CN117534684A - pan-KRAS inhibitor compound - Google Patents

pan-KRAS inhibitor compound Download PDF

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CN117534684A
CN117534684A CN202311516025.2A CN202311516025A CN117534684A CN 117534684 A CN117534684 A CN 117534684A CN 202311516025 A CN202311516025 A CN 202311516025A CN 117534684 A CN117534684 A CN 117534684A
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alkylene
formula
compound
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membered
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吕萌
陈宇锋
李非凡
刘灿丰
程万里
陈凯旋
武朋
杨寒
金超凡
孙钊
刘帅帅
何南海
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Hangzhou Arnold Biomedical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The present invention relates to a pan-type material represented by the formula (I) or (II)KRAS inhibitor compounds and pharmaceutical compositions comprising said compounds, and the use of compounds of formula (I) or formula (II) for the prevention and/or treatment of cancer, tumors, inflammatory disorders, autoimmune disorders or immune-mediated disorders.Or alternatively

Description

pan-KRAS inhibitor compound
Technical Field
The invention relates to a compound, in particular to a pan-KRAS inhibitor with high activity and application thereof.
Background
RAS is one of the most frequently mutated genes in human tumors, which mutations occur in about 30% of tumor patients, with KRAS accounting for about 85% of RAS mutations. Mutations in KRAS exist in 88% of pancreatic cancers, 50% of colorectal adenocarcinomas and 32% of lung adenocarcinomas, and the development of targeted KRAS inhibitors is of great clinical significance and value.
KRAS is a membrane-bound protein with gtpase activity that performs the function of "molecular switching" by cycling between a GDP-bound inactive conformation and a GTP-bound active conformation through nucleotide exchange. KRAS in GTP combined state can activate downstream multiple signal paths including RAF-MEK-ERK and PI3K-AKT, and regulate and control life processes such as cell growth, proliferation, differentiation, apoptosis and the like.
KRAS mutations (e.g., G12C, G12D, G12V, G D, etc.) affect gtpase activator protein (GTPase activating proteins, GAPs) -mediated GTP hydrolysis, increasing KRAS in a GTP-bound activated state, overactivating downstream signaling pathways, ultimately leading to tumor initiation and progression. However, due to the lack of a corresponding hydrophobic pocket suitable for drug binding in KRAS proteins, while their affinity for GTP and GDP is in the picomolar scale (-20 pM), development of inhibitors that competitively bind to KRAS has been difficult, and KRAS has been considered a non-patentable target in the last few decades.
Month 5 2021, AMG510 was approved by the FDA for the treatment of KRAS-carrying conditions G12C The mutated locally advanced or metastatic non-small cell lung cancer breaks the history of KRAS "non-patent drug". However, the G12C mutation is only a small part of KRAS mutation, and there is currently no satisfactory effective inhibitor compound for mutation at other KRAS sites, and there is a great clinical demand that has not yet been satisfied, so that development of an effective pan-KRAS inhibitor compound is a need in the art.
Disclosure of Invention
The present invention provides a pan-KRAS inhibitor. Such structures are different from the prior KRAS which functions by covalent binding G12C InhibitorsBut rather by mediating the formation of ternary complexes of chaperones (e.g., cyclopylin a) with KRAS proteins that are ubiquitous in cells. The ternary complex can block the combination of KRAS and downstream effector molecules (such as RAF) through steric hindrance, inhibit the activation of MAPK and PI3K-AKT signal paths, further inhibit the occurrence and development of tumors, and play a role in treating diseases such as tumors.
In one aspect, the present invention provides a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof:
or alternatively
Wherein:
R 1 represent C 1 -C 6 Alkyl, - (C) 1 -C 6 Alkylene) - (C 3 -C 8 Cycloalkyl) - (C) 1 -C 6 Alkylene) - (4-8 membered heterocycloalkyl), - (C 1 -C 6 Alkylene) -ORa, - (C 1 -C 6 Alkylene) -SRa or- (C 1 -C 6 Alkylene) -nra ra';
R 2 represents halogen, cyano, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) - (C 3 -C 8 Cycloalkyl), or- (C) 0 -C 6 Alkylene) - (4-8 membered heterocycloalkyl) which may be optionally substituted with 0, 1 or 2 substituents: -ORa, -SRa or-nra ra';
R 3 represents hydrogen, -O (C) 0 -C 6 Alkylene group Ra, -S (C) 0 -C 6 Alkylene group Ra, -N (C) 0 -C 6 Alkylene) Ra (C) 0 -C 6 Alkylene) R a ', which may optionally be substituted with 0, 1 or 2 substituents selected from: -ORa, -SRa, or nra ra';
Cy 1 Represent C 3 -C 12 Cycloalkyl or 4-12 membered heterocycloalkyl;
R 4 each independently represents hydrogen, halogen, oxo, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 6 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, - (C 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) SRa, - (C) 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) CORa, - (C) 0 -C 6 Alkylene) COORa, - (C 0 -C 6 Alkylene) CONRaRa', - (C 0 -C 6 Alkylene) NRaCORa', - (C 0 -C 6 Alkylene) oconra' - (C) 0 -C 6 Alkylene) nraconra ra', - (C 0 -C 6 Alkylene) SORa, - (C 0 -C 6 Alkylene) S (O) 2 Ra、-(C 0 -C 6 Alkylene) NRaS (O) 2 Ra’、-(C 0 -C 6 Alkylene) CN, - (C) 0 -C 6 Alkylene) (C6-C10 aryl) or- (C 0 -C 6 Alkylene) (5-12 membered heteroaryl); wherein Cy 1 R on two C atoms of (C) 4 Together with the C atom to which it is attached and the atoms between the two C atoms may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or Cy 1 Two R's on the same C atom 4 Together with the C atom to which it is attached, may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;
R 5 、R 5 ' each independently represents hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl or- (C) 0 -C 6 Alkylene) CN;
L 1 、L 2 each independently represents- (C) 0 -C 6 ) Alkylene-, which optionally may be substituted with 0, 1, 2 or 3C' s 1 -C 3 Alkyl substituted, or two C atoms on the same C atom 1 -C 3 The alkyl substituents may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;
Cy 2 selected from C 3 -C 12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6 -C 12 Aryl or 5-12 membered heteroaryl;
Cy 3 selected from C 3 -C 12 Cycloalkyl or 4-12 membered heterocycloalkyl;
when Cy 2 Or Cy 3 When a heterocycloalkyl group containing an S or P atom is included, optionally the S or P atom can be oxidized to-S (O) 2 -S (O) (NRa) -or-P (O) Ra-;
R 6 each independently selected from: hydrogen, halogen, oxo, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 Cycloalkyl) - (C) 0 -C 6 Alkylene) (4-8 membered heterocycloalkyl), - (C) 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) SRa, - (C) 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) C (O) Ra, - (C) 0 -C 6 Alkylene) OC (O) NRaRa', - (C) 0 -C 6 Alkylene) NRaC (O) ORa', - (C) 0 -C 6 Alkylene) NRaC (O) NRaRa', - (C) 0 -C 6 Alkylene) C (O) ORa, - (C 0 -C 6 Alkylene) C (O) NRaRa', - (C) 0 -C 6 Alkylene) S (O) 2 Ra、-P(O)RaRa’、-(C 0 -C 6 ) Alkylene CN, or Cy 2 Two R's on the same C atom 6 A spiro, bridged or fused ring may be formed, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; or Cy 2 Two R's on two adjacent ring atoms 6 May form a fused ring with the two ring atoms, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; or Cy 2 Two R's on two ring atoms not adjacent to each other 6 Can be combined withThe two ring atoms form a bridged ring, which optionally may contain 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; and optionally, the spiro, parallel or bridged ring may contain 0, 1, 2 or 3 unsaturated bonds;
R 6 ' each independently selected from: hydrogen, halogen, oxo, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 Cycloalkyl) - (C) 0 -C 6 Alkylene) (4-8 membered heterocycloalkyl), - (C) 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) SRa, - (C) 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) C (O) Ra, - (C) 0 -C 6 Alkylene) OC (O) NRaRa', - (C) 0 -C 6 Alkylene) NRaC (O) ORa', - (C) 0 -C 6 Alkylene) NRaC (O) NRaRa', - (C) 0 -C 6 Alkylene) C (O) ORa, - (C 0 -C 6 Alkylene) C (O) NRaRa', - (C) 0 -C 6 Alkylene) S (O) 2 Ra, or- (C) 0 -C 6 ) An alkylene group CN; or Cy 3 Two R's on the same C atom 6 ' may form a spiro, bridged or fused ring, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; or Cy 3 Two R's on two adjacent ring atoms 6 ' may form a fused ring with the two ring atoms, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; or Cy 3 Two R's on two ring atoms not adjacent to each other 6 ' may form a bridged ring with the two ring atoms, which ring may optionally contain 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; and optionally, the spiro, parallel or bridged ring may contain 0, 1, 2 or 3 unsaturated bonds;
or R is 6 And R is R 6 ' may be in conjunction with L 2 Forming a 4-8 membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O, S;
R 7 、R 7 ' each independently selected from hydrogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) C 3 -C 8 Cycloalkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, - (C 1 -C 6 Alkylene) ORa, - (C 1 -C 6 Alkylene) SRa, - (C) 1 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) C 6 -C 12 Aromatic radical, - (C) 0 -C 6 Alkylene) (5-12 membered heteroaryl), - (C) 0 -C 6 Alkylene) NRaC (O) Ra', - (C) 0 -C 6 Alkylene) C (O) NRaRa', - (C) 0 -C 6 Alkylene) C (O) Ra or- (C) 0 -C 6 Alkylene) C (O) ORa, wherein said C 6 -C 12 Optionally, the aryl or 5-12 membered heteroaryl group may be substituted with 0, 1, 2 or 3 groups selected from halogen, C 1 -C 6 Alkyl, C 3 -C 8 Substituted by a cycloalkyl radical or R 7 And R is R 7 ' the N atom to which it is attached forms a 4-8 membered ring, said 4-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O, P or S; when R is 7 、R 7 ' is a ring containing S or P atoms, or R 7 And R is R 7 Where the' formed ring contains S or P atoms, the S or P atoms may optionally be oxidized to-S (O) 2 -S (O) (NRa) -or-P (O) Ra-;
wherein p represents 0, 1, 2, 3 or 4;
q represents 0, 1 or 2;
m, n each independently represent 0, 1, 2, 3 or 4;
ra, ra' each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 4-8 membered heterocycloalkyl; wherein when Ra, ra 'are attached to the same N atom, the Ra and Ra' together with the commonly attached N atom may form a 4-8 membered ring, which 4-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;
the alkyl, cycloalkyl, heterocycloalkyl, alkylene groups each independently may be substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.
In one embodiment, R 1 Represent C 1 -C 6 Alkyl, - (C) 1 -C 6 Alkylene) - (C 3 -C 8 Cycloalkyl) or- (C) 1 -C 6 Alkylene) - (4-8 membered heterocycloalkyl); preferably, R 1 Represent C 1 -C 6 An alkyl group; more preferably, R 1 Represent C 1 -C 3 An alkyl group.
In one embodiment, R 2 Represent C 1 -C 6 Alkyl optionally substituted with 0, 1 or 2-ORa substituents; preferably, R 2 Representation ofStill more preferably, R 2 Representation->More preferably, R 2 Representation->Wherein, is R 2 A site linked to the site linked thereto in formula (I).
In one embodiment, R 3 Represents hydrogen or-O (C) 1 -C 6 ) Alkyl, -O (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, -O (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, which may be optionally substituted with 0 or 1 substituents selected from: ORa, -SRa, or NRaRa'.
In one embodiment, cy 1 Represent C 3 -C 8 Cycloalkyl or 4-8 membered heterocycloalkyl.
In one embodiment, R 4 Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) SRa, - (C) 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) CONRaRa', - (C 0 -C 6 Alkylene) NRaCORa', - (C 0 -C 6 Alkylene) oconra' - (C) 0 -C 6 Alkylene) CN, - (C) 0 -C 6 Alkylene) (5-12 membered heteroaryl), or Cy 1 R on two C atoms of (C) 4 Together with the C atom to which it is attached and the atoms between the two C atoms may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or Cy 1 Two R's on the same C atom 4 Together with the C atom to which it is attached, may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.
