)白色固体(31mg,收率10.4%)。
1H NMR(400m Hz,DMSO-d6)δ8.22-8.19(m,2H),7.94(t,1H),7.63(t,1H),7.47(t,1H),7.34(s,0.25H),7.27(t,1H),7.21(s,0.5H),7.07(s,0.25H),6.44(d,1H),5.78-5.75(m,1H),3.13-3.08(m,2H),2.24(s,3H),1.83(d,6H),1.58(d,3H),1.21-1.16(m,3H)。
LC-MS m/z=451.18[M+H]
+。
实施例31:化合物I-31的合成
合成路线如下所示:
第一步:(R)-6-溴-7-氟-N-(1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)-2-甲基喹唑啉-4-胺(B31-1)的合成
在单口瓶中加入化合物6-溴-4-氯-7-氟-2-甲基喹唑啉(1.0g,3.68mmol),(R)-1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙-1-胺盐酸盐(1.1g,3.68mmol),N,N-2-异丙基乙胺(1.64g,12.7mmol),加入乙醇(10mL),100℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=5:1)得(R)-6-溴-7-氟-N-(1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)-2-甲基喹唑啉-4-胺(B31-1)黄色固体(1.0g,收54.0%)。
第二步:(R)-6-溴-N
7-乙基-N
4-(1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)-2-甲基喹唑啉-4,7-二胺(B31-2)的合成
在封管中加入化合物(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-氟-2-甲基喹唑啉-4-胺(0.61g,1.2mmol),乙胺/四氢呋喃溶液(2M,3mL),加入N,N-2-甲基乙酰胺(5mL),160℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得浅黄色油状物(R)-6-溴-N
7-乙基-N
4-(1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)-2-甲基喹唑啉-4,7-二胺(0.35g,收率56.7%)。
第三步:(R)-(7-(乙基氨基)-4-((1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(I-31)的合成
在单口瓶中加入化合物(R)-6-溴-N
7-乙基-N
4-(1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)-2-甲基喹唑啉-4,7-二胺(0.35g,0.66mmol),二甲基氧化膦(0.26g,3.3mmol),三(二亚苄基丙酮)二钯(0.09g,0.1mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.12g,0.20mmol),三乙胺(0.20g,3.97mmol),加入N,N-2-甲基乙酰胺(5mL),140℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得(R)-(7-(乙基氨基)-4-((1-(2-氟-3-((三氟甲基)磺酰基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(I-31)白色固体(20mg,收率5.7%)。
1H NMR(400m Hz,DMSO-d6)δ8.29(d,1H),8.19(d,1H),8.06(t,1H),7.94(t,2H),7.56(t,1H),6.44(d,1H),5.66-5.59(m,1H),3.11-3.08(m,2H),2.17(s,3H),1.83(d,6H),1.61(d,3H),1.21-1.16(m,3H)。
LC-MS,M/Z(ESI):533.13[M+H]
+。
实施例32:化合物I-32的合成
合成路线如下所示:
第一步:(R)-6-溴-7-氟-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B32-1)的合成
在单口瓶中加入化合物6-溴-4-氯-7-氟-2-甲基喹唑啉(1.0g,3.68mmol),(R)-1-(2-甲基-3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(883mg,3.68mmol),N,N-2-异丙基乙胺(1.64g,12.7mmol),加入乙醇(10mL),100℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=5:1)得(R)-6-溴-7-氟-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B32-1)黄色固体(976mg,收率60.0%)。
第二步:(R)-7-(氮杂环丁烷-1-基)-6-溴-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B32-2)的合成
在封管中加入化合物(R)-6-溴-7-氟-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(0.5g,1.1mmol),环丁胺盐酸盐(0.32g,3.39mol),碳酸铯(1.5g,4.52mmol),加入N,N-2-甲基乙酰胺(5mL),160℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得(R)-7-(氮杂环丁烷-1-基)-6-溴-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B32-2)浅黄色油状物(0.3g,收率55.4%)。
第三步:(R)-(7-(氮杂环丁烷-1-基)-2-甲基-4-(((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-32)的合成
在单口瓶中加入化合物(R)-6-溴-N4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N7-乙基-2-甲基喹唑啉-4,7-二胺(0.3g,0.63mmol),二甲基氧化膦(0.24g,3.1mmol),三(二亚苄基丙酮)二钯(0.09g,0.1mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.11g,0.19mmol),三乙胺(0.38g,3.76mmol),加入N,N-2-甲基乙酰胺(5mL),140℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得(R)-(7-(氮杂环丁烷-1-基)-2-甲基-4-(((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-32)白色固体(30mg,收率10.1%)。
1H NMR(400m Hz,DMSO-d6)δ8.23-8.20(m,2H),7.75(d,1H),7.49(d,1H),7.36-7.31(m,1H),6.64-6.60(m,1H),5.68-5.64(m,1H),4.19(t,4H),2.59(s,3H),2.25-2.21(m,5H),1.79-1.71(m,6H),1.49(d,3H)。
LC-MS m/z=477.20[M+H]
+。
实施例33:目标化合物I-33的制备
合成路线如下所示:
第一步:6-溴-7-(异丙基氨基)-2-甲基喹唑啉-4(3H)-酮(B33-2)的合成
将化合物6-溴-7-氟-2-甲基喹唑啉-4(3H)-酮(2.57g,10.0mmol)加入二甲基乙酰胺(50mL)中,加入碳酸铯(10.0g,30.7mmol),加入异丙胺(3mL),在闷罐中加热至160℃,保持温度反应24小时,降至室温,直接制备色谱分离得产物B33-2(2.0g,收率67.5%)。
第二步:(R)-6-溴-N
4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N
7-异丙基-2-甲基喹唑啉-4,7-二胺(B33-3)
向化合物6-溴-7-(异丙胺)-2-甲基喹唑啉-4(3H)-酮(2.0g,6.8mmol)的二氯甲烷(30mL)溶液中加入2,4,6-三异丙基苯磺酰氯(2.26mg,7.4mmol),4-二甲氨基吡啶(12mg,0.1mmol), 三乙胺(4.1mL,29.7mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(20mL)、三乙胺(4.1mL,29.7mmol)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺盐酸盐(1.5g,6.8mmol),然后反应液80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物(R)-6-溴-N
4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N
7-异丙基-2-甲基喹唑啉-4,7-二胺(1.0g,收率31.7%)。
第三步:(R)-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-(异丙基氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(I-33)
将化合物(R)-6-溴-N4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N7-异丙基-2-甲基喹唑啉-4,7-二胺(1.0g,2.1mmol)溶于DMF(10mL),在氮气保护下加入二甲基氧化膦(250mg,3.2mmol)、三(二亚苄基丙酮)二钯(153mg,0.17mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(194mg,0.34mmol)和三乙胺(0.7g,7.1mmol)。反应液在120℃下搅拌反应24小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物I-33(500mg,收率50.3%)。
1H NMR(400MHz,DMSO)δ8.15(d,1H),8.06(d,1H),7.93(d,1H),7.60(t,1H),7.47(t,1H),7.35-7.07(m,2H),6.45(d,1H),5.79-5.72(m,1H),3.65-3.57(m,1H),2.22(s,3H),1.82(dd,6H),1.57(d,3H),1.15(dd,6H).
LC-MS m/z=465.2[M+H]
+。
实施例34:目标化合物I-34的制备
合成路线如下所示:
合成方法参考化合物I-30,将(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺盐酸盐替换为(R)-1-(3-(三氟甲基)-2-氟苯基)乙-1-胺盐酸盐。
LC-MS m/z=469.20[M+H]
+。
实施例35:目标化合物I-35的制备
合成路线如下所示:
第一步:7-溴-6-碘喹唑啉-4(3H)-酮(B35-1)的合成
在室温下,将2-氨基-4-溴-5-碘苯甲酸(1.00g,2.92mmol)加入到甲酰胺(4.00mL)中,混合物在125度下搅拌12小时,反应完成后过滤,滤饼用乙醇洗涤,之后将滤饼干燥得到黄色固体化合物7-溴-6-碘喹唑啉-4(3H)-酮(B35-1)(772mg,收率75.2%)。
LC-MS,M/Z(ESI):350.7[M+H]
+。
第二步:(R)-7-溴-6-碘-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B35-2)的合成
在室温下,将7-溴-6-碘喹唑啉-4(3H)-酮(622mg,1.77mmol),DBU(337mg,2.21mmol)和三吡咯烷基溴化鏻六氟磷酸盐(894.72mg,1.92mmol)加入到乙腈(9.00mL)中,混合液在室温下搅拌2个小时,然后向其中加入(R)-1-(2-甲基-3-(三氟甲基)苯基)乙胺(300mg,1.48mmol),混合液在室温下搅拌12小时,反应完成后,直接将反应液浓缩得到粗品,再将粗品通过层析硅胶板(二氧化硅,石油醚:乙酸乙酯=3:1)制备得到黄色油状化合物(R)-7-溴-6-碘-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(B35-2)(183mg,收率23.1%)。
LC-MS,M/Z(ESI):537.9[M+H]
+。
第三步:(R)-(7-溴-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(B35-3)的合成
在室温下,将(R)-7-溴-6-碘-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(180mg,336μmol),二甲基氧化膦(31.5mg,403μmol),醋酸钯(7.54mg,33.6μmol),4,5-双(二苯基 磷)-9,9-二甲基氧杂蒽(23.3mg,40.3μmol)和磷酸钾(78.4mg,370μmol)加入到二氧六环(1.00mL)中,混合液在60度下搅拌12小时,反应完成后,向反应液中加入水,之后用乙酸乙酯萃取,有机相用饱和食盐水洗涤和无水硫酸钠干燥后,然后过滤,滤饼用乙酸乙酯洗涤,将滤液浓缩得到粗品。粗品经层析硅胶板(二氧化硅,乙酸乙酯:甲醇=10:1)制备得到白色固体化合物(R)-(7-溴-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(B35-3)(68.0mg,收率41.7%)。
LC-MS,M/Z(ESI):488.0[M+H]
+。
第四步:(R)-(7-(乙胺基)-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基膦氧化(I-35)的合成
在室温下,将(R)-(7-溴-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(40.0mg,82.3μmol),乙胺(11.1mg,2467μmol),碘化亚铜(7.83mg,41.1μmol),碳酸钾(34.1mg,247μmol)和L-脯氨酸(4.74mg,41.1μmol)加入到N,N-二甲基甲酰胺(1.00mL)中,混合液在85度下搅拌2小时,反应完成后,向反应液中加入水,之后用乙酸乙酯萃取,有机相用饱和食盐水洗涤和无水硫酸钠干燥后,然后过滤,滤饼用乙酸乙酯洗涤,将滤液浓缩得到粗品。粗品经反相制备(column:Phenomenex Synergi C18 150*25mm*10um;移动相:[水(0.225%甲酸)-乙腈];B%:33%-63%,9min)分离得到白色固体化合物(R)-(7-(乙胺基)-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基膦氧化(I-35)(8.20mg,收率21.5%)。
1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.5-7.7(m,4H),7.30(s,1H),6.76(d,1H),5.89(br t,1H),3.19(dd,2H),2.54(s,3H),1.89(dd,6H),1.68(d,3H),1.31(t,3H)
LC-MS m/z=451.1[M+H]
+。
实施例36:目标化合物I-36的制备
合成路线如下所示:
合成方法参考化合物I-27第三步,将氨基甲酸叔丁酯替换为4,4,4-三氟丁-2-胺盐酸盐。
1H NMR(400MHz,DMSO-d6)δ8.19(d,1H),8.12(d,1H),8.05(dd,1H),7.60(q,1H),7.47(t,1H),7.35-7.08(m,2H),6.50(d,1H),5.77-5.73(m,1H),3.92-3.86(m,1H),2.23(d,3H),1.89-1.75(m,6H),1.57(d,3H),1.27-1.21(m,5H).