In a more preferred embodiment, R 4 Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) CONRaRa', - (C 0 -C 6 Alkylene) (5-12 membered heteroaryl), or Cy 1 R on two C atoms of (C) 4 Together with the C atom to which it is attached and the atoms between the two C atoms may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or Cy 1 Two R's on the same C atom 4 Together with the C atom to which it is attached, may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.
In one embodiment, R 5 、R 5 ' each independently represents hydrogen or C 1 -C 6 An alkyl group; more preferably, R 5 、R 5 ' each independently represents hydrogen or methyl.
In one embodiment, L 1 、L 2 Each independently represents- (C) 0 -C 3 ) Alkylene-, which optionally may be substituted with 0, 1, 2 or 3C' s 1 -C 3 Alkyl substituted, or two C atoms on the same C atom 1 -C 3 The alkyl substituents may form a 3-4 membered ring;
in one embodiment, cy 2 Selected from C 3 -C 12 Cycloalkyl, 4-12 membered heterocycloalkyl, more preferably Cy 2 Is 4-12 membered heterocycloalkyl, and Cy 2 Can be spiro, bridged, and fused.
In one embodiment, cy 2 Selected from C 6 -C 12 Aryl or 5-12 membered heteroaryl, more preferably Cy 2 Is a 5-12 membered heteroaryl, and Cy 2 Can be spiro, bridged, and fused.
In one embodiment, cy 3 Is 4-12 membered heterocycloalkyl, and Cy 3 Can be spiro, bridged, and fused.
In one embodiment, R 6 Each independently selected from: hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, - (C 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) OC (O) NRaRa', - (C) 0 -C 6 Alkylene) NRaC (O) ORa ', -P (O) RaRa', - (C) 0 -C 6 Alkylene) C (O) Ra, - (C) 0 -C 6 ) Alkylene CN, or as claimed in claim 1, two R 6 A spiro, bridged or fused ring can be formed, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S and optionally containing 0, 1, 2 or 3 unsaturated bonds; when two R 6 When a ring containing an unsaturated bond is formed, the ring is preferably an aromatic heterocycle.
In one embodiment, R 6 ' each independently selected from: hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl- (C 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) OC (O) NRaRa', - (C) 0 -C 6 Alkylene) NRaC (O) ORa', - (C) 0 -C 6 Alkylene) C (O) Ra, - (C) 0 -C 6 ) Alkylene CN, or as claimed in claim 1, two R 6 ' may form a spiro, bridged or fused ring, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S, and the ringOptionally may contain 0, 1, 2 or 3 unsaturated bonds; when two R 6 When the ring containing an unsaturated bond is formed, preferably, the ring is an aromatic heterocycle.
In one embodiment, R 7 、R 7 ' each independently selected from C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, - (C 1 -C 6 Alkylene) ORa, - (C 1 -C 6 Alkylene) SRa, - (C) 1 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) (5-12 membered heteroaryl), - (C) 0 -C 6 Alkylene) NRaC (O) Ra' or- (C) 0 -C 6 Alkylene) C (O) NRaRa', wherein the 5-12 membered heteroaryl optionally may be substituted with 0, 1, 2 or 3 groups selected from halogen, C 1 -C 6 Substituted by alkyl radicals or R 7 And R is R 7 ' the N atom to which it is attached forms a 4-8 membered ring, said 4-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O, P or S; when R is 7 、R 7 ' is a ring containing S or P atoms, or R 7 And R is R 7 Where the' formed ring contains S or P atoms, the S or P atoms may optionally be oxidized to-S (O) 2 -, -S (O) (NRa) -or-P (O) Ra-.
In one embodiment, p is preferably 0, 1 or 2; or q is preferably 0 or 1; or m, n are each independently preferably 0, 1 or 2.
In one embodiment of the present invention, in one embodiment,comprising at least one secondary amine or tertiary amine; preferably, at least one tertiary amine is included; wherein>A site linked to the site linked thereto in formula (I).
In one embodiment, R 7 、R 7 At most one of which is a hydrogen atom.
In one embodiment, the moiety-Cy of formula (I) 1 -(R 4 ) The structure of p is selected from the following:
wherein, represents-Cy 1 -(R 4 ) p is attached to the site of the linkage site in formula (I).
In one embodiment, the structure in formula (I)Selected from the following:
wherein, representA site linked to the site linked thereto in formula (I).
In one embodiment, the structure in formula (II)Selected from the following:
wherein, representA site linked to a site linked thereto in the formula (II).
In one embodiment, the compound of formula (I) has the structure of formula (III) and the compound of formula (II) has the structure of formula (IV):
In another aspect, the invention provides a compound having the structure:
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in one aspect, the invention provides a pharmaceutical composition comprising a compound as described above or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof.
In a further aspect, the present invention provides the use of a compound of the foregoing, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer or pharmaceutical composition thereof, for the manufacture of a medicament for the prevention and/or treatment of cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
In yet another aspect, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of the foregoing compound or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer and/or pharmaceutical composition thereof.
It is particularly noted that, in this context, when referring to "compounds" of the structure of formula (I), formula (II), formula (III) formula (IV), stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof are also generally contemplated.
It is well known to those skilled in the art that salts, solvates, hydrates of a compound are alternative forms of the compound, which can all be converted into the compound under certain conditions, and therefore, particular attention is paid herein to the compounds of the structures of formula (I), formula (II), formula (III) and formula (IV), generally also including pharmaceutically acceptable salts thereof, and further including solvates and hydrates thereof.
Similarly, when a compound is referred to herein, prodrugs, metabolites, and nitrogen oxides thereof are also generally included.
Pharmaceutically acceptable salts according to the invention may be formed using, for example, the following mineral or organic acids: by "pharmaceutically acceptable salt" is meant a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or free acid with a suitable reagent alone, as outlined below. For example, the free base function may be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts of amino groups with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic or malonic) or by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, sodium alginate, ascorbate, aspartic acid salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentanepropionate salts, digluconate salts, dodecylsulfate salts, ethanesulfonate salts, formate salts, fumaric acid salts, glucoheptonate salts, glycerophosphate salts, gluconate salts, southern sulfate salts, heptanoate salts, caproate salts, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, pamoate salts, pectate salts, persulfates, 3-phenylpropionate salts, phosphate salts, bitter salts, pivalate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.
The pharmaceutically acceptable salts of the invention may be prepared by conventional methods, for example by dissolving the compounds of the invention in a water miscible organic solvent (e.g. acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an organic or inorganic acid aqueous solution to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.
The precursors or metabolites of the invention may be precursors or metabolites well known in the art, as long as the precursors or metabolites are converted into compounds by in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the formula described above, for example by metabolism in vivo, or N-demethylation of a compound of the invention.
"solvate" as used herein means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolamides. Solvation methods are well known in the art.
The term "stereoisomers" as used herein is divided into conformational isomerism and configurational isomerism, which may be also divided into cis-trans isomerism and optical isomerism (i.e. optical isomerism), and conformational isomerism refers to a stereoisomerism phenomenon that an organic molecule with a certain configuration makes each atom or group of molecules generate different arrangement modes in space due to rotation or twisting of carbon and carbon single bonds, and commonly includes structures of alkane and cycloalkane compounds, such as chair-type conformations and boat-type conformations, which occur in cyclohexane structures. "stereoisomers" means that when a compound of the invention contains one or more asymmetric centers, it is useful as racemate and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the invention have asymmetric centers, each of which produces two optical isomers, and the scope of the invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogen through displacement of one or more double bonds. For example, the ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds of formula (I) through formula (IV) are included within the scope of the present invention.
The term "isotopically-labeled" as used herein refers to molecules wherein the compound is isotopically labeled. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, 2 h and 3 h is formed; carbon isotopes: 11 C, 13 c and C 14 C, performing operation; chlorine isotopes: 35 cl and Cl 37 Cl; fluorine parityPlain: 18 f, performing the process; iodine isotopes: 123 i and 125 i, a step of I; nitrogen isotopes: 13 n and 15 n; oxygen isotopes: 15 O, 17 o and 18 isotopes of O and sulfur 35 S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. In particular deuterium 3 H and carbon 13 C, because they are easily labeled and conveniently detected, the application is wider. Certain heavy isotopes, such as heavy hydrogen @, for example 2 H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the aim of reducing the dosage and providing curative effect advantages. Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds.
The invention also provides the use of the compounds of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of cancer, tumour, inflammatory disease, autoimmune disease or immune mediated disease.
Furthermore, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising the compound of the present invention as an active ingredient. The pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.
Furthermore, the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease comprising administering to a mammal in need thereof a compound of the present invention.
Representative examples of inflammatory, autoimmune and immune-mediated diseases may include but are not limited to, arthritis, rheumatoid arthritis, spinal arthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic Lupus Erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, pulmonary inflammation, adult Respiratory Distress Syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory diseases, chronic Obstructive Pulmonary Disease (COPD), cardiovascular diseases, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, sjogren's syndrome, autoimmune thyroid disease urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenograft, idiopathic Thrombocytopenic Purpura (ITP), parkinson's disease, alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute Lymphoblastic Leukemia (ALL), chronic Lymphoblastic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), hairy cell leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma and follicular lymphoma.
Representative examples of cancers or tumors may include but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral nerve ectodermal tumors hodgkin's lymphoma, non-hodgkin's lymphoma, burkitt's lymphoma, acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchogenic carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choriocarcinoma, seminoma, rhabdomyosarcoma, craniopharyngeal pipe carcinoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, ewing's sarcoma, or plasmacytoma.
The compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced anticancer effects when administered in combination with additional anticancer agents or immune checkpoint inhibitors for the treatment of cancer or tumors.
Representative examples of anticancer agents for the treatment of cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutalamine, gonadorelin analogs megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, calcium folinate, sirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabotinib, ceridinib, crenolanib, crizotinib, dabrafenib, dacatinib, dacomitinib, dacarbatinib, dasatinib, multi-vitamin tinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, everatinib, imatinib, inipa, lapatinib, lenvatinib, linifanib, linsitinib, martinib, mometatinib, mo Tisha, lenatinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, piciliib, platinib, quizab, genitinib, lotinib, rigosertib, rucaparib, ruxotinib, casatib, and calitinib Tinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, trimetanib, vandetanib, valicarb, vemurafenib, valcanib, valavermectin, bevacizumab, belanto Shan Kangwei statin, katussah-makino, cetuximab, denomab, gemtuzumab, ipilimumab, nituzumab, ofatuzumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitor, CSF1R inhibitor, A2A and/or A2B receptor antagonist, IDO inhibitor, anti-PD-1 antibody, anti-PD-L 1 Antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced therapeutic effects when administered in combination with additional therapeutic agents for the treatment of inflammatory, autoimmune and immune-mediated diseases.
Representative examples of therapeutic agents for the treatment of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydroprednisone, methyl hydroprednisone, cortisone, hydroxy cortisone, betamethasone, dexamethasone, and the like), methotrexate, leflunomide, anti-tnfα agents (e.g., etanercept, infliximab, ada Li Shan resistance, and the like), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, and the like), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, and the like), and at least one or more therapeutic agents selected therefrom may be included in the pharmaceutical compositions of the present invention.
Other features of the present invention will become apparent in the course of describing exemplary embodiments of the invention, which are presented to illustrate the invention and are not intended to be limiting thereof, the following examples being prepared, isolated and characterized using the methods disclosed herein.
The compounds of the present invention may be prepared in a variety of ways known to those skilled in the art of organic synthesis, and may be synthesized using the methods described below as well as synthetic methods known in the art of organic synthetic chemistry or by variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the transformation to be effected. Those skilled in the art of organic synthesis will understand that the functionalities present on the molecule are consistent with the proposed transformations. This sometimes requires judgment to change the order or starting materials of the synthesis steps to obtain the desired compounds of the invention.
Detailed Description
The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In this application, the use of "or" and "means" and/or "unless otherwise indicated.
In the description and claims, a given formula or name shall encompass all stereoisomers and optical isomers thereof, as well as racemates in which the above isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Various geometric isomers of c=c double bonds, c=n double bonds, ring systems, etc. may also be present in the compounds, and all such stable isomers are contemplated within the present invention. The present invention describes cis-and trans- (or E-and Z-) geometric isomers of the compounds of the present invention, and which may be separated into mixtures of isomers or separate isomeric forms. The compounds of the invention may be isolated in optically active or racemic forms. All processes for preparing the compounds of the invention and intermediates prepared therein are considered part of the present invention. When preparing the enantiomeric or diastereomeric products, they can be separated by conventional methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. Both the free form and the salt of these end products are within the scope of the invention. If desired, one form of the compound may be converted to another form. The free base or acid may be converted to a salt; the salt may be converted to the free compound or another salt; mixtures of the isomeric compounds of the invention may be separated into the individual isomers. The compounds of the invention, free forms and salts thereof, may exist in various tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It is to be understood that all tautomeric forms that may exist are included within the invention.
In the present invention, when the linking group is not specified in the linking direction, the linking direction is arbitrary, for exampleWherein L is-C (O) NH-in which case-C (O) NH-may be constituted by linking phenyl and cyclohexyl in the order of reading from left to right>The phenyl and cyclohexyl groups may also be linked in reading order from left to right to form +.>The combination of the linking group and the linked group is only allowed if such would result in a stable compound. Some preferred embodiments of the invention follow a read order from left to right.
Unless otherwise defined, the definition of substituents of the invention are each independent of, and not interrelated with, each other, e.g., by way of example, and not by way of exhaustive, in one aspect, R for a substituent a (or R) a ') which are independent of each other in the definition of the different substituents. Specifically, for R a (or R) a ' when a definition is selected in a substituent, it does not mean that R a (or R) a ') have the same definition in all other substituents. More specifically, for example (by way of non-exhaustive list) for NR a R a In' when R a (or R) a Where the definition of') is selected from hydrogen, it is not meant to be in-C (O) -NR a R a In' R a (or R) a ') is necessarily hydrogen. In another aspect, when more than one R is present in a substituent a (or R) a ') at the same time, these R a (or R) a ') are also independent of each other. For example, in the substituent- (CR) a R a’ ) m -O-(CR a R a’ ) n In the case where m+n is 2 or more, m+n R's therein a (or R) a ') are independent of each other and may have the same or different meanings.
Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkylamino, substituted alkanoylamino, substituted arylamino, substituted aralkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, for example, -SO 2 NH 2 Substituted sulphonylamino, nitro, cyano, carboxyl, carbamoyl, e.g. -CONH 2 Substituted carbamoyl such as-CONH alkyl, -CONH aryl, -CONH arylalkyl or where there are two substituents on the nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclyl.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C 1 -C 6 Alkyl "means having 1 to 6 carbon atomsIs a hydrocarbon group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). The alkyl group may be unsubstituted or substituted, and when substituted, it may be substituted at any useful point of attachment, preferably one or more of deuterium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In this context, alkyl is preferably alkyl having 1 to 6, more preferably having 1 to 4 carbon atoms.
The term "alkylene" as used herein is intended to include branched, straight chain, saturated aliphatic hydrocarbon groups with the indicated number of carbon atoms, with or without cyclic alkyl groups, which are residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. For example, "C 0 -C 6 Alkylene "means an alkylene group having 0 (i.e., bond), 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), propylene (e.g., - (CH) 2 ) 3 -、-(CHCH 3 )CH 2 -、-(CHCH 2 CH) -), butylene (e.g., - (CH) 2 ) 4 -、-CH 2 CH(CH 2 CH 3 )-、-CH 2 (CHCH 2 CH) -and the like), pentylene (e.g., - (CH) 2 ) 5 -、-CH 2 CH(CH(CH 3 ) 2 )-、-CH 2 (CHCH 2 CH)CH 2 -etc.), hexylene (e.g., - (CH) 2 ) 6 -、-CH 2 CH 2 CH(CH(CH 3 ) 2 )-、-CH 2 (CHCH(CH 3 )CH)CH 2 -and the like. In this context, alkylene is preferably alkylene having from 0 to 6, from 0 to 4, from 0 to 3, from 1 to 6, from 1 to 4, from 1 to 3 carbon atoms. In this context, alkylene is preferably alkylene which does not comprise cyclic alkyl groups.
The term "cycloalkyl" refers to a monocyclic, polycyclic, or branched cyclic alkyl group. For example, C 3 -C 12 Including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Cyclic alkyl groups of multiple rings, such as bicyclic and tricyclic, include bridged, spiro, or fused ring cycloalkyl groups. Cycloalkyl groups may be unsubstituted or substituted, and when substituted, they may be substituted at any useful point of attachment, preferably one or more of halogen, hydroxy, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the invention, cycloalkyl is preferably C 3 -C 12 Cycloalkyl groups, more preferably C 3 -C 8 Cycloalkyl groups.
Similarly, the term "heterocycloalkyl" refers to a meta-cyclic structure in which at least one carbon atom on the cyclic structure of the heterocycloalkyl group is replaced with a heteroatom selected from N, O, S and P. Wherein the N atoms are optionally quaternized and the N and S atoms are optionally oxidized (i.e., NO, SO, and SO 2 ). It includes monocyclic, bicyclic and tricyclic heterocyclic ring systems, wherein bicyclic and tricyclic heterocyclic ring systems include spiro, fused and bridged heterocyclic rings. Heterocycloalkyl groups can be unsubstituted or substituted, and when substituted, can be substituted at any useful point of attachment, preferably from one or more of halogen, hydroxy, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the present invention, the heterocycloalkyl group is preferably a 4-12 membered heterocycloalkyl group, more preferably a 4-8 membered heterocycloalkyl group.
In the present invention, the term "fused ring" refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms with each other.
In the present invention, the term "bridged ring" refers to a polycyclic group in which two rings share more than two ring atoms in the system.
In the present invention, the term "spiro" refers to a polycyclic group having one carbon atom (referred to as spiro atom) shared between monocyclic rings.
The term "alkenyl" means containing one or moreStraight or branched hydrocarbon groups having a double bond and typically from 2 to 20 carbon atoms in length. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In this context, alkenyl groups are preferably C 2 -C 6 Alkenyl groups.
The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl means C 3 -C 8 Cyclic alkenyl groups of (c) including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl includes bridged, spiro, or fused cyclic alkenyl.
The term "alkynyl" denotes a straight or branched hydrocarbon radical containing one or more triple bonds and typically ranging in length from 2 to 20 carbon atoms. For example, "C 2 -C 6 Alkynyl "contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like. In this context, alkynyl is preferably C 2 -C 6 Alkynyl groups.
The term "alkoxy" or "alkyloxy" refers to an-O-alkyl group. "C 1 -C 6 Alkoxy "(or alkyloxy) is intended to include C 1 、C 2 、C 3 、C 4 、C 5 、C 6 An alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. In this context, alkoxy groups are preferably alkoxy groups having 1 to 6, more preferably having 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" means a sulfur-bridged alkyl group as defined above having the indicated number of carbon atoms; such as methyl-S-and ethyl-S-. Alkoxy groups may be unsubstituted or substituted, and when substituted, they may be substituted at any useful point of attachment, preferably one or more of deuterium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
The term "carbonyl" refers to an organofunctional group (c=o) formed by the double bond connection of two atoms of carbon and oxygen.
The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl, and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. The dashed lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom. Aryl groups may be unsubstituted or substituted, and when substituted, they may be substituted at any useful point of attachment, preferably one or more of deuterium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
The term "heteroaryl" means a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered aromatic polycyclic heterocycle which is fully unsaturated or partially unsaturated and which contains carbon atoms and 1,2,3 or 4 heteroatoms independently selected from N, O and S; it includes a structure in which a cycloalkane or a heterocycloalkane is condensed with an aromatic ring such as a benzene ring or a heteroaromatic ring such as pyridine, and the site of the structure as a substituent may be located on a cycloalkane, a heterocycloalkyl, an aromatic ring or a heteroaromatic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent if defined). The heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is no greater than 1. Heteroaryl groups may be unsubstituted or substituted, and when substituted, they may be substituted at any useful point of attachment, preferably from one or more of halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of aryl radicals include, but are not limited to, acridinyl, azetidinyl, azepinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazole, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromen, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolyl (indolenyl), indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinyl (atinoyl), isobenzofuranyl, isochromanyl isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, naphthyridinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazinyl, 1,2, 4-thiadiazinyl, 1,2, 5-thiadiazinyl, 1,3, 4-thiadiazinyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 5,6,7, 8-tetrahydro-quinolinyl, 2, 3-dihydro-benzofuranyl, chromanyl, 1,2,3, 4-tetrahydro-quinoxalinyl and 1,2,3, 4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed from "aryl" and monocyclic "heteroaryl" as defined above, such as, but not limited to "-phenyl bipyridyl-", "-phenyl bipyrimidinyl", "-pyridinyl biphenyl", "-pyridinyl bipyrimidinyl-", "-pyrimidinyl biphenyl-"; wherein the invention also includes fused and spiro compounds containing, for example, the above-described heterocycles.
The term "substituted" as used herein means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valence is maintained and that the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., c= C, C =n or n=n).
In the present disclosure, the one or more halogens may each be independently selected from fluorine, chlorine, bromine, and iodine.
"halo" or "halogen" includes fluoro, chloro, bromo and iodo. "haloalkyl"/"haloalkylene" is intended to include branched and straight chain saturated alkyl/alkylene groups having the indicated number of carbon atoms and substituted with 1 or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with 1 or more fluorine atoms. "halocycloalkyl"/"haloheterocycloalkyl" is intended to include cycloalkyl/heterocycloalkyl groups having the indicated number of carbon atoms and substituted with 1 or more halogens. In the present invention, the halogen atom is preferably fluorine or chlorine, more preferably fluorine.
"haloalkoxy" or "haloalkyloxy" means an oxygen-bridged haloalkyl as defined above having the indicated number of carbon atoms. For example, "halo C 1 -C 6 Alkoxy "is intended to include C 1 、C 2 、C 3 、C 4 、C 5 、C 6 Haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a thio-bridged haloalkyl as defined above having the indicated number of carbon atoms; such as trifluoromethyl-S-and pentafluoroethyl-S-.
In the present disclosure, C is used when referring to some substituents x1 -C x2 This means that the number of carbon atoms in the substituent group may be x1 to x 2. For example, C 0 -C 8 Represents that the radical contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 1 -C 8 Representing that the radicals contain 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 2 -C 8 Representing that the radicals contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C 3 -C 8 Representing that the radicals contain 3, 4, 5, 6, 7 or 8 carbon atoms, C 4 -C 8 Representing that the radicals contain 4, 5, 6, 7 or 8 carbon atoms, C 0 -C 6 Represents that the radical contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C 1 -C 6 Representing that the radicals contain 1, 2, 3, 4, 5 or 6 carbon atoms, C 2 -C 6 Representing that the radicals contain 2, 3, 4, 5 or 6 carbon atoms, C 3 -C 6 Meaning that the group contains 3, 4, 5 or 6 carbon atoms.
In the present disclosure, the expression "x1-x2 membered ring" is used when referring to a cyclic group (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the number of ring atoms of the group can be x1 to x 2. For example, the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, the number of ring atoms of which may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring represents that the cyclic group may be a 3, 4, 5 or 6 membered ring, and the number of ring atoms may be 3, 4, 5 or 6; the 3-8 membered ring represents that the cyclic group may be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring represents that the cyclic group may be a 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8 or 9; the 4-7 membered ring represents that the cyclic group may be a 4, 5, 6 or 7 membered ring, and the number of ring atoms may be 4, 5, 6 or 7; the 5-8 membered ring represents that the cyclic group may be a 5, 6, 7 or 8 membered ring, and the number of ring atoms may be 5, 6, 7 or 8; the 5-12 membered ring represents that the cyclic group may be a 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 5, 6, 7, 8, 9, 10, 11 or 12; the 6-12 membered ring means that the cyclic group may be a 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 6, 7, 8, 9, 10, 11 or 12. The ring atom may be a carbon atom or a heteroatom, for example a heteroatom selected from N, O and S. When the ring is a heterocyclic ring, the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example heteroatoms selected from N, O and S.