LC-MS m/z=533.2[M+H]
+。
实施例37:目标化合物I-37的制备
合成路线如下所示:
将化合物(R)-(6-(二甲基膦酰基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-7-基)氨基(100mg,0.23mmol)溶于二氯甲烷(5mL)中,加入三乙胺(70mg,0.69mmol),降温至0℃,然后滴加氯甲酸甲酯(26mg,0.28mmol),升温至室温搅拌1小时,浓缩至干。制备色谱分离得产物I-37(38mg,收率33.5%)。
1H NMR(400MHz,DMSO)δ11.53(s,1H),8.47(d,1H),8.28(d,1H),7.72(d,1H),7.53(d,1H),7.35(t,1H),5.70(t,1H),3.68(s,3H),2.59(s,3H),2.30(s,3H),1.90(dd,6H),1.56(d,3H).
LC-MS m/z=495.1[M+H]
+。
实施例38:目标化合物I-38的制备
合成路线如下所示:
第一步:(R)-7-溴-6-碘-2-甲基-N-(1-(3-(五氟-λ
6-硫烷基)苯基)乙基)喹唑啉-4-胺
向化合物7-溴-6-碘-2-甲基喹唑啉-4(3H)-酮(365mg,1.0mmol)的二氯甲烷(8mL)溶液中加入2,4,6-三异丙基苯磺酰氯(363mg,1.2mmol),4-二甲氨基吡啶(12mg,0.1mmol),三乙胺(303mg,3.0mmol)。然后反应液室温反应过夜。将反应液减压浓缩得到粗品,向粗品中加入DMSO(4mL)、三乙胺(303mg,3.0mmol)和(R)-1-(3-(五氟-λ
6-硫烷基)苯基)乙-1-胺盐酸盐(284mg,1.0mmol),然后反应液80℃反应过夜。反应液冷却至室温。向反应液中加入水,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品经柱层析分离纯化,得到化合物(R)-7-溴-6-碘-2-甲基-N-(1-(3-(五氟-λ
6-硫烷基)苯基)乙基)喹唑啉-4-胺(200mg,收率33.7%)。
第二步:(R)-(7-溴-2-甲基-4-((1-(3-(五氟-λ
6-硫烷基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(B38-2)
将化合物(R)-7-溴-6-碘-2-甲基-N-(1-(3-(五氟-λ
6-硫烷基)苯基)乙基)喹唑啉-4-胺(200mg,0.34mmol)溶于DMF(3mL),在氮气保护下加入二甲基氧化膦(39.4mg,0.5mmol)、三(二亚苄基丙酮)二钯(25mg,0.03mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(43mg,0.08mmol)和三乙胺(140mg,1.4mmol)。反应液在90℃下搅拌反应24小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物B38-2(100mg,收率54.6%)。
第三步:(R)-(7-(乙基氨基)-2-甲基-4-((1-(3-(五氟-λ
6-硫烷基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(B38-3)
将化合物(R)-(7-溴-2-甲基-4-((1-(3-(五氟-λ
6-硫烷基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(100mg,0.18mmol)溶于1,4-二氧六环(2mL)和甲苯(2mL),在氮气保护下加入乙胺四氢呋喃溶液(94mg,0.8mmol)、醋酸钯(3.3mg,0.02mmol)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(17mg,0.03mmol)和碳酸铯(180mg,0.55mmol)。反应液在90℃下搅拌反应12小时。反应完全后,反应液直接浓缩得到粗品。粗品经制备色谱分离纯化,得到目标化合物I-38(16mg,收率17.13%)。
1H NMR(400MHz,DMSO)δ8.14(s,1H),8.09(t,1H),7.93(s,1H),7.87(t,1H),7.74-7.68(d,2H),7.55(t,1H),6.44(d,1H),5.63-5.56(m,1H),3.13-3.06(m,2H),2.25(s,3H),1.80(dd,6H),1.60(d,3H),1.18(t,3H).
LC-MS m/z=509.3[M+H]
+。
实施例39:化合物I-39的合成
合成路线如下所示:
第一步:(R)-6-溴-N7-乙基-2-甲基-N4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺(B39-1)的合成
在封管中加入化合物(R)-6-溴-7-氟-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(0.5g,1.1mmol),乙胺四氢呋喃溶液(2M,2mL),加入N,N-2-甲基乙酰胺(5mL),160℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得(R)-6-溴-N
7-乙基-2-甲基-N
4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺(B39-1)浅黄色油状物(0.3g,收率56.6%)。
LC-MS,M/Z(ESI):467.10[M+H]
+。
第二步:(R)-二乙基(7-(乙基氨基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧化膦(I-39)的合成
在单口瓶中加入化合物(R)-6-溴-N
7-乙基-2-甲基-N4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺(0.3g,0.64mmol),二乙基氧化膦(0.14g,1.3mmol),三(二亚苄基丙酮)二钯(0.12g,0.13mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.15g,0.26mmol),三乙胺(0.39g,3.9mmol),加入N,N-2-甲基乙酰胺(5mL),140℃搅拌反应20h。浓缩,残留物 用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得(R)-二乙基(7-(乙基氨基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧化膦(I-39)白色固体(80mg,收率25.3%)。
1H NMR(400m Hz,DMSO-d6)δ8.16(d,1H),8.08-8.05(m,2H),7.68(d,1H),7.51(d,1H),7.33(t,1H),6.41(d,1H),5.69-5.65(m,1H),3.09-3.06(m,2H),2.58(s,3H),2.21(s,3H),2.08-2.03(m,4H),1.52(d,3H),1.16(t,3H),1.06-1.00(m,6H)。
LC-MS m/z=493.23[M+H]
+。
实施例40:目标化合物I-40的制备
合成路线如下所示:
第一步:(2E)-N-(3-溴-2-氯苯基)-2-(肟基)乙酰胺(B40-2)的合成
在25℃下,向3-溴-2-氯苯胺(20.0g,96.8mmol),2,2,2-三氯乙烷-1,1-二醇(19.2g,116mmol,15.1mL)和硫酸钠(89.4g,629mmol)的水(600mL)溶液中加入羟胺盐酸盐(24.9g,358mmol),反应液在50℃下搅拌12小时。反应完成后,将反应液过滤得到黄色固体,固体干燥后悬浮在二氯甲烷(500mL)中搅拌0.5小时候过滤得到白色固体(E)-N-(3-溴-2-氯苯基)-2-(肟基)乙酰胺(B40-2)(24.0g,收率89.2%)。
第二步:6-溴-7-氯二氢吲哚-2,3-二酮(B40-3)的合成
在室温下,将(E)-N-(3-溴-2-氯苯基)-2-(肟基)乙酰胺(14.0g,50.4mmol)加入到浓硫酸(60.0mL)中,反应液在80度搅拌1小时。反应完成后,将反应液缓慢倒入冰水中,然后过滤将固体干燥得到白色固体6-溴-7-氯二氢吲哚-2,3-二酮(B40-3)(12.0g,粗品)。
第三步:2-氨基-4-溴-3-氯苯甲酸(B40-4)的合成
在0℃下,向6-溴-7-氯二氢吲哚-2,3-二酮(12.0g,46.0mmol)和氢氧化钠(11.0g,276mmol)的水(120mL)溶液中缓慢滴加双氧水(15.6g,138mmol,13.2mL,30%purity),反应液在25℃搅拌12小时。反应完成后,将反应液pH调节至4后用加入亚硫酸钠水溶液,过滤得到白色固体2-氨基-4-溴-3-氯苯甲酸(B40-4)(10.5g,粗品)。
第四步:2-氨基-4-溴-3-氯-5-碘苯甲酸(B40-5)的合成
在25℃下,向2-氨基-4-溴-3-氯苯甲酸(1.30g,5.19mmol)的N,N-二甲基甲酰胺(15.0mL)溶液中加入碘代丁二酰亚胺(1.75g,7.79mmol),反应液在70℃搅拌12小时。反应完成后,反应完成后,将反应液缓慢倒入冰水中,然后过滤将固体干燥得到白色固体2-氨基-4-溴-3-氯-5-碘苯甲酸(B40-5)(2.10g,粗品)。
第五步:7-溴-8-氯-6-碘-2-甲基喹唑啉-4(3H)-酮(B40-6)的合成
将2-氨基-4-溴-3-氯-5-碘苯甲酸(2.00g,5.31mmol)溶解在乙酸酐(20.0mL)中,反应液在140℃下搅拌12小时后过滤得到黄色固体,将固体悬浮在乙醇(5.00mL)和氨水(20.0mL)中,混合液在80℃下搅拌5小时。反应完成后,将反应液过滤得到白色固体7-溴-8-氯-6-碘-2-甲基喹唑啉-4(3H)-酮(B40-6)(2.40g,粗品)。
第六步:7-溴-8-氯-6-碘-2-甲基喹唑啉-4-基2,4,6-三异丙基苯磺酸酯(B40-7)的合成
在25℃下,向7-溴-8-氯-6-碘-2-甲基喹唑啉-4(3H)-酮(300mg,751μmol),4-二甲氨基吡啶(9.18mg,75.1μmol)和三乙胺(228mg,2.25mmol,313μL)的二氯甲烷(5.00mL)溶液中加入2,4,6-三异丙基苯磺酰氯(295mg,976μmol),反应液在25℃下搅拌2小时。反应完成后,将反应液浓缩的到粗品,粗品通过层析硅胶板(二氧化硅,石油醚:乙酸乙酯=5:1)纯化得到白色固体7-溴-8-氯-6-碘-2-甲基喹唑啉-4-基2,4,6-三异丙基苯磺酸酯(B40- 7)(330mg,粗品)。
第七步:(R)-7-溴-8-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-碘-2-甲基喹唑啉-4-胺(B40-8)的合成
在25℃下,向7-溴-8-氯-6-碘-2-甲基喹唑啉-4-基2,4,6-三异丙基苯磺酸酯(330mg,495μmol)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺盐酸盐(167mg,743μmol)的二甲基亚砜(5.00mL)溶液中加入三乙胺(250mg,2.48mmol),反应液在90℃下搅拌12小时。反应完成后,向反应液中加入冰水(50.0mL),混合液用乙酸乙酯(20.0mL)萃取,有机相用饱和氯化钠水溶液(20.0mL)洗涤,无水硫酸钠干燥后过滤浓缩得到粗品,粗品用层析硅胶板(二氧化硅,石油醚:乙酸乙酯=5:1)纯化得到白色固体(R)-7-溴-8-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-碘-2-甲基喹唑啉-4-胺(B40-8)(150mg,收率41.2%)。
LC-MS m/z=571.2[M+H]
+。
第八步:(R)-(7-溴-8-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(B40-9)的合成
在25℃下,向(R)-7-溴-8-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-碘-2-甲基喹唑啉-4-胺(100mg,175μmol),醋酸钯(3.93mg,17.5μmol)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(10.1mg,17.5μmol)的N,N-二甲基甲酰胺(1.00mL)溶液中加入二甲基氧化膦(20.5mg,262μmol)和磷酸钾(37.2mg,175μmol),反应液在70℃搅拌4小时。反应完成后,向反应液中加入冰水(50.0mL),混合液用乙酸乙酯(20.0mL)萃取,有机相用饱和氯化钠水溶 液(20.0mL)洗涤,无水硫酸钠干燥后过滤浓缩得到粗品,粗品用层析硅胶板(二氧化硅,乙酸乙酯:甲醇=5:1)纯化得到白色固体(R)-(7-溴-8-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(B40-9)(238mg,收率65.2%)。
第九步:(R)-(8-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-(乙胺基)-2-甲基喹唑啉-6-基)二甲基氧化膦(I-40)的合成
在25℃下,向(R)-(7-溴-8-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(50.0mg,96.0μmol),(2S)-吡咯烷-2-羧酸(5.53mg,48.0μmol)和乙胺(12.9mg,288μmol)的N,N-二甲基甲酰胺(2.00mL)溶液中加入碘化亚铜(9.14mg,48.0μmol)和碳酸钾(39.8mg,288μmol),反应液在80℃搅拌4小时。反应完成后,向反应液中加入冰水(50.0mL),混合液用乙酸乙酯(20.0mL)萃取,有机相用饱和氯化钠水溶液(20.0mL)洗涤,无水硫酸钠干燥后过滤浓缩得到粗品,粗品用高效液相色谱法进行分离,分离方法为(柱子:Waters Xbridge 150*25mm*5um;溶剂:[水(0.05%氨水v/v)-乙腈];B%:33%-63%,9分钟)得到白色固体(R)-(8-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-(乙胺基)-2-甲基喹唑啉-6-基)二甲基氧化膦(I-40)(33.0mg,收率17.5%)。
1H NMR(400MHz,DMSO-d6):δppm 8.38(d,1H)8.21(d,1H)7.78(t,1H)7.64(br t,1H)7.50(br t,1H)7.08-7.42(m,2H)5.72-5.85(m,1H)3.48-3.59(m,2H)2.33(s,3H)1.90(d,6H)1.61(d,3H)1.15(t,3H)
LC-MS m/z=485.1[M+H]
+。
实施例41:目标化合物I-41的制备
合成路线如下所示:
I-41的合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为5-(三氟甲基)吡啶-2-胺。
1H NMR(400MHz,DMSO)δ11.80(s,1H),8.80(d,1H),8.66(s,1H),8.46(d,1H),8.37(d,1H),7.96(d,1H),7.65(t,1H),7.49(t,1H),7.36-7.09(m,2H),6.89(d,1H),5.80-5.76(m,1H),2.31(s,3H),1.96(dd,6H),1.61(d,3H).