In the case where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention. Thus, the nitrogen atoms shown and claimed are considered to both encompass the nitrogen shown and its N-oxides to obtain the derivatives of the invention.
When any variable occurs more than one time in any composition or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3R, then the group may optionally be substituted with up to three R groups, and R is independently selected at each occurrence from the definition of R. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "patient" as used herein refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, monkey, horse, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.
The term "effective amount" as used herein means the amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount of: such amounts result in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, as compared to a corresponding subject not receiving such amounts. An effective amount may be administered in one or more administrations, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an effective amount to enhance normal physiological function.
The term "treatment" as used herein includes any effect that results in an improvement in a condition, disease, disorder, etc., such as a reduction, decrease, modulation, improvement or elimination, or improvement of symptoms thereof.
The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are: it is suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic response, and/or other problems or complications commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.
The phrase "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" as used herein means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium or zinc stearate, or stearic acid), or solvent encapsulating material, which involves carrying or transporting the subject compound from one organ or body part to another organ or body part. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
The term "pharmaceutical composition" means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant a medium commonly accepted in the art for delivery of bioactive agents to animals, particularly mammals, including (i.e., adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, perfuming, antibacterial, antifungal, lubricating, and dispersing agents, depending on the mode of administration and nature of the dosage form.
Specific pharmaceutical and medical terminology
The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
The term "cancer", as used herein, refers to an abnormal growth of cells that is not controllable and is capable of metastasis (transmission) under certain conditions. Cancers of this type include, but are not limited to, solid tumors (e.g., bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organ (e.g., thyroid), prostate, skin (melanoma), or hematological tumors (e.g., non-leukemia).
The term "co-administration" or similar terms, as used herein, refers to administration of several selected therapeutic agents to a patient, administered at the same or different times, in the same or different modes of administration.
The term "enhance" or "potentiating," as used herein, means that the intended result can be increased or prolonged in either efficacy or duration. Thus, in enhancing the therapeutic effect of a drug, the term "capable of enhancing" refers to the ability of the drug to increase or prolong the efficacy or duration of the drug in the system. As used herein, "potentiating value" means that the ability of another therapeutic agent to be maximally enhanced in an ideal system.
The term "immunological disorder" refers to a disease or condition that produces an adverse or detrimental response to an endogenous or exogenous antigen. As a result, the cells are often dysfunctional, or thus destroyed and dysfunctional, or destroy organs or tissues that may develop immune symptoms.
The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; domestic animals such as rabbits and dogs; laboratory animals include rodents such as rats, mice, guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In a preferred aspect, the mammal selected is a human.
The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing and/or treating signs caused by diseases or symptoms.
As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
Examples
Universal procedure
When the preparation route is not included, the raw materials and reagents used in the present invention are known products, and can be synthesized according to the methods known in the art, or can be obtained by purchasing commercial products. The commercial reagents used were all used without further purification.
Room temperature refers to 20-30 ℃.
The reaction examples are not particularly described, and the reactions are all carried out under nitrogen atmosphere. The nitrogen atmosphere is defined as the reaction flask being attached to a balloon of about 1L of nitrogen.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times. The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L.
Microwave reaction is usedInitiator + microwave reactor.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was determined using (Bruker Assetnd TM 500) nuclear magnetic resonance apparatus, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS). The following abbreviations are used for multiplicity of NMR signals: s=singlet, brs=broad, d=doublet, t=triplet, m=multiplet. Coupling constants are listed as J values, measured in Hz.
Reverse phase preparative chromatography a Thermo (UltiMate 3000) reverse phase preparative chromatograph was used. Quick column chromatography using Ai Jieer (FS-9200T) automatic column passing machine, silica gel pre-packed column using SantaiAnd (5) preassembling the column. The specification of the thin layer chromatography separation and purification product adopted by the smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm.
The LC-MS analysis method is as follows:
1) Mass spectrometry method: thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameter setting: the temperature of the drying gas is 350 ℃; the flow rate of the drying gas is 10L/min; MS Range 120-1000.
2) Liquid phase conditions: chromatographic column: waters XBiridge (3.5 μm,50 mm. Times.4.6 mm); mobile phase a was an aqueous solution containing 0.1% ammonium bicarbonate and mobile phase B was an acetonitrile solution, and linear gradient elution was performed according to table 1; flow rate: 2mL/min; column temperature: 30 ℃; ultraviolet detection wavelength: 214nm,254nm,280nm; the sample volume was 2. Mu.L.
TABLE 1 gradient elution conditions
The HPLC analysis method is as follows:
chromatographic column: waters XBridge phenyl (3.5 μm,150 mm. Times.4.6 mm); mobile phase a was an aqueous solution containing 0.1% ammonium bicarbonate, mobile phase B was an acetonitrile solution, and linear gradient elution was performed according to table 2; flow rate: 1mL/min; column temperature: 30 ℃; ultraviolet detection wavelength: 214nm,254nm,280nm; the sample volume was 2. Mu.L.
TABLE 2 gradient elution conditions
The synthesis method of some intermediates in the invention is as follows:
intermediate 1
Intermediate 1 was prepared by the following steps:
the first step: 2.2-dimethyl-3-hydroxy methyl propionate INT-1a (100 g,756.7 mmol) was dissolved in N, N-dimethylformamide (1L), imidazole (128.8 g,1.89 mol) was added, and the solution was stirred and tert-butyldiphenylchlorosilane (228.8 g,832.3 mmol) was added dropwise at room temperature, and stirring was continued for 4 hours after the addition was completed. After the reaction was complete, the reaction solution was poured into 3L ice water and the suspension was extracted with ethyl acetate (1L x 2)The organic phase was taken, washed 3 times with water and concentrated under reduced pressure to give INT-1b as a colorless oil, which was used directly in the next step without purification. ESI-MS (m/z): 371.2[ M+H ]] + 。
And a second step of: the residue INT-1b obtained in the previous step was added to 2L of methanol, and 360g of a prepared 33% aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 17 hours. After the reaction is finished, 1L of water is added, methanol is removed under reduced pressure, the residual liquid is extracted by petroleum ether (1L of 5), the pH value of the extracted water phase is adjusted to 4-5 by hydrochloric acid, stirring is continued for 30 minutes, suction filtration is carried out, and white solid INT-1c (269 g, yield 90%) is obtained after drying. ESI-MS (m/z): 357.8[ M+H ] ] + 。
And a third step of: INT-1c (130 g,364.6 mmol) was dissolved in 500mL of dichloromethane, thionyl chloride (130.1 g,1.09mol,79.4 mL) was added at room temperature, stirred for 3 hours at 60℃and at the end of the reaction, dichloromethane and the remaining thionyl chloride were removed under reduced pressure to give INT-1d as a pale yellow oil, which was not purified, and 200mL of dichloromethane was added for use.
Fourth step: INT-1e (64.8 g,331 mmol) was dissolved in 400mL of methylene chloride, 198mL of diethyl aluminum chloride solution (2M in hexanes) was added dropwise at 0℃under a controlled temperature of not more than 5℃and stirred for 30 minutes after the completion of the addition, and the resulting methylene chloride solution of INT-1d was added dropwise to a reaction flask. The temperature is controlled to be not higher than 10 ℃ in the dripping process, and stirring is continued for 2 hours after the dripping is finished. After the reaction was completed, the reaction solution was poured into 1L of ice water, stirred for 30 minutes, concentrated under reduced pressure to remove dichloromethane, the residual liquid was extracted with ethyl acetate (1 l×2), washed with water, and the organic phase was concentrated under reduced pressure to give a brown oil, and the oil was added to 2L of a petroleum ether/ethyl acetate=10/1 mixed solution, stirred to precipitate a solid, and suction-filtered to give a yellow solid INT-1f (139 g, yield 78%). ESI-MS (m/z): 534.8[ M+H ]] + 。
Fifth step: INT-1f (100 g,187.1 mmol) was dissolved in 500mL tetrahydrofuran, lithium borohydride (12.2 g,561.2 mmol) was added, stirring was continued overnight at 60℃and after the starting material disappeared, the reaction mixture was quenched by adding 200mL ice water, extracted with ethyl acetate (500 mL. Times.3), the organic phase was washed with water, dried, concentrated under reduced pressure, the residue was dissolved in 500mL dichloromethane and 2, 6-dimethyl-1, 4-dihydro was added Diethyl-3, 5-pyridinedicarboxylate (28.4 g,112.2 mmol) and p-toluenesulfonic acid (21.4 g,112.2 mmol) were stirred at room temperature for 3 hours, after the reaction was completed, concentrated under reduced pressure, methylene chloride was removed, the residue was dissolved in 500mL of methanol, and a pre-prepared 14% aqueous solution of lithium hydroxide (100 mL) was added, stirred at room temperature for 3 hours, and suction filtration was performed to obtain INT-1g (84 g, yield 86.3%) as a yellow solid. ESI-MS (m/z): 520.2[ M+H ]] + 。
Sixth step: INT-1g (50 g,96 mmol) was dissolved in 250mL tetrahydrofuran, tetrabutylammonium fluoride (1M in THF, 197mL) was added, stirred overnight at 60℃and after the reaction was completed, the reaction mixture was added to 300mL water, extracted with ethyl acetate (200 mL. Times.3), washed with water, and concentrated under reduced pressure to give a brown oil. The resulting residue was dissolved in 40mL of methanol, 20mL of water was added, the mixed solution was washed with petroleum ether (40 mL x 5), concentrated under reduced pressure to remove methanol, the residue was extracted with ethyl acetate (50 mL x 2), and the organic phase was washed with water and dried to give a pale yellow oil INT-1h (25 g, yield 90.4%). ESI-MS (m/z): 282.8[ M+H ]] + 。
Seventh step: compound INT-1h (22 g,77 mmol) was dissolved in 100mL of dichloromethane. 4-dimethylaminopyridine (467 mg,3.82 mmol), triethylamine (23.2 g,230 mmol) and acetic anhydride (7.9 g,77 mmol) were added dropwise at 0deg.C, after the addition was completed, the mixture was warmed naturally, stirred overnight, and after the reaction was completed, the reaction solution was washed with water, dried and concentrated to give a brown oil, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give a pale yellow oil INT-1i (22.5 g, yield 90.7%). ESI-MS (m/z): 324.2[ M+H ] ] + 。
Eighth step: compound INT-1i (40 g,123.4 mmol) was dissolved in dioxane (400 mL) and potassium acetate (30.3 g,308.4 mmol) was added, [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (10 g,12.3 mmol), pinacol diboronate (78.3 g,308.4 mmol), and under nitrogen protection at 90℃for 3 hours, LCMS monitors complete reaction of the starting materials, the reaction solution is concentrated directly under reduced pressure, the residue is dissolved in ethyl acetate (300 mL), washed with water, brine, and the organic phase is purified by silica gel column chromatography to give the white solid compound INT-1j (35 g, yield 76.4%). ESI-MS (m/z): 372.5[ M+H ]] + 。
Ninth step: combining Compound INT-1j (35 g,94.3 mmol) with CompoundINT-1k (37.9 g,103.7 mmol) was dissolved in dioxane (300 mL) and water (30 mL) and potassium phosphate (50 g,235.7 mmol) and [1,1' -bis (diphenylphosphine) ferrocene were added]Palladium dichloride (6.89 g,9.43 mmol), under nitrogen protection at 90 ℃ overnight, LCMS monitoring complete reaction of the starting materials, direct concentration of the reaction solution under reduced pressure, dissolution of the residue in ethyl acetate (300 mL), water washing, brine washing, purification of the organic phase by silica gel column chromatography gave INT-1l (28 g, yield 56.08%) as a yellow oil. ESI-MS (m/z): 530.7[ M+H ]] + 。
Tenth step: compound INT-1l (28 g,52.9 mmol) was dissolved in N, N-dimethylformamide (280 mL), N-iodosuccinimide (11.9 g,52.9 mmol) was added, the reaction was monitored by LCMS for complete reaction at 50℃for 2 hours, the reaction solution was poured into water (800 mL), extracted with ethyl acetate (200 mL. Times.2), the organic phase was saturated brine, dried, filtered, and purified by silica gel column chromatography to give compound INT-1m (22 g, yield 63.5%) as a yellow solid. ESI-MS (m/z): 656.6[ M+H ] ] + 。
Eleventh step: the compound INT-1m (5 g,7.63 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (939.4 mg,2.29 mmol), tris (dibenzylideneacetone) dipalladium (838.1 mg,0.915 mmol), potassium acetate (2.6 g,26.7 mmol) were dissolved in toluene (100 mL), pinacolone borane (4.9 g,38.1 mmol) was added under nitrogen protection, reacted at 50℃for 5 hours under nitrogen protection, LCMS monitored the starting material reaction completed, the reaction liquid was filtered and purified by silica gel column chromatography to give the yellow oily compound INT-1 (4.5 g, yield 90%). ESI-MS (m/z): 656.5[ M+H ]] + 。
Intermediate 2
Intermediate 2 was prepared by the following steps:
the first step: compound INT-1m (12 g,18.3 mmol) was dissolved in tetrahydrofuran (120 mL) and water (20 mL) and lithium hydroxide monohydrate (3.84 g,91.5 mmol) was added to the chamberAfter overnight incubation, LCMS monitored complete reaction of the starting material, the reaction was concentrated directly under reduced pressure, the residue was dissolved in water (100 mL), pH was adjusted to 4-5 with 4M hydrochloric acid, dichloromethane (100 mL x 3) was used for extraction, the organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-2a as a white solid (10.6 g, 96.6% yield). ESI-MS (m/z): 600.7[ M+H ]] + 。
And a second step of: compound INT-2a (9.5 g,15.9 mmol) and compound INT-2b (11.7 g,31.7 mmol) were dissolved in acetonitrile (190 mL), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (6.67 g,23.8 mmol) and 1-methylimidazole (6.51 g,79.2 mmol) were added at 0deg.C, reaction was completed at 0deg.C, LCMS monitored the starting material reaction was complete, the reaction solution was poured into water (200 mL), dichloromethane (100 mL of 3) was extracted, the organic phase was washed with water, and purified by silica gel column chromatography to give compound INT-2c (9.6 g, yield 83.5%) as a yellow solid. ESI-MS (m/z): 726.3[ M+H ] ] + 。
And a third step of: compound INT-2c (9.6 g,13.2 mmol) was dissolved in tetrahydrofuran (100 mL) and water (10 mL), lithium hydroxide monohydrate (1.39 g,33.1 mmol) was added, the reaction was completed at room temperature for 4 hours, LCMS was monitored to complete the reaction, the reaction solution was concentrated directly under reduced pressure, the residue was dissolved in water (100 mL), 4M hydrochloric acid was adjusted to pH 4-5, a white solid was precipitated, the solid was washed with water, and dried to give compound INT-2d (8.3 g, yield 88.2%) as a white solid. ESI-MS (m/z): 712.6[ M+H ]] + 。
Fourth step: compound INT-2d (3.5 g,4.9 mmol), 1-hydroxybenzotriazole (1.99 g,14.8 mmol), 4-dimethylaminopyridine (1.8 g,14. Mmol) were dissolved in dichloromethane (170 mL), N-diisopropylethylamine (6 mL,34.4 mmol) was added at 0deg.C, after which 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.71 g,24.6 mmol) was added and reacted overnight at room temperature, LCMS monitored the starting material was complete, the reaction solution was washed with saturated aqueous ammonium chloride solution, dried over sodium sulfate and purified by silica gel column chromatography to give compound INT-2e (2 g, yield 58.6%) as a yellow solid. ESI-MS (m/z): 694.6[ M+H ]] + 。
Fifth step: the compound INT-2e (500 mg,0.721 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethyl-biphenyl (88.8 mg,0.216 mmol), tris (dibenzylideneacetone) dipalladium (79 mg,0.086 mmol), potassium acetate (247 mg,2.52 mmol) was dissolved in tetralin To tetrahydrofuran (20 mL), pinacol borane (463mg, 3.6 mmol) was added under nitrogen and the reaction was completed at 50deg.C under nitrogen for 3 hours, LCMS monitored complete reaction, the reaction solution was filtered and purified by silica gel column chromatography to give yellow solid compound INT-2 (400 mg, yield 80%). ESI-MS (m/z): 694.6[ M+H ]] + 。
Intermediate 3
Intermediate 3 was prepared by the following steps:
the first step: compound INT-2e (1.7 g,2.45 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added and reacted at room temperature for 2 hours, LCMS monitored complete reaction of the starting material, the reaction solution was concentrated directly under reduced pressure, the residue was dissolved in DCM (50 mL), saturated NaHCO 3 The aqueous solution was washed twice, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated to give the yellow solid compound INT-3a (1.3 g, yield 89.4%). ESI-MS (m/z): 594.7[ M+H ]] + 。
And a second step of: compound INT-3a (1.3 g,2.19 mmol) and compound INT-3b (0.24 g,2.41 mmol) were dissolved in acetonitrile (30 mL), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (921.9 mg,3.29 mmol) and 1-methylimidazole (414 mg,5.04 mmol) were added at 0deg.C, the reaction was monitored by LCMS for 1 hour, the reaction solution was poured into water (50 mL), dichloromethane (50 mL) was extracted, the organic phase was washed with water, and the mixture was purified by column chromatography to give compound INT-3c (1.3 g, yield 87.9%) as a white solid. ESI-MS (m/z): 675.7[ M+H ] ] + 。
And a third step of: the compound INT-3c (1.1 g,1.63 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethyl-biphenyl (200.5 mg,0.188 mmol), tris (dibenzylideneacetone) dipalladium (178 mg,0.195 mmol), potassium acetate (559 mg,5.7 mmol) were dissolved in toluene (30 mL), pinacolone borane (1.04 g,8.14 mmol) was added under nitrogen protection, reacted at 50℃for 3 hours under nitrogen protection, and LCMS was monitored to complete the reaction of the starting materialAll the reaction solution was filtered and purified by silica gel column chromatography to give the yellow solid compound INT-3 (990 mg, yield 90%). ESI-MS (m/z): 676.9[ M+H ]] + 。
Intermediate 4
Intermediate 4 was prepared by the following steps:
the first step: compound INT-3a (2.2 g,3.71 mmol) and compound INT-4a (0.47 g,4.08 mmol) were dissolved in dichloromethane (50 mL), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (1.56 g,5.56 mmol) and 1-methylimidazole (0.70 g,8.53 mmol) were added at 0deg.C, the reaction was monitored by LCMS for 1 hour, the reaction solution was poured into water (50 mL), dichloromethane (50 mL) was extracted, the organic phase was washed with water, and the mixture was purified by column chromatography to give compound INT-4b (2.3 g, yield 90.0%) as a white solid. ESI-MS (m/z): 690.2[ M+H ]] + 。
And a second step of: compound INT-4b (2.1 g,3.05 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethyl-biphenyl (375.0 mg,0.91 mmol), tris (dibenzylideneacetone) dipalladium (334.6 mg,0.365 mmol), potassium acetate (1.05 g,10.7 mmol) were dissolved in toluene (30 mL), pinacolone borane (1.95 g,15.2 mmol) was added under nitrogen protection, reacted at 50℃for 3 hours under nitrogen protection, LCMS monitored the starting material reaction was complete, the reaction solution was filtered and purified by silica gel column chromatography to give yellow solid compound INT-4 (1.8 g, yield 85.7%). ESI-MS (m/z): 690.3[ M+H ] ] + 。
Intermediate 5
Intermediate 5 was prepared by the following steps:
the first step: intermediate INT-5a (1.0 g,4.69 mmol) and intermediate INT-5b (534 mg,1.56 mmol) were dissolved in toluene (5 mL) and cuprous iodide (59 mg,0.31 mmol), 1.10-phenanthroline (56 mg,0.31 mmol) and cesium carbonate (1.02 g,3.13 mmol) were added. The reaction system was heated to 120℃and stirred for 50 hours after nitrogen substitution. After the reaction solution was cooled to room temperature, water was then added to the reaction system, extraction was performed with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give INT-5c as a white solid (543 mg, yield 81%). ESI-MS (m/z): 427.7[ M+H ]] + 。
And a second step of: intermediate INT-5c (447 mg,1.04 mmol) was dissolved in dichloromethane (12 mL) and trifluoroacetic acid (4 mL) was added dropwise to the reaction solution at 0deg.C. The reaction solution was stirred at room temperature for 30 minutes. After completion of LCMS monitoring the reaction, the reaction mixture was concentrated to give intermediate INT-5d. ESI-MS (m/z): 327.5[ M+H ]] + 。
And a third step of: intermediate INT-5d (399 mg,1.04 mmol) and diisopropylethylamine (669 mg,5.18 mmol) were dissolved in tetrahydrofuran (8 mL), followed by the addition of benzyl chloroformate (353 mg,2.07 mmol). The reaction solution was stirred at room temperature for 4 hours. After completion of LCMS monitoring, water was added to the reaction system, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give INT-5e as a white solid (431 mg, yield 90%). ESI-MS (m/z): 461.6[ M+H ] ] + 。
Fourth step: the reaction flask was charged with intermediate INT-5e (439mg, 0.93 mmol), pinacol biborate (356 mg,1.40 mmol), tris (dibenzylideneacetone) dipalladium (86 mg,0.093 mmol), tricyclohexylphosphine (53 mg,0.19 mmol), potassium acetate (367 mg,3.74 mmol) and 1, 4-dioxane in this order. The reaction system was replaced with nitrogen, heated to 100℃and stirred for 24 hours. After the reaction solution was cooled to room temperature, water was then added to the reaction system, extraction was performed with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a neutral alumina column (dichloromethane)Alkane/methanol=5/1) to give INT-5 as a yellow oil (303 mg, 76% yield). ESI-MS (m/z): 427.7[ M+H ]] + 。
Intermediate 6
Intermediate 6 was prepared by the following steps:
the first step: intermediate INT-6a (921 mg,7.02 mmol) and intermediate INT-5b (600 mg,1.75 mmol) were dissolved in toluene (5 mL), and cuprous iodide (67 mg,0.35 mmol), 1.10-phenanthroline (63 mg,0.35 mmol) and cesium carbonate (1.14 g,3.51 mmol) were added. The reaction system was replaced with nitrogen, heated to 120℃and stirred for 72 hours. After the reaction solution was cooled to room temperature, water was then added to the reaction system, extraction was performed with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give INT-6 (270 mg, yield 44%) as a pale yellow oil. ESI-MS (m/z): 345.4[ M+H ] ] + 。
Intermediate 7
Intermediate 7 was prepared by the following steps:
the compound INT-7 can be obtained by a similar method and reaction procedure, substituting INT-7a for INT-6a in the intermediate INT-6 synthesis procedure. ESI-MS (m/z): 429.5[ M+H ]] + 。
Intermediate 8
Intermediate 8 was prepared by the following steps:
the compound INT-8 can be obtained by a similar method and reaction procedure, substituting INT-8a for INT-6a in the intermediate INT-6 synthesis procedure. ESI-MS (m/z): 429.6[ M+H ]] + 。
Intermediate 9
Intermediate 9 was prepared by the following steps:
the INT-9 compound can be obtained by a similar method and reaction procedure by replacing INT-6a in the intermediate INT-6 synthesis procedure with INT-9 a. ESI-MS (m/z): 431.5[ M+H ]] + 。
Intermediate 10
Intermediate 10 is prepared by the following steps
The INT-10 compound can be obtained by a similar method and reaction procedure by replacing INT-6a in the intermediate INT-6 synthesis procedure with INT-10 a. ESI-MS (m/z): 415.4[ M+H ]] + 。
Intermediate 11
Intermediate 11 is prepared by the following steps
The first step: compound INT-11a (20.0 g,92.56 mmol) was dissolved in tetrahydrofuran (200 mL), and then methoxy (cyclooctadiene) iridium dimer (606 mg,0.925 mmol), 4 '-di-tert-butyl-2, 2' -bipyridine, and pinacol diboronate (35.3 g,138.8 mmol) were added and the reaction was reacted under nitrogen at 75℃for 16 hours. LCMS monitored complete reaction of starting material, reaction was filtered through celite and filtrate was concentrated. The residue was dissolved in ethyl acetate (200 mL), ph=10 was adjusted with aqueous sodium hydroxide solution, the organic phase was discarded, the aqueous phase was adjusted to ph=6 with hydrochloric acid, and a white solid was precipitated, and was dried by filtration to give compound INT-11b (20 g, yield 83.1%) as a white solid. ESI-MS (m/z): 260.3[ M+H ] ] + 。
And a second step of: compound INT-11b (20.0 g,76.95 mmol) was dissolved in water (100 mL), then aqueous sodium hydroxide (2M, 76.95 mL) and hydrogen peroxide (13.1 g,384.8 mmol) and the reaction was allowed to react at room temperature for 2 hours. LCMS monitored complete reaction of starting material, adjusted to ph=7 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound INT-11 as a white solid (15 g, 84.0% yield). ESI-MS (m/z): 232.4[ M+H ]] + 。
Intermediate 12
Intermediate 12 is prepared by the following steps
The first step: intermediate INT-11 (213 mg,1.83 mmol) and potassium carbonate (633 mg,4.58 mmol) were dissolved in N, N-dimethylformamide (5 mL), followed by addition of intermediate INT-12a (315 mg,1.83 mmol). The reaction solution was stirred at room temperature for 5 hours. After LCMS monitoring the reaction, water is added into the reaction system, ethyl acetate is used for extraction, and the mixture is combinedThe organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give INT-12 (101 mg, yield 34%) as a pale yellow solid. ESI-MS (m/z): 323.5[ M+H ]] + 。
Intermediate 13
Intermediate 13 is prepared by the following steps
The first step: intermediate INT-11 (75 mg,0.32 mmol) and cesium carbonate (210.6 mg,0.64 mmol) were dissolved in dimethyl sulfoxide (2 mL), followed by addition of intermediate INT-13a (81 mg,0.64 mmol). The reaction solution was stirred at room temperature for 16 hours. After completion of LCMS monitoring, water was added to the reaction system, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give INT-13b as a pale yellow solid (71 mg, yield 65.2%). ESI-MS (m/z): 337.3[ M+H ] ] + 。
And a second step of: INT-13b (71 mg,0.21 mmol) was dissolved in 1, 2-dichloroethane (5 mL), morpholine (36.7 mg,0.42 mmol) was added, and after stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (89.3 mg,0.42 mmol) was added. The reaction was stirred at room temperature for 30 min and LCMS monitored for reaction completion. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give INT-13 as a pale yellow oily liquid (80 mg, yield 93.1%). ESI-MS (m/z): 408.4[ M+H ]] + 。
Intermediate 14
Intermediate 14 is prepared by the following steps
The first step: intermediate INT-11 (50 mg,0.22 mmol) and N, N-diisopropylethylamine (83 mg,0.66 mmol) were dissolved in isopropanol (2 mL) and then intermediate INT-14a (32 mg,0.23 mmol) was added thereto. The reaction solution was stirred at room temperature for 16 hours. After completion of LCMS monitoring, water was added to the reaction system, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give INT-14b as a pale yellow solid (58 mg, yield 79.6%). ESI-MS (m/z): 338.2[ M+H ] ] + 。
And a second step of: INT-14b (58 mg,0.17 mmol) was dissolved in 1, 2-dichloroethane (5 mL), morpholine (30 mg,0.34 mmol) was added, and after stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (72.7 mg,0.34 mmol) was added. The reaction was stirred at room temperature for 30 min and LCMS monitored for reaction completion. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give INT-14 as a pale yellow oily liquid (30 mg, yield 42.7%). ESI-MS (m/z): 409.4[ M+H ]] + 。
The synthesis method of the compound of the embodiment is as follows:
example 1
(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((2-methyl-2-azaspir o[3.3]heptan-6-yl)oxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide
Example 1 was prepared by the following steps:
the first step: intermediate INT-2e (50 mg,0.072 mmol) and intermediate INT-5 (61 mg,0.144 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and water (0.2 mL), and [1,1' -bis (diphenylphosphine) ferrocene was added]Palladium dichloride (10 mg,0.014 mmol) and potassium carbonate (30 mg,0.216 mmol). The reaction system was replaced with nitrogen, heated to 90℃and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give compound 1a (52 mg, yield 76%) as a pale yellow solid. ESI-MS (m/z): 948.4[ M+H ] ] + 。
And a second step of: compound 1a (50 mg,53 umol) was dissolved in DMF (2 mL), cesium carbonate (35 mg,106 umol) was added thereto, and then ethyl iodide (33 mg,0.21 mmol) was added dropwise to the reaction solution, which was stirred at room temperature for 16 hours. After completion of LCMS detection, saturated brine was added to the reaction solution, extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 1b (40 mg, yield 78%) as a pale yellow solid by silica gel column chromatography (dichloromethane/methanol=20/1). ESI-MS (m/z): 976.5[ M+H ]] + 。
And a third step of: intermediate 1b (40 mg,41 umol) and palladium hydroxide (20 mg) were dissolved in methanol, and hydrogen was replaced by a hydrogen balloon and reacted under a hydrogen atmosphere at room temperature for 12 hours. After completion of LCMS detection, the reaction was filtered through celite and the filtrate was concentrated to give compound 1c. ESI-MS (m/z): 843.0[ M+H ]] + 。
Fourth step: aqueous formaldehyde (11 mg,114 mol, 37%) was added dropwise to 1, 2-dichloroethane (2 mL) of compound 1c (32 mg,38 mol). After the reaction solution was stirred at room temperature for 20 minutes, sodium triacetoxyborohydride (48 mg,228 umol) was added thereto, and the reaction solution was further stirred at room temperature for 30 minutes. After LCMS monitoring the reaction, the reaction is quenched by adding saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organics are combined The phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give compound 1d. ESI-MS (m/z): 856.6[ M+H ]] + 。
Fifth step: trifluoroacetic acid (0.6 mL) was added dropwise to dichloromethane (2 mL) of the above crude product 1d. After the reaction was stirred at room temperature for 30 minutes, LCMS monitored the reaction to end. The reaction solution was concentrated by distillation under the reduced pressure, saturated aqueous sodium carbonate solution was added, extraction was performed with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give crude product 1e. ESI-MS (m/z): 756.5[ M+H ]] + 。
Sixth step: the crude product of the above compound 1e was dissolved in N, N-dimethylformamide (2 mL), to which were added (1S, 2S) -2-methylcyclopropane carboxylic acid INT-3b (8 mg,75 umol), N-diisopropylethylamine (15 mg,0.112 mmol) and (2-oximino-cyanoethyl acetate) -N, N-dimethyl-morpholinylurea hexafluorophosphate (32 mg,75 umol). The reaction mixture was stirred under ice bath for 1 hour. After completion of the reaction, water was added to the reaction system, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative liquid chromatography to give a mixture of compounds 1 and 1' (2 mg, yield 7%). The absolute configuration drawn for the two compounds is an empirically made assumption. Compound 1 and its epimer 1' cannot be isolated and purified by reverse phase preparative liquid chromatography. Both epimers have the same retention time in LC-MS and HPLC.
Compound 1+1':
ESI-MS(m/z):838.5[M+H] + the method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.67 min. HPLC retention time rt=11.55 min.
Example 2
(1r,2R,3S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(2-morpholinoeth oxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-o xa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2,3-di
methylcyclopropane-1-carboxamide
Example 2 was prepared by the following steps:
the first step: intermediate INT-4 (80 mg,116 umol) and intermediate INT-6 (40 mg,116 umol) were dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and water (0.2 mL), and [1,1' -bis (diphenylphosphine) ferrocene was added]Palladium dichloride (17 mg,23 umol) and potassium phosphate (74 mg,348 umol). The reaction system was replaced with nitrogen, heated to 70℃and stirred for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give compound 2a (51 mg, yield 53%) as a pale yellow solid. ESI-MS (m/z): 829.2[ M+H ]] + 。
And a second step of: compound 2a (50 mg,60 umol) was dissolved in DMF (2 mL), cesium carbonate (59 mg,0.18 mmol) was added, and then ethyl iodide (28 mg,0.18 mmol) was added dropwise to the reaction solution, which was stirred at room temperature for 16 hours. LCMS monitored the end of the reaction. Saturated brine was added to the reaction system, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to give compound 2 (4 mg, yield 8%) as a white solid and compound 2' (8 mg, yield 16%) as an epimer. The absolute configuration drawn for both compounds is empirically assumed, compound 2 is the isomer that remains longer in LCMS or HPLC, and 2' is the isomer that remains shorter in LCMS or HPLC.
Compound 2
ESI-MS(m/z):856.6[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.82 min. HPLC retention time rt=12.78 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.49(s,1H),8.46(d,J＝2.9Hz,1H),8.39(d,J＝8.9Hz,1H),7.81(s,1H),7.74(dd,J＝8.6,1.6Hz,1H),7.57(d,J＝8.7Hz,1H),7.37(d,J＝2.9Hz,1H),5.55(t,J＝9.0Hz,1H),5.09-5.04(m,1H),4.33-4.11(m,7H),3.57(d,J＝4.6Hz,6H),3.22(s,3H),3.19-3.14(m,1H),2.98-2.93(m,1H),2.79-2.68(m,3H),2.49-2.43(m,5H),2.11-2.04(m,1H),1.84-1.71(m,2H),1.56-1.45(m,1H),1.34(d,J＝6.0Hz,3H),1.24-1.12(m,5H),1.10-1.05(m,6H),0.93-0.87(m,5H),0.34(s,3H).
Compound 2'
ESI-MS(m/z):856.6[M+H] + . LC-MS retention time rt=1.81 min. HPLC retention time rt=12.68 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.53(s,1H),8.48(d,J＝2.8Hz,1H),8.40(d,J＝9.0Hz,1H),7.81(s,1H),7.73(d,J＝8.3Hz,1H),7.55-7.50(m,2H),5.54(t,J＝9.1Hz,1H),5.06-5.01(m,1H),4.28-4.13(m,5H),4.01-3.81(m,4H),3.71-3.65(m,1H),3.59-3.54(m,5H),3.19-3.14(m,1H),3.08(s,3H),3.06-3.00(m,1H),2.79-2.68(m,3H),2.48-2.39(m,5H),2.16-2.08(m,1H),1.84-1.73(m,2H),1.58-1.47(m,1H),1.25-1.15(m,6H),1.11-1.06(m,8H),0.93(s,3H),0.52(s,3H).