LC-MS m/z=568.2[M+H]
+。
实施例42:目标化合物I-42的制备
合成路线如下所示:
化合物I-42的合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为5-氟吡啶-2-胺。
1H NMR(400MHz,DMSO)δ11.37(s,1H),8.64(d,1H),8.40(d,1H),8.31-8.28(m,2H),7.66-7.62(m,2H),7.49(t,1H),7.36-7.08(m,2H),6.83(dd,1H),5.80-5.76(m,1H),2.28(s,3H),1.94(dd,6H),1.60(d,3H).
LC-MS m/z=518.1[M+H]
+。
实施例43:目标化合物I-43的制备
合成路线如下所示:
I-43的合成方法参考I-32,将环丁胺盐酸盐替换为三氘代甲氨盐酸盐。
1H NMR(400MHz,DMSO)δ8.17(d,1H),8.09(d,1H),7.80(s,1H),7.62(t,1H),7.47(t,1H),7.35-7.07(m,2H),6.43(d,1H),5.79-5.72(m,1H),2.22(s,3H),1.83(dd,6H),1.57(d,3H).
LC-MS m/z=440.2[M+H]
+。
实施例44:目标化合物I-44的制备
合成路线如下所示:
I-44的合成方法参考I-27,第三步将氮碳酸叔丁酯替换为环丙甲酰胺。
1H NMR(400MHz,DMSO)δ12.24(s,1H),8.56(d,1H),8.46(d,1H),8.38(d,1H),7.64(t,1H),7.49(t,1H),7.35-7.08(m,2H),5.78-5.73(m,1H),2.29(s,3H),1.94(dd,6H),1.61(d,3H),1.53-1.49(m,1H),0.86(t,4H).
LC-MS m/z=491.2[M+H]
+。
实施例45:目标化合物I-45的制备
合成路线如下所示:
I-45的合成方法参考I-37,将氯甲酸甲酯替换为氯甲酸-2,2-二氟乙基酯。
1H NMR(400MHz,DMSO)δ11.75(s,1H),8.47(d,1H),8.41(d,1H),8.28(d,1H),7.64(t,1H),7.49(t,1H),7.35-7.08(m,2H),6.43-6.15(m,1H),5.79-5.75(m,1H),4.44-4.36(m,2H),2.31(s,3H),1.93(dd,6H),1.61(d,3H).
LC-MS m/z=531.2[M+H]
+。
实施例46:目标化合物I-46的制备
合成路线如下所示:
I-46的合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为1-(三氟甲氧基)丙-2-胺盐酸盐。
LC-MS m/z=549.2[M+H]
+。
实施例47:目标化合物I-47的制备
合成路线如下所示:
I-47合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为3,3-二氟环丁烷-1-胺盐酸 盐。
1H NMR(400MHz,DMSO)δ8.34(d,1H),8.23(d,1H),8.15(d,1H),7.61(t,1H),7.47(t,1H),7.35-7.07(m,2H),6.37(d,1H),5.79-5.72(m,1H),3.86-3.83(m,1H),3.20-3.10(m,2H),2.40-2.34(m,2H),2.23(s,3H),1.85(dd,6H),1.57(d,3H).
LC-MS m/z=513.2[M+H]
+。
实施例48:目标化合物I-48的制备
合成路线如下所示:
I-48的合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为环戊胺。
1H NMR(400MHz,DMSO)δ8.17(d,1H),8.12(d,1H),8.04(d,1H),7.61(t,1H),7.47(t,1H),7.35-7.07(m,2H),6.46(d,1H),5.79-5.72(m,1H),3.79-3.75(m,1H),2.22(s,3H),1.96-1.94(m,2H),1.82(dd,6H),1.63-1.58(m,7H),1.43-1.40(m,2H).
LC-MS m/z=491.2[M+H]
+。
实施例49:目标化合物I-49的制备
合成路线如下所示:
I-49的合成方法参考I-24,将氨基甲酸叔丁酯替换为1-甲基-1H-吡唑-5-胺。
1H NMR(400MHz,DMSO)δ10.24(s,1H),8.40-8.36(m,2H),7.71(d,1H),7.52(d,1H),7.42(d,1H),7.35(t,1H),6.64(d,1H),6.16(d,1H),5.72-5.65(m,1H),3.62(s,3H),2.58 (s,3H),2.22(s,3H),1.95(dd,6H),1.55(d,3H).
LC-MS m/z=517.2[M+H]
+。
实施例50:目标化合物I-50的制备
合成路线如下所示:
I-50的合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为1-甲基-1H-吡唑-5-胺。
1H NMR(400MHz,DMSO)δ10.25(s,1H),8.39(d,1H),8.29(d,1H),7.63(t,1H),7.48(t,1H),7.42(d,1H),7.35-7.08(m,2H),6.65(d,1H),6.16(d,1H),5.79-5.72(m,1H),3.63(s,3H),2.23(s,3H),1.94(dd,6H),1.60(d,3H).
LC-MS m/z=503.2[M+H]
+。
实施例51:目标化合物I-51的制备
合成路线如下所示:
I-51的合成方法参考I-30,将二甲基氧化膦替换为二乙基氧化膦。
1H NMR(400MHz,DMSO)δ8.20-8.06(m,3H),7.59(t,1H),7.47(t,1H),7.29-7.07(m,2H),6.43(d,1H),5.79-5.72(m,1H),3.12-3.05(m,2H),2.21(s,3H),2.08-2.03(m,4H),1.57(d,3H),1.17(t,3H),1.09-1.00(m,6H).
LC-MS m/z=479.2[M+H]
+。
实施例52:目标化合物I-52的制备
合成路线如下所示:
I-52的合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为环己胺。
1H NMR(400MHz,DMSO)δ8.15(d,1H),8.07-8.02(m,2H),7.60(t,1H),7.47(t,1H),7.34-7.07(m,2H),6.46(d,1H),5.79-5.72(m,1H),3.10-2.90(m,1H),2.21(s,3H),1.92-1.88(m,2H),1.82(dd,6H),1.67-1.64(m,2H),1.57-1.53(m,4H),1.41-1.33(m,2H),1.25-1.21(m,3H)。
LC-MS m/z=505.2[M+H]
+。
实施例53:目标化合物I-53的制备
合成路线如下所示:
I-53的合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为(1r,4r)-4-甲氧基环己-1-胺。
1H NMR(400MHz,DMSO)δ8.15(d,1H),8.07(d,1H),8.01(d,1H),7.60(t,1H),7.47(t,1H),7.34-7.07(m,2H),6.48(d,1H),5.79-5.72(m,1H),3.22(s,3H),3.18-3.16(m,2H),2.21(s,3H),2.01-1.91(m,4H),1.82(dd,6H),1.57(d,3H),1.37-1.29(q,2H),1.25-1.18(m,2H).
LC-MS m/z=535.2[M+H]
+。
实施例54:目标化合物I-54的制备
合成路线如下所示:
合成方法参考I-51,将乙胺替换为3,3-二氟环丁烷-1-胺盐酸盐。
1H NMR(400MHz,DMSO)δ8.55(d,1H),8.14(t,2H),7.59(t,1H),7.47(t,1H),7.34-7.07(m,2H),6.36(d,1H),5.78-5.71(m,1H),3.85-3.81(m,1H),3.18-3.09(m,2H),2.36-2.31(m,2H),2.23(s,3H),2.18-1.97(m,4H),1.58(d,3H),1.10-1.00(m,6H).
LC-MS m/z=541.2[M+H]
+。
实施例55:目标化合物I-55的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为环丁胺。
1H NMR(400m Hz,DMSO-d6)δ8.13-8.21(m,3H),7.61(t,1H),7.47(t,1H),7.21-7.34(m,2H),7.07(t,1H),6.32(s,1H),5.75(t,1H),3.87(m,3H),2.40-2.48(m,3H),2.22(s,3H),1.77-1.84(m,6H),1.56(d,3H).
LC-MS m/z=477.3[M+H]
+。
实施例56:目标化合物I-56的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为(1r,3r)-3-氟环丁烷-1-胺。
1H NMR(400m Hz,DMSO-d6)δ8.23(s,1H),8.11-8.19(m,1H),7.60(t,1H),7.49(t,1H),7.30-7.32(m,2H),7.25(t,1H),6.25(s,1H),5.75-5.78(m,1H),5.18-5.32(m,1H),4.04(s,1H),2.62-2.65(m,2H),2.22(s,3H),1.82(d,6H),1.56(d,3H).
LC-MS m/z=495.3[M+H]
+。
实施例57:目标化合物I-57的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为(1s,3s)-3-氟环丁烷-1-胺。
1H NMR(400m Hz,DMSO-d6)δ8.23(d,1H),8.11-8.18(m,1H),7.60(t,1H),7.49(t,1H),7.30-7.32(m,2H),7.25(t,1H),6.25(s,1H),5.75-5.78(m,1H),5.18-5.32(m,1H),4.04(s,1H),2.62-2.65(m,2H),2.22(s,3H),1.82(d,6H),1.56(d,3H).
LC-MS m/z=495.3[M+H]
+。
实施例58:目标化合物I-58的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为丁基-2-胺。
1H NMR(400MHz,DMSO-d6)δ8.15(d,1H),8.07(d,1H),7.92(d,1H),7.60(t,1H),7.47(t,1H),7.34-7.07(m,2H),6.44(d,1H),5.78-5.71(m,1H),3.44-3.40(m,1H),2.21(s,3H),1.82(dd,6H),1.57(d,3H),1.53-1.47(m,2H),1.12(t,3H),0.90(q,3H).
LC-MS m/z=479.2[M+H]
+。
实施例59:化合物I-59的制备
合成路线如下所示:
第一步:(R)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-7-氟-2-甲基喹唑啉-4-胺(B59-1)
化合物6-溴-4-氯-7-氟-2-甲基喹唑啉(0.87g,3.17mmol),(R)-1-(3-(二氟甲基)-2-甲基苯基)乙烷-1-胺盐酸盐(0.7g,3.17mmol),三乙胺(3.21g,31.7mmol),加入乙醇(10mL),100℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化,得到目标化合物B59-1(1.0g,产率74.6%)。
第二步:(R)-6-溴-N4-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-N7-异丙基-2-甲基喹唑啉-4,7-二胺(B59-2)
往封管加入化合物(R)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-7-氟-2-甲基喹唑啉-4-胺(1.0g,2.4mmol),异丙胺四氢呋喃溶液(2M,2mL),加入N,N-2-甲基乙酰胺(10mL),160℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化,得到目标化合物B59-2(0.5g,产率45.9%)。
第三步:(R)-(4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-7-(异丙基氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(I-59)
单口瓶中加入化合物(R)-6-溴-N4-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-N7-异丙基-2-甲基喹唑啉-4,7-二胺(0.5g,1.08mmol),二甲基氧化膦(0.25g,3.2mmol),三(二亚苄基丙酮)二钯(0.10g,0.11mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.13g,0.22mmol),三乙胺(0.44g,4.32mmol),加入N,N-二甲基乙酰胺(5mL),140℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化,得到目标化合物(170mg,产率34.2%)。
1H NMR(400m Hz,DMSO-d6)δ8.16-8.10(m,2H),7.90(d,1H),7.59(d,1H),7.37- 7.27(m,2H),7.26(s,0.25H),7.15(s,0.5H),7.04(s,0.25H),6.44(d,1H),5.74-5.70(m,1H),3.61-3.56(m,1H),2.51-2.48(m,3H),2.24(s,3H),1.82(d,6H),1.50(d,3H),1.14(t,6H)。
LC-MS m/z=461.22[M+H]
+。
实施例60:化合物I-60的制备
合成路线如下所示:
第一步:(R)-6-溴-N7-(3,3-二氟环丁基)-2-甲基-N4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺
封管中加入化合物(R)-6-溴-7-氟-2-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(1.1g,2.5mmol),3,3-二氟环丁烷-1-胺盐酸盐(0.72g,5.0mmol),碳酸铯(3.26g,10.0mmol),加入N,N-二甲基乙酰胺(10mL),160℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化,得到目标化合物B60-1(0.35g,产率26.4%)。
第二步:(R)-(7-((3,3-二氟环丁基)氨基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-60)
往单口瓶中加入化合物(R)-6-溴-N7-(3,3-二氟环丁基)-2-甲基-N4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺(0.35g,0.66mmol),二甲基氧化膦(0.26g,3.3mmol),三(二亚苄基丙酮)二钯(0.09g,0.1mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.12g,0.20mmol),三乙胺(0.20g,3.97mmol),加入N,N-二甲基乙酰胺(5mL),140℃反应20h。浓缩,残留物用硅胶柱分离纯化,得到目标化合物I-60(60mg,产率16.2%)。
1H NMR(400m Hz,DMSO-d6)δ8.33-8.21(m,3H),7.70(d,1H),7.50(d,1H),7.33(t,1H),6.36(d,1H),5.69-5.66(m,1H),3.84-3.82(m,1H),3.17-3.10(m,2H),2.58(s,3H),2.38-2.34(m,2H),2.23(s,3H),1.84(d,6H),1.52(d,3H)。
LC-MS m/z=527.19[M+H]
+。
实施例61:目标化合物I-61的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为1-甲氧基丙-2-胺。
1H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.09(d,1H),7.95(d,1H),7.61(t,1H),7.47(t,1H),7.35-7.07(m,2H),6.51(d,1H),5.78-5.71(m,1H),3.71-3.66(m,1H),3.44-3.40(m,2H),3.27(d,3H),2.22(s,3H),1.82-1.79(m,6H),1.57(d,3H),1.15-1.12(m,3H).
LC-MS m/z=495.2[M+H]
+。
实施例62:目标化合物I-62的制备
合成路线如下所示:
第一步:(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-溴-7-氟-2-甲基喹唑啉-4-胺
往单口瓶中加入化合物6-溴-4-氯-7-氟-2-甲基喹唑啉(0.87g,3.17mmol),(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺盐酸盐(0.77g,3.17mmol),三乙胺(3.21g,31.7mmol),加入乙醇(10mL),100℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化,得到目标化合物B62-1(0.9g,产率64.3%)。
第二步:(R)-N4-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-溴-N7-异丙基-2-甲基喹唑啉-4,7-二胺
往封管加入化合物(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-溴-7-氟-2-甲基喹唑啉-4-胺(0.9g,2.0mmol),异丙胺四氢呋喃溶液(2M,2mL),加入N,N-二甲基乙酰胺(10mL),160℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化,得到目标化合物B62-2(0.4 g,产率41.7%)。
第三步:(R)-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-(异丙基氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(I-62)
单口瓶中加入化合物(R)-N
4-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-溴-N
7-异丙基-2-甲基喹唑啉-4,7-二胺(0.40g,0.83mmol),二甲基氧化膦(0.13g,1.7mmol),三(二亚苄基丙酮)二钯(0.07g,0.08mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.1g,0.16mmol),三乙胺(0.20g,3.97mmol),加入N,N-二甲基乙酰胺(5mL),140℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化,得到目标化合物I-62(20mg,产率4.6%)。
1H NMR(400mHz,DMSO-d6)δ8.17-8.10(m,2H),7.96(d,1H),6.81(d,2H),6.68(s,1H),6.46(d,1H),5.57-5.54(m,3H),3.63-3.58(m,1H),2.29(s,3H),1.79(d,6H),1.52(d,3H),1.21-1.15(m,6H)。
LC-MS m/z=480.21[M+H]
+。
实施例63:目标化合物I-63的制备
合成路线如下所示:
将(R)-(7-溴-8-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(30.0mg,57.6μmol),乙酰丙酮铜(22.6mg,86.4μmol)溶于二氧六环(2.00mL)和氨的甲醇溶液(2.00mL),氮气氛围下90℃搅拌12小时。反应结束后,直接浓缩得到粗品,粗品经过层析板分离,再经反相制备,得到目标化合物I-63(8.60mg,收率16.7%)。
1H NMR(400MHz,CDCl
3)δ8.32-8.13(m,1H),7.77-7.67(m,1H),7.52-7.44(m,1H),7.24-7.17(m,1H),6.90(t,1H),6.68-6.50(s,2H)5.94-5.86(m,1H),2.61(s,3H),2.01-1.96(m,6H),1.77(d,3H).
LC-MS m/z=457.0[M+H]
+。
实施例64:目标化合物I-64的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为1,1,1-三氟丙-2-胺。
1H NMR(400MHz,DMSO-d6)δ8.36(d,1H),8.24(d,1H),8.18(d,1H),7.61(t,1H),7.48(t,1H),7.35-7.07(m,2H),6.84(d,1H),5.78-5.71(m,1H),4.66-4.58(m,1H),2.24(d,3H),1.90-1.79(m,6H),1.58(d,3H),1.29(q,3H).
LC-MS m/z=519.2[M+H]
+。
实施例65:目标化合物I-65的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为1-环丙基乙烷-1-胺。
1H NMR(400MHz,DMSO-d6)δ8.14(d,1H),8.08(d,1H),7.94(d,1H),7.60(t,1H),7.47(t,1H),7.35-7.07(m,2H),6.46(d,1H),5.79-5.72(m,1H),3.26-3.21(m,1H),2.21(s,3H),1.81(dd,6H),1.57(d,3H),1.15(d,3H),0.96-0.91(m,1H),0.42-0.39(m,2H),0.25- 0.20(m,2H).
LC-MS m/z=491.2[M+H]
+。
实施例66:目标化合物I-66的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为1-乙基-3-甲基-1H-吡唑-5-胺。
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.43-8.38(m,2H),7.72(d,1H),7.52(d,1H),7.34(t,1H),6.73(d,1H),5.95(s,1H),5.72-5.64(m,1H),3.89(q,2H),2.59(s,3H),2.22(s,3H),2.13(s,3H),1.94(d,6H),1.54(d,3H),1.22(t,3H).
LC-MS m/z=545.2[M+H]
+。
实施例67:目标化合物I-67的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为丙氨酸乙酯。
1H NMR(400MHz,DMSO-d6)δ8.30-8.17(m,3H),7.70(d,1H),7.51(d,1H),7.33(t,1H),6.34(d,1H),5.67(t,1H),4.19-4.05(m,3H),2.58(s,3H),2.21(s,3H),1.85(d,6H),1.52(d,3H),1.38(dd,3H),1.14(q,3H).
LC-MS m/z=537.2[M+H]
+。
实施例68:目标化合物I-68的制备
合成路线如下所示:
第一步:2-(苄氨基)-3,3,3-三氟丙烷-1-醇(B68-2)
将3,3,3-三氟-2-氧代丙酸甲酯(5.0g,32.0mmol)溶于二氯甲烷(20mL),加入苄胺(3.78g,35.2mmol),氮气保护,室温反应一天,0℃加入硼氢化钠(2.42g.64.1mmol),缓慢升温至室温反应一天。0℃加入饱和氯化铵淬灭反应,分液,水相二氯甲烷萃取,合并二氯甲烷相,无水硫酸钠干燥,硅胶柱层析纯化,得到目标化合物B68-2(1.6g,收率22.8%)。
第二步:叔丁基苄基(1,1,1-三氟-3-羟基丙-2-基)氨基甲酸酯(B68-3)
将2-(苄氨基)-3,3,3-三氟丙烷-1-醇(1.56g,7.13mmol)溶于四氢呋喃(10mL),0℃加入三乙胺(0.72g,7.13mmol),再加入二碳酸二叔丁酯(1.71g,7.85mmol),室温反应过夜。将反应液减压浓缩得到粗品,用硅胶柱分离纯化,得到目标化合物B68-3(2.1g,收率92.2%)。
第三步:叔丁基苄基(1,1,1-三氟-3-甲氧基丙-2-基)氨基甲酸酯(B68-4)
将叔丁基苄基(1,1,1-三氟-3-羟基丙-2-基)氨基甲酸酯(2.1g,6.58mmol)溶于四氢呋喃(10mL),0℃加入钠氢(60%,0.38g,9.57mmol),0℃搅拌10min,再室温搅拌10min,0℃加入碘甲烷(1.25g,8.83mmol),缓慢恢复至室温搅拌过夜。加入乙酸乙酯与水,分液,水相用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩得到粗品,用硅胶柱分离纯化,得到目标化合物B68-4(2.05g,收率93.6%)。
第四步:1,1,1-三氟-3-甲氧基丙-2-胺盐酸盐(B68-5)
将叔丁基苄基(1,1,1-三氟-3-甲氧基丙-2-基)氨基甲酸酯(2.05g,6.15mmol)溶于氯化氢的二氧六环溶液(4M,15mL),室温搅拌4h,反应完全后,减压浓缩得白色固体,加甲醇(50mL)与10%Pd/C(0.75g),氮气置换3次,再氢气置换3次,于室温搅拌17小时,反应完全后,硅藻土过滤,滤液减压浓缩,得到目标化合物B68-5(1.05g,收率95.1%)。
第五步:(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7-((1,1,1-三氟-3-甲氧基丙-2-基)氨基)喹唑啉-6-基)二甲基氧化膦(I-68)
将1,1,1-三氟-3-甲氧基丙-2-氯化铵(55mg,0.31mmol)溶于无水二氧六环溶液(15mL),加入(R)-(7-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(100mg,0.21mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(35.7mg,0.06mmol)、三二亚苄 基丙酮二钯(28.2mg,0.03mmol)与碳酸铯(335.0mg,1.03mmol),氮气置换3次,氮气保护,于90℃反应过夜。反应完全后,减压蒸馏除去反应溶剂,加乙酸乙酯与水分液,水相用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,硅藻土过滤,滤液减压浓缩,制备色谱纯化,得到目标化合物I-68(25mg,收率22.1%)。
1H NMR(400MHz,DMSO-d6)δ8.29–8.16(m,3H),7.65(t,1H),7.50(t,1H),7.39–7.09(m,3H),6.59(d,1H),5.79(p,1H),4.23–4.12(m,1H),3.53(s,3H),2.26(s,3H),1.88(d,3H),1.84(d,3H),1.60(d,3H),1.23(s,1H).
LC-MS m/z=549.5[M+H]
+。
实施例69:目标化合物I-69的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为1,1,1-三氟丁-2-胺。
1H NMR(400MHz,DMSO-d6)δ8.34(d,1H),8.24(d,1H),8.17(d,1H),7.61(t,1H),7.48(t,1H),7.35-7.08(m,2H),6.85(d,1H),5.78-5.71(m,1H),4.45(b,1H),2.23(s,3H),1.89-1.82(m,7H),1.58(d,3H),1.53-1.47(m,1H),0.97(q,3H).