Example 3
(1r,2R,3S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(((S)-1-methylpip eridin-2-yl)methoxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-he xahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaph ane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide
Example 3 was prepared by the following steps:
the first step: intermediate INT-4 (80 mg,116 umol) and intermediate INT-7 (50 mg,116 umol) were dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and water (0.2 mL), and [1,1' -bis (diphenylphosphine) ferrocene was added]Palladium dichloride (17 mg,23 umol) and potassium phosphate (74 mg,348 umol). The reaction system was heated to 70℃after nitrogen substitution and stirred for 16 hours. LCMS monitoringThe reaction was completed, the solvent was distilled off under reduced pressure, diluted with ethyl acetate, the mixture was filtered with celite, and the filtrate was concentrated and purified by preparative thin layer chromatography (dichloromethane/methanol=20/1) to give compound 3a (60 mg, yield 56%). ESI-MS (m/z): 912.5[ M+H ]] + 。
And a second step of: compound 3a (60 mg,66 umol) was dissolved in DMF (2 mL), cesium carbonate (64 mg, 197umol) was added thereto, and then ethyl iodide (31 mg, 197umol) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. After completion of the LCMS detection reaction, saturated brine was added to the reaction solution, extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product 3b. ESI-MS (m/z): 940.7[ M+H ] ] + 。
And a third step of: trifluoroacetic acid (0.5 mL) was added dropwise to dichloromethane (2 mL) of the above crude product 3 b. After the reaction was stirred at room temperature for 30 minutes, LCMS monitored the reaction to end. The reaction solution was concentrated by distillation under the reduced pressure, saturated aqueous sodium carbonate solution was added, extraction was performed with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and after concentration, the organic phase was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to give 3c (25 mg, two-step yield 45%). ESI-MS (m/z): 840.4[ M+H ]] + 。
Fourth step: aqueous formaldehyde (7 mg,89 mol, 37%) was added dropwise to a solution of compound 3c (25 mg,30 mol) in 1, 2-dichloroethane (2 mL). After the reaction solution was stirred at room temperature for 20 minutes, sodium triacetoxyborohydride (38 mg, 178 umol) was added thereto, and the reaction solution was further stirred at room temperature for 30 minutes. After LCMS monitored the end of the reaction, the reaction was quenched by addition of saturated aqueous ammonium chloride, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative thin layer chromatography (dichloromethane/methanol=20/1) to give compound 3 (2 mg, yield 8%) as a white solid and compound 3' (4 mg, yield 16%) as an epimer. The absolute configuration drawn for both compounds is empirically assumed, compound 3 is the isomer that remains longer in LCMS or HPLC, and 3' is the isomer that remains shorter in LCMS or HPLC.
Compound 3
ESI-MS(m/z):854.6[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.92 min. HPLC retention time rt=14.30 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.49(d,J＝1.7Hz,1H),8.45(d,J＝2.9Hz,1H),8.39(d,J＝9.2Hz,1H),7.81(s,1H),7.74(dd,J＝8.6,1.7Hz,1H),7.57(d,J＝8.6Hz,1H),7.37(d,J＝2.9Hz,1H),5.55(t,J＝9.1Hz,1H),5.08-5.03(m,1H),4.34-4.28(m,1H),4.26-4.11(m,5H),4.09-4.03(m,1H),3.57(s,2H),3.23(s,3H),3.17-3.12(m,1H),2.98-2.93(m,1H),2.79-2.72(m,2H),2.49-2.43(m,1H),2.28-2.22(m,4H),2.10-1.98(m,2H),1.81-1.68(m,4H),1.58-1.42(m,4H),1.37-1.32(m,4H),1.19-1.11(m,4H),1.09-1.05(m,5H),1.05-1.02(m,1H),0.93-0.89(m,5H),0.69-0.63(m,1H),0.34(s,3H).
Compound 3'
ESI-MS(m/z):854.6[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.88 min. HPLC retention time rt=13.95 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.53(d,J＝1.6Hz,1H),8.47(d,J＝2.8Hz,1H),8.41(d,J＝9.0Hz,1H),7.81(s,1H),7.73(dd,J＝8.6,1.7Hz,1H),7.53(dd,J＝5.8,2.9Hz,2H),5.54(t,J＝9.2Hz,1H),5.06-5.01(m,1H),4.27-4.19(m,2H),4.18-4.13(m,1H),4.07-4.03(m,1H),3.99-3.92(m,1H),3.91-3.83(m,2H),3.71-3.67(m,1H),3.58-3.53(m,1H),3.18-3.11(m,1H),3.08(s,3H),3.03(d,J＝14.4Hz,1H),2.79-2.73(m,2H),2.43-2.38(m,1H),2.26-2.21(m,4H),2.16-2.08(m,1H),2.09-1.99(m,1H),1.83-1.74(m,3H),1.73-1.66(m,1H),1.55-1.44(m,3H),1.39-1.31(m,2H),1.25-1.16(m,8H),1.12-1.04(m,8H),0.93(s,3H),0.53(s,3H).
Example 4
(1r,2R,3S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(((R)-1-methylpiperidin-2-yl)methoxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide
Example 4 was prepared by the following steps:
INT-8 was used instead of INT-7 in the synthetic procedure of Compound 3, and Compound 4 and epimer compound 4' were obtained in a similar manner and reaction procedure. The absolute configuration drawn for both compounds is empirically assumed, compound 4 is the isomer that remains longer in LCMS or HPLC, and 4' is the isomer that remains shorter in LCMS or HPLC.
Compound 4
ESI-MS(m/z):854.6[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.92 min. HPLC retention time rt=14.27 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.49(d,J＝1.6Hz,1H),8.46(d,J＝2.9Hz,1H),8.39(d,J＝8.9Hz,1H),7.81(s,1H),7.74(dd,J＝8.6,1.7Hz,1H),7.57(d,J＝8.6Hz,1H),7.37(d,J＝2.9Hz,1H),5.56(t,J＝9.1Hz,1H),5.08-5.04(m,1H),4.34-4.27(m,1H),4.26-4.12(m,5H),4.06-4.01(m,1H),3.58(s,2H),3.22(s,3H),3.18-3.13(m,1H),2.98-2.94(m,1H),2.79-2.72(m,2H),2.49-2.43(m,1H),2.26-2.19(m,4H),2.11-1.99(m,2H),1.81-1.66(m,4H),1.57-1.37(m,5H),1.34(d,J＝6.0Hz,3H),1.25-1.14(m,6H),1.10-1.05(m,5H),0.93-0.88(m,5H),0.34(s,3H).
Compound 4'
ESI-MS(m/z):854.7[M+H] + . LC-MS retention time rt=1.88 min. HPLC retention time rt=13.95 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.53(d,J＝1.7Hz,1H),8.47(d,J＝2.9Hz,1H),8.40(d,J＝9.0Hz,1H),7.81(s,1H),7.73(dd,J＝8.7,1.7Hz,1H),7.56-7.50(m,2H),5.54(t,J＝9.2Hz,1H),5.06-5.01(m,1H),4.27-4.18(m,3H),4.00-3.82(m,4H),3.71-3.67(m,1H),3.58-3.54(m,1H),3.17-3.13(m,1H),3.07(s,3H),3.06-3.01(m,1H),2.77-2.73(m,2H),2.46-2.40(m,1H),2.23(s,4H),2.15-2.10(m,1H),2.05-2.01(m,1H),1.83-1.73(m,8H),1.72-1.65(m,1H),1.56-1.43(m,3H),1.39-1.28(m,2H),1.26-1.14(m,8H),1.13-1.04(m,8H),0.93(s,3H),0.52(s,3H).
Example 5
(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(pyridin-3-ylmethoxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide
Example 5 was prepared by the following steps:
substitution of INT-12 for INT-6 and INT-3 for INT-4, respectively, in the synthetic procedure for Compound 2, and similar procedures and reaction procedures were followed, compound 5 and epimer compound 5' were obtained. The absolute configuration drawn for both compounds is empirically assumed, compound 5 is the isomer that remains longer in LCMS or HPLC, and 5' is the isomer that remains shorter in LCMS or HPLC.
Compound 5
ESI-MS(m/z):820.8[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.73 min. HPLC retention time rt=12.86 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.69(s,1H),8.59-8.46(m,4H),7.89(d,J＝7.9Hz,1H),7.80(s,1H),7.74(d,J＝8.7Hz,1H),7.56(d,J＝8.6Hz,1H),7.46-7.39(m,2H),5.55(t,J＝9.1Hz,1H),5.36(s,2H),5.08-5.03(m,1H),4.34-4.10(m,5H),3.54(s,2H),3.23(s,3H),3.16-3.11(m,1H),2.89-2.85(m,1H),2.79-2.72(m,1H),2.26-2.20(m,1H),＝2.14-2.05(m,1H),1.84-1.75(m,2H),1.55-1.47(m,2H),1.32(d,J＝6.1Hz,3H),1.08-1.05(m,4H),0.90-0.81(m,7H),0.57-0.52(m,1H),0.26(s,3H).
Compound 5'
ESI-MS(m/z):820.8[M+H] + . LC-MS retention time rt=1.72 min. HPLC retention time rt=12.33min。
1 H NMR(500MHz,DMSO-d 6 )δ8.68(d,J＝2.2Hz,1H),8.57(d,J＝2.9Hz,1H),8.55(dd,J＝4.8,1.7Hz,1H),8.54-8.50(m,2H),7.89(dt,J＝7.9,2.0Hz,1H),7.80(s,1H),7.73(dd,J＝8.6,1.7Hz,1H),7.58(d,J＝2.9Hz,1H),7.53(d,J＝8.6Hz,1H),7.43(dd,J＝7.8,4.8Hz,1H),5.55(t,J＝9.2Hz,1H),5.38-5.34(m,1H),5.31-5.27(m,1H),5.06-5.01(m,1H),4.28-4.18(m,2H),3.92-3.80(m,3H),3.68-3.63(m,1H),3.56-3.51(m,1H),3.18-3.13(m,1H),3.08(s,3H),3.04-3.00(m,1H),2.82-2.74(m,1H),2.43-2.39(m,1H),2.16-2.08(m,1H),1.84-1.77(m,2H),1.54-1.47(m,2H),1.21(d,J＝6.3Hz,3H),1.08-1.02(m,7H),0.93-0.86(m,4H),0.58-0.53(m,1H),0.40(s,3H).
Example 6
(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(((R)-4-methylmorpholin-2-yl)methoxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide
Example 6 was prepared by the following steps:
substitution of INT-9 for INT-7 and INT-3 for INT-4, respectively, in the synthetic procedure for Compound 3, compound 6 and epimer compound 6' were obtained in a similar manner and reaction procedure. The absolute configuration drawn for both compounds is empirically assumed, compound 6 is the isomer that remains longer in LCMS or HPLC, and 6' is the isomer that remains shorter in LCMS or HPLC.
Compound 6
ESI-MS(m/z):842.9[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.69 min. HPLC retention time rt=12.40 min.
Compound 6'
ESI-MS(m/z):842.9[M+H] + . LC-MS retention time rt=1.68 min. HPLC retention time rt=12.26 min.
Example 7
(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(((S)-1-methylpiperidin-3-yl)oxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide
Example 7 was prepared by the following steps:
substitution of INT-10 for INT-7, INT-3 for INT-4, respectively, in the synthetic procedure for Compound 3, and similar procedures and reaction procedures were followed to afford Compound 7 and epimer Compound 7'. The absolute configuration drawn for both compounds is empirically assumed, compound 7 is the isomer that remains longer in LCMS or HPLC, and 7' is the isomer that remains shorter in LCMS or HPLC. .
Compound 7
ESI-MS(m/z):826.9[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.83 min. HPLC retention time rt=13.41 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.54-8.48(m,2H),8.44(d,J＝2.8Hz,1H),7.80(s,1H),7.74(dd,J＝8.6,1.7Hz,1H),7.57(d,J＝8.6Hz,1H),7.39(d,J＝2.9Hz,1H),5.56(t,J＝9.1Hz,1H),5.10-5.05(m,1H),4.62-4.55(m,1H),4.35-4.12(m,5H),3.60-3.55(m,2H),3.23(s,3H),3.18-3.13(m,1H),2.97-2.93(m,1H),2.82-2.73(m,2H),2.46-2.41(m,1H),2.15(s,3H),2.13-2.00(m,3H),1.99-1.92(m,1H),1.83-1.69(m,3H),1.58-1.37(m,5H),1.34(d,J＝6.1Hz,3H),1.10-1.03(m,4H),0.92-0.84(m,7H),0.58-0.52(m,1H),0.34(s,3H).
Compound 7'
ESI-MS(m/z):826.9[M+H] + . LC-MS retention time rt=1.80 min. HPLC retention time rt=13.22 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.56-8.49(m,2H),8.44(d,J＝2.8Hz,1H),7.80(s,1H),7.73(d,J＝8.5Hz,1H),7.54(d,J＝7.1Hz,1H),7.38(s,1H),5.55(t,J＝9.2Hz,1H),5.08-5.03(m,1H),4.57-4.49(m,1H),4.28-4.19(m,2H),3.95-3.84(m,3H),3.71-3.67(m,1H),3.58-3.52(m,1H),3.18-3.13(m,1H),3.09(s,3H),3.06-3.01(m,1H),2.82-2.73(m,2H),2.46-2.40(m,1H),2.15(s,3H),2.13-2.01(m,3H),1.99-1.91(m,1H),1.85-1.69(m,4H),1.58-1.47(m,3H),1.40(d,1H),1.22(d,J＝6.2Hz,3H),1.12-1.04(m,7H),0.94(s,3H),0.90-0.85(m,1H),0.60-0.50(m,4H).