LC-MS m/z=533.2[M+H]
+。
实施例70:目标化合物I-70的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为3-甲氧基-3-甲基丁-2-胺。
LC-MS m/z=537.2[M+H]
+。
实施例71:目标化合物I-71的制备
合成路线如下所示:
第一步:3-氨基-4,4,4-三氟丁酸乙酯
将4,4,4-三氟-3-氧代丁酸乙酯(20.0g,109.0mmol)溶于乙醇(200mL),加入醋酸铵(33.5g,435mmol),氮气保护,80℃回流反应6小时。反应完毕后,冷却至室温,减蒸除去大部分溶剂,加水,二氯甲烷萃取,无水硫酸钠干燥,过滤,浓缩,得17.72g黄色液体,加入无水乙醇(100mL)与10%Pd/C(3g),氮气置换3次,再氢气置换3次,氢气下60℃反应2天。硅藻土过滤,滤液浓缩,硅胶柱层析纯化,得到目标化合物B71-2(10.8g,收率53.7%)。
第二步:3-((叔丁氧羰基)氨基)-4,4,4-三氟丁酸乙酯
将3-氨基-4,4,4-三氟丁酸乙酯(6.10g,32.9mmol)溶于无水四氢呋喃(40mL),0℃加 入三乙胺(7.33g,72.5mmol),再加入二碳酸二叔丁酯(14.38g,65.9mmol),室温反应过夜。反应完毕后,减蒸除去反应溶剂,加乙酸乙酯与10%碳酸氢钠溶液,分液,水相用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,硅胶柱层析纯化,得到目标化合物B71-3(5.29g,收率56.3%)。
第三步:(1,1,1-三氟-4-羟基丁-2-基)氨基甲酸叔丁酯
在-20℃条件下向四氢铝锂(1.82g,47.9mmol)的无水四氢呋喃(50mL)溶液滴加3-((叔丁氧羰基)氨基)-4,4,4-三氟丁酸乙酯(6.83g,23.94mmol),20分钟滴毕,继续搅拌20分钟,移至0℃反应0.5小时,反应完毕后,-5℃滴加2mL 15%NaOH水溶液,再滴加2mL水,搅拌5分钟,补加10mL水,室温继续搅拌,加入50mL乙酸乙酯稀释反应液,硅藻土过滤,分液,乙酸乙酯洗滤饼,分液,水相乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,硅胶柱层析纯化,得到目标化合物B71-4(3.18g,收率54.6%)。
第四步:(1,1,1-三氟-4-甲氧基丁-2-基)氨基甲酸叔丁酯
将(1,1,1-三氟-4-羟基丁-2-基)氨基甲酸叔丁酯(1.01g,4.15mmol)溶于无水乙腈(15mL),加氧化银(4.81g,20.76mmol),氮气吹一分钟,加入碘甲烷(5.89g,41.5mmol),密封,于室温避光反应2天,过滤,滤液浓缩,硅胶柱层析纯化,得到目标化合物B71-5(0.86g,收率80.5%)
第五步:1,1,1-三氟-4-甲氧基丁-2-胺盐酸盐
将(1,1,1-三氟-4-甲氧基丁-2-基)氨基甲酸叔丁酯(0.86g,3.34mmol)溶于4M HCl的 二氧六环(20mL),于室温反应一天,减蒸至干,得到目标化合物B71-6(0.65g,收率100%)。
第六步:(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-7-((1,1,1-三氟-4-甲氧基丁-2-基)氨基)喹唑啉-6-基)二甲基氧化膦(I-71)
合成方法参照化合物I-68,分离得到两个TLC极性不同的异构体I-71A和I-71B。
分离方法:使用Agilent 1260II Prime-iQ型号液质联用仪(规格为1.9μm,2.1*30mm)进行分离,流动相A为0.1%氨水,流动相B为乙腈。梯度条件:流速1.5mL/min,在0min到1.5min,流动相A由50%到10%,保持0.3min后;在1.81min到2.0min,流动相A由10%到50%;柱温保持在50℃,柱压保持在100bar。化合物I-71A的保留时间为1.467min,化合物I-71B的保留时间为1.438min。
I-71A:
1H NMR(400MHz,dmso)δ10.77(s,2H),9.29(d,1H),9.20(d,1H),7.97(d,1H),7.54(t,1H),7.35(dd,2H),6.79(s,1H),6.01–5.95(m,1H),4.35(d,1H),3.50(dt,1H),3.41(dd,1H),3.17(s,3H),2.48(s,3H),2.21–2.11(m,1H),2.01(s,3H),1.97(s,3H),1.72(d,3H).
I-71B:
1H NMR(400MHz,dmso)δ10.58(s,2H),9.22(d,1H),9.11(d,1H),7.94(t,1H),7.54(t,1H),7.35(dd,2H),6.79(d,1H),6.00–5.91(m,1H),4.37(d,1H),3.54–3.48(m,1H),3.45–3.40(m,1H),3.19(s,3H),2.46(s,3H),2.20–2.10(m,1H),2.00(d,3H),1.96(d,3H),1.71(d,3H).
LC-MS m/z=563.5[M+H]
+。
实施例72:目标化合物的制备
合成路线如下所示:
合成方法参考I-64,将1,1,1-三氟丙-2-胺替换为(S)-1,1,1-三氟丙-2-胺。
LC-MS m/z=519.2[M+H]
+。
实施例73:目标化合物的制备
合成路线如下所示:
第一步:6-溴-7-(异丙胺)-2-甲基喹唑啉-4(3H)-酮(B73-2)
在封管中加入化合物6-溴-7-氟2-甲基喹唑啉-4(3H)-酮(0.61g,1.2mmol),异丙胺(12mmol,1.03mL),加入N,N-2-甲基乙酰胺(5mL),160℃搅拌反应20h。浓缩,残留物用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)=10:1)得6-溴-7-(异丙胺)-2-甲基喹唑啉-4(3H)-酮(B73-2)(288mg,收率88%)。
第二步:(R)-6-溴-N
7-异丙基-2-甲基-N
4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺(B73-3)
将化合物6-溴-7-(异丙胺)-2-甲基喹唑啉-4(3H)-酮(2.00g,6.75mmol)加至二氯甲烷(20mL),加入4-二甲氨基吡啶(0.083mg,0.675mmol),2,4,6-三异丙基苯-1-磺酰氯(3.07g,10.13mmol),室温搅拌过夜。向反应液中加入三乙胺(1.88mL,13.51mmol)和(R)-1-(2-甲基-3-(三氟甲基)苯基)乙胺盐酸盐(3.24g,13.51mmol),室温反应6小时。反应液旋浓缩,残留物用硅胶柱分离纯化,得到目标化合物B73-3(2.5g,收率76.9%)。
第二步:(R)–(7-(异丙基氨基)-2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-73)
将(R)-6-溴-N
7-异丙基-2-甲基-N
4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4,7-二胺(150mg,0.312mmol)溶于DMF(2mL),加入二甲基氧化膦(36.5mg,0.467mmol),三(二亚苄基丙酮)二钯(22.83mg,0.025mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(28.8mg,0.05mmol),三乙胺(95mg,0.935mmol),氮气置换三次后120℃搅拌12小时。加入10mL水,用乙酸乙酯(10mL*3)萃取,合并有机相,用无水硫酸钠干燥,过滤浓缩,浓缩物经过柱层析,得到目标化合物I-73(50mg,收率33.5%)。
1H NMR(400m Hz,DMSO-d6)δ8.50(s,1H),8.23(d,1H),8.09(d,1H),7.72(d,1H),7.52(d,1H),7.35(t,1H),6.43(d,1H),5.67-5.72(m,1H),3.55-3.63(m,1H),2.58(s,3H),2.25(s,3H),1.83(d,6H),1.54(d,3H),1.15(t,6H).
LC-MS m/z=479.2[M+H]
+。
实施例74:目标化合物I-74的制备
合成路线如下所示:
第一步:(R)-6-溴-N
7-异丙基-2-甲基-N
4-(1-(3-(五氟磺胺基)苯基)乙基)喹唑啉-4,7-二胺
将化合物6-溴-7-(异丙胺)-2-甲基喹唑啉-4(3H)-酮(2.00g,6.75mmol)加至二氯甲烷(20mL),加入4-二甲氨基吡啶(0.083mg,0.675mmol),2,4,6-三异丙基苯-1-磺酰氯(3.07g,10.13mmol),室温搅拌过夜。向反应液中加入三乙胺(1.88mL,13.51mmol)和(R)-1-(3-(五氟磺胺基)苯基)乙烷-1-胺盐酸盐(3.83g,13.51mmol),室温反应6小时。反应液浓缩,残留物用硅胶柱分离纯化,得到目标化合物B74-1(2.4g,收率74.9%)。
第二步:(R)-(7-(异丙基氨基)-2-甲基-4-((1-(3-(五氟磺酰)苯基)乙基)氨基)喹唑啉-6-基)二甲基氧化膦(I-74)
将化合物(R)-6-溴-N
7-异丙基-2-甲基-N
4-(1-(3-(五氟磺胺基)苯基)乙基)喹唑啉-4,7-二胺(220mg,0.419mmol)溶于DMF(2mL),加入二甲基氧化膦(49mg,0.628mmol),三(二亚苄基丙酮)二钯(30.7mg,0.033mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(38.8mg,0.067mmol),三乙胺(127mg,1.256mmol),氮气置换三次后120℃搅拌12小时。加入10mL水,用乙酸乙酯(10mL*3)萃取,合并有机相,用无水硫酸钠干燥,过滤浓缩,浓缩物经 过柱层析,得到目标化合物I-74(45mg,产率20.5%)。
1H NMR(400m Hz,DMSO-d6)δ8.26(s,1H),8.12(d,1H),8.01(s,1H),7.94(s,1H),7.69-7.75(m,2H),7.54-7.58(m,1H),6.45(d,1H),5.60-5.63(m,1H),3.58-3.63(m,1H),2.27(s,3H),1.80(q,6H),1.78(d,3H),1.16(t,6H).
LC-MS m/z=523.1[M+H]
+。
实施例75:目标化合物I-75的制备
合成路线如下所示:
将化合物(R)-(7-氨基-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)二甲基氧化膦(200mg,0.47mmol)溶入硝基甲烷(5mL),加入三氟甲磺酸铜(171mg,0.47mmol),冰浴下滴加2,2,2-三氯乙酰亚胺叔丁酯(308mg,1.41mmol),室温搅拌48小时,浓缩至干,制备色谱分离得目标产物I-75(15mg,产率6.6%)。
1H NMR(400MHz,DMSO-d6)δ8.17-8.07(m,3H),7.60(t,1H),7.47(t,1H),7.34-7.07(m,2H),6.62(d,1H),5.78-5.72(m,1H),2.21(s,3H),1.82(d,6H),1.57(d,3H),1.35(s,9H).
LC-MS m/z=479.2[M+H]
+。
实施例76:目标化合物I-76的制备
合成路线如下所示:
将化合物(6-(二甲基磷酰基)-2-甲基-4-(((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-7-基)丙氨酸乙酯(100mg,0.19mmol)溶于无水四氢呋喃(5mL),氮气保护,降温至0℃,慢慢滴加甲基溴化镁的四氢呋喃溶液(2M)(1mL,2mmol),室温搅拌3小时,饱和氯化铵淬灭反应。乙酸乙酯(10mL×3)萃取。有机相无水硫酸钠干燥,浓缩。制备色谱分离得目标产物I-76(16mg,产率16%)。
1H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.11(d,1H),7.91(d,1H),7.69(d,1H),7.50(d,1H),7.32(t,1H),6.47(d,1H),5.70-5.63(m,1H),4.47(d,1H),2.58(s,3H),2.20(s,3H),1.81(dd,6H),1.51(d,3H),1.14-1.05(s,9H).
LC-MS m/z=523.2[M+H]
+。
实施例77:目标化合物I-77的制备
合成路线如下所示:
合成方法参考I-27第三步,将氨基甲酸叔丁酯替换为1-(三氟甲基)环丙烷-1-胺。
LC-MS m/z=531.2[M+H]
+。
实施例78:目标化合物I-78的制备
合成路线如下所示:
合成方法参考I-64,将(S)-1,1,1-三氟丙-2-胺替换为(R)-1,1,1-三氟丙-2-胺。
LC-MS m/z=519.2[M+H]
+。
实施例79:目标化合物I-79的制备
合成路线如下所示:
合成方法参考I-33,将二甲基氧化膦替换为磷杂环戊烷1-氧化物。
LC-MS m/z=491.20[M+H]
+。
实施例80:目标化合物I-80的制备
合成路线如下所示:
I-80的合成方法参考I-32,将环丁胺盐酸盐替换为甲氨盐酸盐。
1H NMR(400MHz,DMSO)δ8.16(d,1H),8.08(d,1H),7.81(s,1H),7.61(t,1H),7.48(t,1H),7.35-7.05(m,2H),6.41(d,1H),5.79-5.73(m,1H),2.62(s,3H),2.31(s,3H),1.82(dd,6H),1.58(d,3H).
LC-MS m/z=437.2[M+H]
+。
在本发明的测试例中,对照化合物I的制备参考专利WO2018115380A1、对照化合物II的制备参考专利WO2018172250A1,其结构如下:
测试例1:化合物对KRAS G12C::SOS1结合抑制试验
待测化合物使用DMSO配制成10mM的储备液,并使用1X测试缓冲液将化合物进行梯度稀释。转移0.1μL不同浓度的化合物溶液至384孔板中,加入5μL GST-KRAS G12C至384孔板,以1000rpm的转速离心1分钟。加入5μL His-SOS1至384孔板,以1000rpm的转速离心1分钟,室温孵育15分钟。
孵育结束向测试孔中加入10μL抗6his-Tb单抗(Cisbio,Cat.No.61HI2TLA)和抗GST-XL665单抗(Cisbio,Cat.No.61GSTXLA)混合溶液,以1000rpm的转速离心1分钟,室温孵育1小时。
孵育结束后在多功能酶标仪(Perkin Elmer,Envision 2104)上读取665nm和615nm波长的荧光信号比值,采用Graphpad 5软件计算IC
50值。
表1测试化合物对KRAS G12C::SOS1结合抑制结果
测试化合物 | IC 50(nM) |
对照化合物II | 14.6 |
对照化合物I | 7.9 |
I-1 | 9.2 |
I-3 | 8.5 |
I-4 | 42.1 |
I-5 | 67.0 |
I-10 | 8.3 |
I-11 | 15.1 |
I-16 | 8.1 |
I-17 | 14.0 |
I-12 | 91.9 |
I-14 | 74.3 |
I-15 | 26.9 |
I-20 | 39.4 |
I-25 | 60.9 |
I-26 | 12.4 |
I-27 | 7.7 |
I-28 | 7.3 |
I-23 | 11.2 |
I-29 | 33.5 |
I-30 | 6.9 |
I-32 | 267.5 |
I-34 | 5.1 |
I-35 | 9.9 |
I-37 | 26.6 |
I-38 | 5.0 |
I-39 | 11.7 |
I-40 | 35.4 |
I-33 | 6.6 |
I-42 | 15.6 |
I-43 | 4.9 |
I-44 | 17.4 |
I-45 | 18.4 |
I-47 | 5.0 |
I-48 | 11.2 |
I-51 | 24.9 |
I-52 | 29.4 |
I-53 | 11.4 |
I-54 | 22.6 |
I-55 | 7.1 |
I-56 | 6.6 |
I-57 | 5.4 |
I-80 | 4.2 |
实验结果表明,本发明中的化合物对KRAS G12C::SOS1结合具有显著的结合抑制作用。
测试例2:化合物对KRAS G12C-SOS1活性抑制试验
将待测化合物用DMSO配制成10mM的储备液,并使用1X测试缓冲液(改良Tris缓冲液)进行梯度稀释。将所得化合物液转移至384孔板中,DMSO的最终含量为0.25%,另设置不含化合物的DMSO孔作为高信号对照。
制备1X测试缓冲液(改良Tris缓冲液),用测试缓冲液分别配制KRAS G12C(SignalChem,Cat.No.R06-32DH-BULK)、SOS1(Cytoskeleton,Inc.Cat.No.GE02-XL)、GTP溶液(BellBrook,Cat.No.3014-1K)。将10μL KRAS G12C转移到384孔板上,另转移10μL缓冲液至空的孔中作为低信号对照。分别转移5μL的SOS1和5μL GTP至384孔板中。
用测试缓冲液配制GDP检测试剂,将10μL检测试剂溶液转移至384孔板上,在室温下孵育2小时。孵育结束后在多功能酶标仪(SpectraMax Paradigm)上读板,激发波长为580nm,发射波长为620nm。读取荧光信号,计算抑制率:
抑制百分比=(高信号对照-样品信号)/(高信号对照-低信号对照)*100,采用Graphpad 5软件计算IC
50值。
表2测试化合物对KRAS G12C-SOS1活性抑制结果
测试化合物 | IC 50(nM) |
对照化合物II | 85 |
对照化合物I | 44 |
I-1 | 82 |
I-2 | 64 |
I-3 | 70 |
I-4 | 85 |
I-5 | 110 |
I-6 | 80 |
I-8 | 167 |
I-9 | 50 |
I-10 | 67 |
I-11 | 96 |
I-16 | 20 |
I-17 | 35 |
实验结果表明,本发明中的化合物对KRAS G12C-SOS1具有显著的抑制作用,特别是化合物I-16、I-17显示较为优良的活性。
测试例3:化合物对DLD-1细胞ERK磷酸化水平的抑制试验
采用细胞内western blot定量分析法检测化合物对DLD-1细胞ERK磷酸化抑制水平。
将DLD-1细胞(ATCC,CCL-221)按2.5×10
6个细胞/瓶接种于T75培养瓶中,在含10%FBS的RPMI 1640培养基中培养2天。第3天将细胞接种于384孔板上,37℃,5%CO
2培养过夜。过夜后加入系列稀释的化合物(DMSO终含量为0.5%),阴性组加入DMSO,在37℃,5%CO
2培养箱中孵育。
固定细胞,使用PBS清洗一遍,给细胞破膜,室温下封闭1小时。去除封闭液加入一抗(CST,Cat.No.#4370S),4℃孵育过夜。使用PBST(PBS溶液加入0.05%吐温20)清洗3次,每次浸泡2分钟。加入二抗(LI-COR,Cat.No.926-32211),室温避光孵育。使用PBST清洗3次,每次浸泡2分钟。培养板以1000rpm的转速离心1分钟,在双色红外激光成像系统(
CLX)上扫描,读取信号。
相对信号=800通道信号值/700通道信号值。
ERK磷酸化相对表达水平=(测试化合物-对照化合物)/(DMSO组-对照化合物)
采用Graphpad 5软件计算IC
50值。
表3测试化合物对DLD-1细胞ERK磷酸化水平抑制结果
测试化合物 | IC 50(nM) |
对照化合物I | 72 |
I-1 | 132 |
I-3 | 84 |
I-4 | 140 |
I-5 | 67 |
I-11 | 66 |
I-16 | 50 |
I-17 | 70 |
I-27 | 53 |
I-28 | 63 |
I-30 | 79 |
I-35 | 46 |
I-39 | 49 |
I-33 | 57 |
I-42 | 83 |
I-43 | 132 |
I-47 | 34 |
I-48 | 45 |
I-49 | 64 |
I-52 | 45 |
I-53 | 45 |
I-55 | 97 |
I-56 | 106 |
I-57 | 105 |
I-59 | 33 |
I-60 | 41 |
I-58 | 45 |
I-61 | 67 |
I-64 | 33 |
I-68 | 36 |
I-69 | 47 |
I-36 | 26 |
I-71A | 31 |
I-71B | 68 |
I-73 | 43 |
I-74 | 24 |
I-67 | 51 |
I-75 | 28 |
I-76 | 132 |
实验结果表明,本发明中的化合物对DLD-1细胞ERK磷酸化水平显示显著的抑制作用。
测试例4:化合物抑制3D细胞增殖试验
将H358细胞接种于T75培养瓶中,在含10%FBS的RPMI 1640培养基中培养2天,以备后续培养或接种于384孔板进行实验。
第1天将细胞接种于384孔板上,每孔加入40μL培养基,每孔加入梯度稀释的化合物或DMSO,另设置不接种细胞加入培养基的孔作为空白对照。37℃,5%CO
2培养7天,第8天加入3D CellTiter-Glo试剂(Promega,Cat.No.G9683),以320rpm的速度震荡20分钟,室温放置2小时。在多功能酶标仪上读取luminescence信号。计算细胞活力抑制率:
细胞活力抑制率=(DMSO组-测试化合物)/(DMSO组-空白对照组)×100%
采用Graphpad 5软件计算IC
50值。
表4测试化合物对H358细胞3D增殖抑制结果
测试化合物 | IC 50(nM) |
对照化合物I | 31 |
I-11 | 30 |
I-16 | 16 |
I-17 | 37 |
I-28 | 24 |
I-30 | 30 |
I-38 | 36 |
I-39 | 89 |
I-40 | 100 |
I-33 | 55 |
I-47 | 47 |
I-59 | 29 |
I-58 | 35 |
I-61 | 26 |
I-64 | 34 |
实验结果表明,本发明中的化合物对H358细胞3D增殖显示较好的抑制作用,特别是化合物I-16显示较为优良的活性。
测试例5:化合物对人正常肝细胞毒性评价
人正常肝细胞LO2在含10%FBS的DMEM培养基中培养,在细胞生长状态良好时,按照3000/孔,30μL/孔密度接种于384孔板。放入37℃,5%CO
2培养箱过夜。
每孔加入梯度稀释的化合物或DMSO,另设置不接种细胞加入培养基的孔作为空白对照。放入37℃,5%CO
2培养箱培养20小时后,根据CytoTox-Glo
TM Cytotoxicity Assay试剂盒(Promega,Cat.No.G9290)说明书准备CytoTox-Glo
TM Cytotoxicity检测试剂和裂解试剂。按10μL/孔加入CytoTox-Glo
TM Cytotoxicity检测试剂,室温放置15分钟,在多功能酶标仪上读取死细胞luminescence信号。按10μL/孔加入裂解试剂,室温放置15分钟后在多功能酶标仪上读取总的luminescence信号。活细胞信号=总信号-死细胞信号。计算细胞活力抑制率:
细胞活力抑制率=(DMSO组-测试化合物)/(DMSO组-空白对照组)×100%
采用Graphpad 5软件计算IC
50值。
表5测试化合物LO2细胞活力抑制结果
测试化合物 | IC 50(μM) |
对照化合物I | 34.3 |
I-1 | 93.8 |
I-3 | 70.6 |
I-10 | 54.0 |
I-11 | >200 |
实验结果表明,本发明中的化合物对LO2细胞毒性较小,特别是化合物I-11的IC
50大于200μM,对LO2细胞毒性低。
测试例6:人肝微粒体稳定性试验
人肝微粒体稳定性试验采用化合物与人肝微粒体体外共孵育进行检测。首先将待测化合物在DMSO溶剂中配制成10mM的储备液,随后使用乙腈将化合物稀释至0.5mM。 使用PBS稀释人肝微粒体(Corning)成微粒体/缓冲液溶液,并使用该溶液稀释0.5mM的化合物成为工作溶液,工作溶液中化合物浓度为1.5μM,人肝微粒体浓度为0.75mg/ml。取深孔板,每孔加入30μL工作溶液,然后加入15μL预热好的6mM NADPH溶液启动反应,37℃孵育。在孵育的0、5、15、30、45分钟时,加入135μL乙腈至相应的孔中终止反应。在最后45分钟时间点用乙腈终止反应后,深孔板涡旋振动10分钟(600rpm/min),然后离心15分钟。离心后取上清,1:1加入纯化水后进行LC-MS/MS检测,获得每个时间点化合物峰面积与内标峰面积比值,将5、15、30、45分钟时化合物的峰面积比值与0分钟时的峰面积比值进行比较,计算每个时间点化合物的剩余百分比,使用Graphpad 5软件计算T
1/2。
表6人肝微粒体稳定性试验结果
实验结果表明,本发明中的化合物表现出较为优良的肝代谢稳定性。
测试例7:化合物对细胞色素P450的抑制试验
检测化合物对细胞色素P450(CYP450)亚型CYP3A4(2种底物咪达唑仑和睾酮)的抑制潜力。首先将待测化合物在DMSO溶剂中配制成10mM的储备液,CYP3A4抑制剂酮康唑在DMSO溶剂中配制成2.5mM的储备液。用乙腈将待测化合物和酮康唑稀释至400倍终浓度(化合物:10μM,酮康唑:2.5μM)。
用磷酸钾缓冲液(0.1M,pH 7.4)配制4倍终浓度的NADPH辅因子(10mL磷酸钾缓冲液中加入66.7mg NADPH)和底物,咪达唑仑4倍终浓度为20μM,睾酮4倍终浓度为320μM。
在冰上用磷酸钾缓冲液配制人肝微粒体溶液,浓度为0.2mg/mL。在冰上用人肝微粒体溶液配制2倍终浓度的待测化合物或对照抑制剂(BI-3406)溶液。向测试孔中分别加入30μL的待测化合物和对照抑制剂溶液,并加入15μL底物,进行复孔操作。在37℃下孵育96孔测定板和NADPH溶液5分钟,将15μL预热的8mM NADPH溶液添加到测定板中以启动反应。37℃下孵育5分钟。加入120μL乙腈终止反应,淬灭后,在振动器 (IKA,MTS 2/4)上摇动平板10分钟(600rpm/min),然后离心15分钟。离心后取上清,1:1加入纯化水后进行LC-MS/MS检测,获得化合物峰面积与内标峰面积比值,化合物的峰面积比值与对照抑制剂的峰面积比值进行比较,计算抑制率。
表7测试化合物对CYP450酶抑制试验结果
实验结果表明,与对照化合物相比,本发明中的化合物10μM时对CYP3A4酶没有抑制作用,潜在的药物药物相互作用风险低。
测试例8:小鼠药代动力学试验
使用雄性ICR小鼠,20-25g,禁食过夜。取3只小鼠,口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g,2-8℃离心6分钟,收集血浆,于-80℃保存。取各时间点血浆,加入3-5倍量含内标的乙腈溶液混合,涡旋混合1分钟,13000转/分钟,4℃离心10分钟,取上清液加入3倍量水混合,取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。
表8小鼠药代动力学试验结果
小鼠实验结果表明,本发明化合物表现出优良的药代动力学性质,成药性好。
测试例9:Mia Paca-2胰腺癌体内药效实验
小鼠适应性饲养一周后,将处于对数期的Mia Paca-2细胞重悬于无血清DMEM,与Matrigel 1:1混合后,按100μL/只将1x 10
7Mia Paca-2细胞接种于小鼠右侧胁肋部皮下,定期观察肿瘤生长情况,待肿瘤生长至平均体积150-200mm
3时,根据肿瘤大小和小鼠体重随机分为模型组和给药组,给药前和给药过程中测量、记录肿瘤大小和动物体重,治疗结束后比较模型组和给药组肿瘤大小差异以确定药效。
表9测试化合物在肿瘤重量水平的抑瘤能力
实验结果图1和表9表明,本发明化合物具有显著的抑制Mia Paca-2癌生长的作用。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (30)
- 式I所示6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:其中,Z为碳原子或氮原子;且当Z为氮原子时,R 2不存在;R 11、R 12各自独立地为C 1-C 6烷基或C 1-C 6烷氧基;所述C 1-C 6烷基、或所述C 1-C 6烷氧基分别独立地被一个或多个R 13取代,所述R 13为选自下列的取代基:羟基、氨基、硝基、卤素、氰基;当取代基为多个时,所述的取代基相同或不同;R a分别独立地为氢或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、3-8元环烷基;所述C 1-C 6烷基、或所述3-8元环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;m为1、2、3或4;R 21、R 22、R 23、R 24各自独立地为氢或选自下列的取代基:C 1-C 6烷基、3-8元环烷基、4-8元杂环烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;L为不存在或选自下列的基团:C 1-C 6烷基、氘代C 1-C 6烷基、3-8元环烷基、4-8元杂环烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、-COOC 1-C 6烷基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、或所述-COOC 1-C 6烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;环A为不存在或选自3-15元环烷基或4-15元杂环烷基、5-15元芳环基或5-15元杂芳环基;R b分别独立地为氢或选自下列的基团:羟基、氨基、硝基、卤素、氰基、 C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6酰胺基、C 1-C 6酯基、C 1-C 6羰基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、所述C 2-C 6酰胺基、所述C 1-C 6酯基、或所述C 1-C 6羰基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;n为1、2、3或4;当R b为多个时,R b为相同或不同的取代基;R 3为氢或选自下列的取代基:卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、3-8元环烷基、4-8元杂环烷基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、所述3-8元环烷基、或4-8元杂环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;R 4为氢或选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6烷氧基、3-8元环烷基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、所述3-8元环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;R 5为氢或选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;R 6为5-8元环烷基、或5-8元芳环基、或5-10元杂芳环基;所述5-8元环烷基、或 所述5-8元芳环基、或5-10元杂芳环基任选地被一个或多个,相同或不同的选自下列的取代基取代:羟基、氨基、硝基、卤素、氰基、-SF 5、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、3-8元环烷基、4-10元杂环烷基、-SO 2-C 1-C 6烷基;所述羟基、氨基任选地被C 1-C 6烷基、3-8元环烷基或4-10元杂环烷基取代;其中,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、3-8元环烷基、4-10元杂环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;所述R f为选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、3-8元环烷基、3-8元卤代环烷基、4-10元杂环烷基、C 1-C 6酰基、C 1-C 6羰基、C 1-C 6砜基、C 1-C 6卤代砜基;所述杂环烷基或杂芳环基中,杂原子选自N、O、S和P中的一种或多种,杂原子数为1-3个。
- 式I所示6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:其中,Z为碳原子或氮原子;且当Z为氮原子时,R 2不存在;R 11、R 12各自独立地为C 1-C 6烷基或C 1-C 6烷氧基;所述C 1-C 6烷基、或所述C 1-C 6烷氧基分别独立地被一个或多个R 13取代,所述R 13为选自下列的取代基:羟基、氨基、硝基、卤素、氰基;当取代基为多个时,所述的取代基相同或不同;R a分别独立地为氢或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1- C 6烷基、3-8元环烷基;所述C 1-C 6烷基、或所述3-8元环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;m为1、2、3或4;R 21、R 22、R 23、R 24各自独立地为氢或选自下列的取代基:C 1-C 6烷基、3-8元环烷基、4-8元杂环烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;L为不存在或选自下列的基团:C 1-C 6烷基、3-8元环烷基、4-8元杂环烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基、或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;环A为不存在或选自3-15元环烷基或4-15元杂环烷基、5-15元芳环基或5-15元杂芳环基;R b分别独立地为氢或选自下列的基团:羟基、氨基、硝基、卤素、氰基、 C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6酰胺基、C 1-C 6酯基、C 1-C 6羰基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、所述C 2-C 6酰胺基、所述C 1-C 6酯基、或所述C 1-C 6羰基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;n为1、2、3或4;当R b为多个时,R b为相同或不同的取代基;R 3为氢或选自下列的取代基:卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、3-8元环烷基、4-8元杂环烷基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、所述3-8元环烷基、或4-8元杂环 烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;R 4为氢或选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6烷氧基、3-8元环烷基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、所述3-8元环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;R 5为氢或选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;R 6为5-8元环烷基、或5-8元芳环基、或5-10元杂芳环基;所述5-8元环烷基、或所述5-8元芳环基、或5-10元杂芳环基任选地被一个或多个,相同或不同的选自下列的取代基取代:羟基、氨基、硝基、卤素、氰基、-SF 5、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、3-8元环烷基、4-10元杂环烷基、-SO 2-C 1-C 6烷基;所述羟基、氨基任选地被C 1-C 6烷基、3-8元环烷基或4-10元杂环烷基取代;其中,所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、3-8元环烷基、4-10元杂环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;所述R f为选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、3-8元环烷基、3-8元卤代环烷基、4-10元杂环烷基、C 1-C 6酰基、C 1-C 6羰基、C 1-C 6砜基、C 1-C 6卤代砜基;所述杂环烷基或杂芳环基中,杂原子选自N、O、S和P中的一种或多种,杂原子数为1-3个。
- 如权利要求1或2所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,其满足下述情形中的任一个:(1)所述的 中,L为不存在或选自下列的基团:C 1-C 6烷基、氘代C 1-C 6烷基、3-8元环烷基、4-8元杂环烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;(2)所述的 中,L为不存在或选自下列的基团:C 1-C 6烷基、3-8元环烷基、4-8元杂环烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、-COOC 1-C 6烷基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、或所述-COOC 1-C 6烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;(3)所述的 中,L为不存在或选自下列的基团:C 1-C 6烷基、氘代C 1-C 6烷基、3-8元环烷基、4-8元杂环烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述3-8元环烷基、所述4-8元杂环烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、-COOC 1-C 6烷基;所述C 1-C 6烷基、所述C 1-C 6烷氧基、或所述-COOC 1-C 6烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;当R 1为 时,R a1为C 1-C 6烷基、3-8元环烷基,所述C 1-C 6烷基、或所述3-8元环烷基分别独立地被一个或多个R f取代,当取代基为多个时,所述R f相同或不同,所述的R a1不为C 1-C 3烷基、其中,m的定义如本发明第一方面中所述;(7)当Z为碳原子,R 1为 时,R 11、R 12各自独立地为C 1-C 6烷基或C 1-C 6烷氧基,所述C 1-C 6烷基、或所述C 1-C 6烷氧基分别独立地被一个或多个R 13取代,所述R 13为选自下列的取代基:羟基、氨基、硝基、卤素、氰基;当取代基为多个时,所述的取代基相同或不同;R 2为氢或选自下列的取代基:羟基、氨基、硝基、氰基、 其中,Y为不存在或选自下列的基团:当Z为氮原子,R 1为 时,R 6为5-8元环烷基、或5-8元芳环基、或5-10元杂芳环基,所述5-8元环烷基、或所述5-8元芳环基、或5-10元杂芳环基任选地被两个,相同或不同的取代基取代,所述取代基的定义如本发明的第一方面所述;(8)所述式I所示6-取代磷酰基喹唑啉类衍生物不为:(10)L为不存在或选自下列的基团:C 1-C 6烷基、氘代C 1-C 6烷基、C 2-C 6烯基、C 2- C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;所述R e为选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6卤代烷基;较佳地,L为不存在或选自下列的基团:C 1-C 6烷基、氘代C 1-C 6烷基、C 1-C 6烷氧基;更佳地L为不存在或选自下列的基团:C 1-C 3烷基、氘代C 1-C 3烷基、C 1-C 3烷氧基;(11)M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基、或所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;所述R e为选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6卤代烷基较佳地,M为不存在或选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6烷氧基;更佳地,M为不存在或选自下列的取代基:卤素、C 1-C 3烷基、C 1-C 3烷氧基;(12)环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;较佳地,环A为不存在或选自3-6元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;更佳地,环A为不存在或3-6元环烷基或5-6元杂环烷基、5-6元芳环基或5-6元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;(13)R b分别独立地为氢或选自下列的基团:羟基、氨基、卤素、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;n为1、2或3;其中所述R e为选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6卤代烷基;当R b为多个时,R b为相同或不同的取代基;较佳地,R b为氢、卤素、C 1-C 6烷基、C 1-C 6环烷基、C 1-C 6卤代烷基、C 1-C 6卤代环烷基、C 1-C 6烷氧基;更佳地R b为氢、C 1-C 6烷基、C 1-C 6卤代烷基。
- R a分别独立地为氢或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、3-8元环烷基;所述C 1-C 6烷基、或所述3-8元环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;R a1为C 1-C 6烷基、3-8元环烷基;所述C 1-C 6烷基、或所述3-8元环烷基分别独立地被一个或多个R f取代;当取代基为多个时,所述R f相同或不同;所述R f为选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、3-8元环烷基、3-8元卤代环烷基、4-10元杂环烷基、C 1-C 6酰基、C 1-C 6羰基、C 1-C 6砜基、C 1-C 6卤代砜基;m为1、2、3或4。
- 环D、环E各自独立地选自:3-15元环烷基或4-15元杂环烷基、5-15元芳环基或5-15元杂芳环基;R b、n定义如权利要求1中所述;较佳地,环D、环E各自独立地选自:3-10元环烷基或4-10元杂环烷基、5-8元芳环基或5-8元杂芳环基;n为1、2、3或4;R b分别独立地为氢或选自下列的基团:卤素、 C 1-C 6烷基、C 2-C 6酰胺基、C 2-C 6酯基、C 2-C 6羰基;所述C 1-C 6烷基、所述C 2-C 6酰胺基、所述C 2-C 6酯基、或所述C 2-C 6羰基分别独立地被一个或多个R g取代;当取代基为多个时,所述R g相同或不同;其中所述R g为选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6卤代烷基;当R b为多个时,R b为相同或不同的取代基。
- 如权利要求1或2所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R 3为氢或选自下列的取代基:卤素、氰基、C 1-C 4烷基、C 1-C 4卤代烷基。
- 如权利要求1或2所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R 4为氢或选自下列的取代基:卤素、C 1-C 4烷基、C 1-C 4卤代烷基、3-6元环烷基;较佳地,R 4为C 1-C 4烷基;较佳地,R 4为甲基。
- 如权利要求1或2所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R 5为氢或选自下列的取代基:卤素、C 1-C 4烷基、C 1-C 4卤代烷基。
- 如权利要求1或2所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,其具有结构Ia或结构Ib或结构Ic或结构Id在所述结构Ia、Ib、Ic或Id中,R 1、R 2、R 3、R 4、R 5的定义如权利要求1所述;R 61、R 62、R 63、R 64、R 65各自独立地为氢或选自下列取代基:羟基、氨基、硝基、卤素、氰基、SF 5、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、3-8元环烷基、4-10元杂环烷基、3-8元卤代环烷基、C 1-C 6酰胺基、C 1-C 4酯基、C 1-C 6砜基、C 1-C 6卤代砜基;较佳地,R 61、R 62、R 63、R 64、R 65各自独立地为氢或选自下列取代基:羟基、氨基、硝基、卤素、氰基、SF 5、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6砜基、C 1-C 6卤代砜基。
- 如权利要求12所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,在所述结构Ia、Ib、Ic或Id中,R 63、R 64、R 65为氢,R 61、R 62各自独立地为氢或选自下列取代基:羟基、氨基、硝 基、卤素、氰基、SF 5、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、3-8元环烷基、4-10元杂环烷基、3-8元卤代环烷基、C 1-C 6酰胺基、C 1-C 4酯基、C 1-C 6砜基、C 1-C 6卤代砜基;较佳地,R 63、R 64、R 65为氢,R 61、R 62各自独立地为氢或选自下列取代基:羟基、氨基、硝基、卤素、氰基、SF 5、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6砜基、C 1-C 6卤代砜基;更佳地,R 63、R 64、R 65为氢,R 61、R 62各自独立地为氢或选自下列取代基:卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6砜基、C 1-C 6卤代砜基。
- 如权利要求12所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,在所述结构Ia、Ib、Ic或Id中,R 63、R 64、R 65为氢,R 61为氢、C 1-C 6烷基或卤素,R 62为C 1-C 6卤代烷基;较佳地,R 63、R 64、R 65为氢,R 61为氢、甲基或氟,R 62为三氟甲基、二氟甲基。
- 如权利要求12所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,在所述结构Ia、Ib、Ic或Id中,R 21、R 22、R 23各自独立地为氢或C 1-C 6烷基;所述C 1-C 6烷基被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;L为不存在或选自下列的基团:C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基、或所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;所述杂环烷基或杂芳环基中,杂原子选自N、O、S和P中的一种或多种,杂原子数为1-3个;R b分别独立地为氢或选自下列的基团:羟基、氨基、卤素、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;其中所述R e为选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6卤代烷基;n为1、2或3;当R b为多个时,R b为相同或不同的取代基。
- 如权利要求12所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,在所述结构Ia、Ib、Ic或Id中,在基团 中,Y为不存在或选自下列的基团: R 23为氢或C 1-C 6烷基;L为不存在或选自下列的基团:C 1-C 6烷基、C 1-C 6烷氧基;M为不存在或选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6烷氧基;环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子选自N或O,杂原子数为1-3个;当杂原子为多个时,所述杂原子相同或不同;较佳地,环A为不存在或5-6元环烷基或5-6元杂环烷基、5-6元芳环基或5-6元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子选自N或O,杂原子数为1或2个;当杂原子为多个时,所述杂原子相同或不同;R b为氢、C 1-C 6烷基、C 1-C 6环烷基、C 1-C 6卤代烷基、C 1-C 6卤代环烷基、C 1-C 6烷氧基;较佳地R b为氢、C 1-C 6烷基、C 1-C 6卤代烷基。
- 如权利要求12所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,在所述结构Ia、Ib、Ic或Id中,在基团 中,Y为不存在或选自下列的基团:其中,R 23为氢或C 1-C 6烷基、C 1-C 6卤代烷基;较佳地,R 23为氢或C 1-C 3烷基、C 1-C 3卤代烷基;L为不存在或选自下列的基团:C 1-C 6烷基、C 1-C 6烷氧基;较佳地L为不存在或选自下列的基团:C 1-C 3烷基、C 1-C 3烷氧基;M为不存在或选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6烷氧基;较佳地,M为不存在或选自下列的取代基:卤素、C 1-C 3烷基、C 1-C 3烷氧基;环A为不存在或选自3-6元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;较佳地,环A为不存在或3-6元环烷基或5-6元杂环烷基、5-6元芳环基或5-6元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;R b为氢、C 1-C 6烷基、C 1-C 6环烷基、C 1-C 6卤代烷基、C 1-C 6卤代环烷基、C 1-C 6烷氧基;较佳地R b为氢、C 1-C 6烷基、C 1-C 6卤代烷基。
- 如权利要求1、2或12任一所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R 2为氢或选自下列的取代基:卤素、C 1-C 6烷氧基、C 1-C 6烷氧基取代的C 1-C 6烷氧基、5-6元含N或O的杂环烷基取代的C 1-C 6烷氧基、-NH-C 1-C 6烷基、-NH-C 3-C 6环烷基、-NH-卤代C 1-C 6烷基、-NH-卤代C 3-C 6环烷基、-N(C 1-C 6烷基) 2;较佳地;R 2为氢或选自下组的取代基:氟、-NH-C 1-C 6烷基、-NH-C 3-C 6环烷基、-N(C 1-C 6烷基) 2;所述C 1-C 6烷基、C 3-C 6环烷基被1个或多个选自下列取代基取代:卤素或C 1-C 6烷氧基;当取代基为多个时,所述取代基相同或不同;更佳地,R 2为氢或选自下组的取代基:氟、-NH-C 1-C 6烷基、-N(C 1-C 6烷基) 2、-NH-C 3-C 6环烷基;所述C 1-C 6烷基或C 3-C 6环烷基被1个或多个氟或者1个或多个C 1-C 6烷氧基取代。
- 如权利要求1、2或19任一所述的式I所示的6-取代磷酰基喹唑啉类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,其满足下述情形(1)或(2):其中,L为不存在或选自下列的基团:C 1-C 6烷基、氘代C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述C 2-C 6烯基、所述C 2-C 6炔基、或所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;M为不存在或选自下列的取代基:羟基、氨基、硝基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基、或所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;环A为不存在或选自5-10元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;R b分别独立地为氢或选自下列的基团:羟基、氨基、卤素、C 1-C 6烷基、C 1-C 6烷氧基;所述C 1-C 6烷基、所述C 1-C 6烷氧基分别独立地被一个或多个R e取代;当取代基为多个时,所述R e相同或不同;n为1、2或3;其中所述R e为选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6卤代烷基;当R b为多个时,R b为相同或不同的取代基;(2)R 2为 其中,L为不存在或选自下列的基团:C 1-C 6烷基、氘代C 1-C 6烷基、C 1-C 6烷氧基;较佳地L为不存在或选自下列的基团:C 1-C 3烷基、氘代C 1-C 3烷基、C 1-C 3烷氧基;M为不存在或选自下列的取代基:卤素、C 1-C 6烷基、C 1-C 6烷氧基;较佳地,M为不存在或选自下列的取代基:卤素、C 1-C 3烷基、C 1-C 3烷氧基;环A为不存在或选自3-6元环烷基或4-10元杂环烷基、5-10元芳环基或5-10元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;较佳地,环A为不存在或3-6元环烷基或5-6元杂环烷基、5-6元芳环基或5-6元杂芳环基;在所述杂环烷基或杂芳环基中,杂原子为N;R b为氢、卤素、C 1-C 6烷基、C 1-C 6环烷基、C 1-C 6卤代烷基、C 1-C 6卤代环烷基、C 1- C 6烷氧基;较佳地R b为氢、C 1-C 6烷基、C 1-C 6卤代烷基。
- 如权利要求22所述的制备方法,其特征在于,所述方法还包括选自下组的一种或多种步骤:iv)中间体B-1转化为B-1的胺盐后,再与中间体B-2、B-3、B-5或B-6反应;v)所述步骤ii)在钯催化剂存在下反应,得到式I所示喹唑啉衍生物;或者,所述步骤ii)在钯催化剂和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽共同存在下反应,得到式I所示喹唑啉衍生物;vi)所述步骤ii)在惰性气体保护条件下反应,得到式I所示喹唑啉衍生物。
- 一种药物组合物,其特征在于,所述药物组合物包括:如权利要求1-21中任一所述的式I所示磷酰基喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药;和药学上可接受的载体。
- 一种药物组合物,其特征在于,所述药物组合物包括如权利要求1-21中任一所述的式I所示磷酰基喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药;和至少一种其他药理学活性抑制剂。
- 如权利要求27所述的药物组合物,其特征在于,所述其他药理学活性抑制剂为MEK及/或其突变体的抑制剂。
- 一种如权利要求1-21中任一所述的式I所示磷酰基喹唑啉衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途,或权利要求26 所述的药物组合物的用途,或权利要求27所述的药物组合物的用途,所述用途包括:抑制SOS1与RAS家族蛋白的相互作用;和/或,预防和/或治疗SOS1与RAS家族蛋白相关的疾病;和/或,制备用于抑制SOS1与RAS家族蛋白的相互作用,和/或预防和/或治疗SOS1与RAS家族蛋白相关的疾病的药物、药物组合物或制剂;和/或,制备药物,例如制备用于预防和/或治疗癌症、RAS病的药物。
- 如权利要求29所述的用途,其特征在于,所述SOS1与RAS家族蛋白相关的疾病包括:癌症、RAS病;所述RAS病包括努南综合征、心面皮肤综合征、1型遗传性齿龈纤维瘤病、1型神经纤维瘤病、毛细血管畸形-动静脉畸形综合征、科斯特洛综合症和莱格斯综合征;和/或,所述的癌症为胰腺癌;和/或,所述的RAS家族蛋白为KRAS,例如KRASG12C。
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WO2019201848A1 (en) * | 2018-04-18 | 2019-10-24 | Bayer Pharma Aktiengesellschaft | 2-methyl-aza-quinazolines |
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WO2019201848A1 (en) * | 2018-04-18 | 2019-10-24 | Bayer Pharma Aktiengesellschaft | 2-methyl-aza-quinazolines |
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