Example 8
(1r,2R,3S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((5-(morpholinomethyl)pyridin-2-yl)oxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundec aphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide
Example 8 was prepared by the following steps:
INT-13 was used instead of INT-6 in the synthetic procedure of Compound 2, and Compound 8 and epimer compound 8' were obtained in a similar manner and reaction procedure. The absolute configuration drawn for both compounds is empirically assumed, compound 8 is the isomer that remains longer in LCMS or HPLC, and 8' is the isomer that remains shorter in LCMS or HPLC. .
Compound 8
ESI-MS(m/z):919.6[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.90 min. HPLC retention time rt=14.03min。
1 H NMR(500MHz,DMSO-d 6 )δ8.63(d,J＝2.6Hz,1H),8.48(d,J＝1.6Hz,1H),8.39(d,J＝9.0Hz,1H),8.02(d,J＝2.3Hz,1H),7.83(dd,J＝8.4,2.4Hz,1H),7.81(s,1H),7.74(dd,J＝8.7,1.6Hz,1H),7.62(d,J＝2.7Hz,1H),7.58(d,J＝8.6Hz,1H),7.16(d,J＝8.3Hz,1H),5.56(t,J＝9.1Hz,1H),5.10-5.04(m,1H),4.41-4.34(m,1H),4.30(q,J＝6.1Hz,1H),4.26-4.14(m,3H),3.62-3.53(m,8H),3.45(s,2H),3.31(s,1H),3.28(d,J＝3.2Hz,3H),3.16-3.10(m,1H),2.93-2.89(m,1H),2.79-2.75(m,1H),2.34(t,J＝4.4Hz,4H),2.08(d,J＝12.1Hz,1H),1.79(s,2H),1.56-1.51(m,1H),1.38(d,J＝6.0Hz,3H),1.16(d,J＝5.2Hz,2H),1.08(d,J＝6.0Hz,3H),1.06(d,J＝5.4Hz,3H),0.94(s,3H),0.91(t,J＝7.1Hz,3H),0.38(s,3H).
Compound 8'
ESI-MS(m/z):919.6[M+H] + . LC-MS retention time rt=1.84 min. HPLC retention time rt=12.49 min.
1 H NMR(500MHz,DMSO-d6)δ8.65(d,J＝2.7Hz,1H),8.53(d,J＝1.6Hz,1H),8.41(d,J＝9.0Hz,1H),8.03(d,J＝2.4Hz,1H),7.85-7.79(m,2H),7.76(d,J＝2.7Hz,1H),7.73(dd,J＝8.7,1.6Hz,1H),7.53(d,J＝8.7Hz,1H),5.53(t,J＝9.2Hz,1H),5.07-5.02(m,1H),4.25-4.20(m,2H),4.00-3.95(m,2H),3.87-3.79(m,1H),3.67-3.62(m,1H),3.57-3.50(m,6H),3.45(s,2H),3.31(s,1H),3.18-3.15(m,1H),3.11(s,3H),3.10-3.04(m,1H),2.78-2.74(m,1H),2.45-2.40(m,1H),2.34(d,J＝4.6Hz,5H),2.15-2.10(m,1H),1.80(s,2H),1.53(q,J＝9.6,7.4Hz,1H),1.26(d,J＝6.2Hz,3H),1.21-1.16(m,3H),1.12(d,J＝7.1Hz,3H),1.09(d,J＝6.0Hz,4H),1.07(d,J＝5.8Hz,3H),0.96(s,3H),0.53(s,3H).
Example 9
(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((5-(morpholinomethyl)pyrimidin-2-yl)oxy)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundeca phane-4-yl)-2-methylcyclopropane-1-carboxamide
Example 9 was prepared by the following steps:
INT-14 was used instead of INT-6 in the synthetic procedure of Compound 2, and Compound 9 and epimer compound 9' were obtained in a similar manner and reaction procedure. The absolute configuration drawn for both compounds is empirically assumed, compound 9 is the isomer that remains longer in LCMS or HPLC, and 9' is the isomer that remains shorter in LCMS or HPLC.
Compound 9
ESI-MS(m/z):920.6[M+H] + The method comprises the steps of carrying out a first treatment on the surface of the LC-MS retention time rt=1.77 min. HPLC retention time rt=12.81 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.69(d,J＝2.7Hz,1H),8.56(s,2H),8.48(d,J＝1.7Hz,1H),8.39(d,J＝9.0Hz,1H),7.81(s,1H),7.78(d,J＝2.7Hz,1H),7.75-7.72(m,1H),7.59(d,J＝8.6Hz,1H),5.56(t,J＝9.1Hz,1H),5.09-5.04(m,1H),4.39-4.34(m,1H),4.31(d,J＝6.1Hz,1H),4.22-4.15(m,2H),3.58(s,2H),3.55(t,J＝4.6Hz,6H),3.48(s,2H),3.31(s,1H),3.28(s,3H),3.18-3.08(m,1H),2.96-2.88(m,1H),2.82-2.72(m,1H),2.39-2.34(m,5H),2.10-2.06(m,1H),1.79-1.74(m,2H),1.55-1.50(m,1H),1.39(d,J＝6.0Hz,3H),1.21-1.14(m,2H),1.10-1.05(m,7H),0.93(s,3H),0.91(d,J＝7.3Hz,2H),0.39(s,3H).
Compound 9'
ESI-MS(m/z):920.6[M+H] + . LC-MS retention time rt=1.75 min. HPLC retention time rt=12.59 min.
1 H NMR(500MHz,DMSO-d 6 )δ8.71(d,J＝2.6Hz,1H),8.57(s,2H),8.53(d,J＝1.6Hz,1H),8.41(d,J＝9.0Hz,1H),7.91(d,J＝2.7Hz,1H),7.81(s,1H),7.73(dd,J＝8.7,1.6Hz,1H),7.53(d,J＝8.7Hz,1H),5.53(t,J＝9.2Hz,1H),5.06-5.00(m,1H),4.27-4.19(m,2H),4.01-3.97(m,2H),3.85-3.80(m,1H),3.68-3.63(m,1H),3.55(q,J＝4.6Hz,6H),3.48(s,2H),3.31(s,1H),3.19-3.15(m,1H),3.13(s,3H),3.10-3.05(m,1H),2.79-2.73(m,1H),2.45-2.40(m,1H),2.36(t,J＝4.6Hz,4H),2.15-2.10(m,1H),1.80(s,2H),1.58-1.48(m,1H),1.26(d,J＝6.2Hz,3H),1.19-1.16(m,2H),1.13(d,J＝7.1Hz,3H),1.11(s,1H),1.09(d,J＝6.0Hz,3H),1.07(d,J＝5.8Hz,3H),0.97(s,3H),0.55(s,3H).
Biological screening and results of RAS inhibitors
Test example 1: in vitro cell proliferation inhibition assay due to the diversity of RAS mutations, we selected KRAS in order to evaluate the activity of compounds in different RAS mutant cell lines WT 、KRAS G12C 、KRAS G12D 、KRAS G12V And BRAF mutant cell lines (see table below) in vitro activity assessment and screening of compounds.
Cell Line Histotype Mutant
NCI-H358 Lung；Bronchiole KRAS(p.G12C)
MIAPaCa-2 Pancreas KRAS(p.G12C)
LS513 Large intestine；Cecum KRAS(p.G12D)
AsPC-1 Pancreas KRAS(p.G12D)
HCC1588 Lung KRAS(p.G12D)；BRAF(p.E204L)
SW480 Large intestine；Colon KRAS(p.G12V)
NCI-H727 Lung；Bronchus KRAS(p.G12V)
NCI-H520 Lung KRAS WT ；
HT-29 Colon KRAS WT ；BRAF(p.V600E)
Experimental protocol:Cell Luminescent Viability Assay(Promega)
depending on the doubling time of the different cell lines, different numbers of cells (1000-5000 cells/well) were seeded in 96-well plates containing 180. Mu.l of the corresponding medium in a medium containing 5% CO 2 Is cultured overnight at 37 ℃. The next day, the compound to be tested is subjected to 3-time gradient dilution in advance by using a culture medium, and the maximum concentration is 100 mu M, and the total concentration gradient is 10; then 20. Mu.l of medium containing different concentrations of the compound was added to the cells of the 96-well plate, ensuring that the final concentration of the compound was up to 10. Mu.lM, 10 concentration gradients of 3-fold dilution. After incubation of cells with the compound for 72h, the 96-well plate was removed from the incubator, equilibrated at room temperature for 30min, and 25 μl was added to each well Reagent was thoroughly mixed and incubated at room temperature for 10min, after which 100. Mu.l of sample was transferred to a white 96-well plate (OptiPlate) TM -96, perkinelmer) using a multifunctional microplate reader @i3x, molecular devices) reads the fluorescence signal value. The signal values were then normalized and curve fitted using a four parameter fitting regression equation to calculate the half-inhibitory concentration of the compound on the cell line (half maximal inhibitory concentration, IC 50).
Table 3: antiproliferative activity of the compounds of the invention on KRAS cell mutants
* NT indicates undetected.

Claims (26)

1. A compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof:
or alternatively
Wherein:
R 1 represent C 1 -C 6 Alkyl, - (C) 1 -C 6 Alkylene) - (C 3 -C 8 Cycloalkyl) - (C) 1 -C 6 Alkylene) - (4-8 membered heterocycloalkyl), - (C 1 -C 6 Alkylene) -ORa, - (C 1 -C 6 Alkylene) -SRa or- (C 1 -C 6 Alkylene) -nra ra';
R 2 represents halogen, cyano, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) - (C 3 -C 8 Cycloalkyl), or- (C) 0 -C 6 Alkylene) - (4-8 membered heterocycloalkyl) which may be optionally substituted with 0, 1 or 2 substituents: -ORa, -SRa or-nra ra';
R 3 represents hydrogen, -O (C) 0 -C 6 Alkylene group Ra, -S (C) 0 -C 6 Alkylene group Ra, -N (C) 0 -C 6 Alkylene) Ra (C) 0 -C 6 Alkylene) R a ’ Which may optionally be substituted with 0, 1 or 2 substituents selected from the group consisting of: -ORa, -SRa, or nra ra';
Cy 1 represent C 3 -C 12 Cycloalkyl or 4-12 membered heterocycloalkyl;
R 4 each independently represents hydrogen, halogen, oxo, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 6 ) Cycloalkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, - (C 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) SRa, - (C) 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) CORa, - (C) 0 -C 6 Alkylene) COORa, - (C 0 -C 6 Alkylene) CONRaRa', - (C 0 -C 6 Alkylene) NRaCORa', - (C 0 -C 6 Alkylene) oconra' - (C) 0 -C 6 Alkylene) nraconra ra', - (C 0 -C 6 Alkylene) SORa, - (C 0 -C 6 Alkylene) S (O) 2 Ra、-(C 0 -C 6 Alkylene) NRaS (O) 2 Ra’、-(C 0 -C 6 Alkylene) CN, - (C) 0 -C 6 Alkylene) (C6-C10 aryl) or- (C 0 -C 6 Alkylene) (5-12 membered heteroaryl); wherein Cy 1 R on two C atoms of (C) 4 Together with the C atom to which it is attached and the atoms between the two C atoms may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or Cy 1 Two R's on the same C atom 4 Together with the C atom to which it is attached, may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;
R 5 、R 5 ' each independently represents hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl or- (C) 0 -C 6 Alkylene) CN;
L 1 、L 2 each independently represents- (C) 0 -C 6 ) Alkylene-, which optionally may be substituted with 0, 1, 2 or 3C' s 1 -C 3 Alkyl substituted, or two C atoms on the same C atom 1 -C 3 The alkyl substituents may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;
Cy 2 selected from C 3 -C 12 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6 -C 12 Aryl or 5-12 membered heteroaryl;
Cy 3 selected from C 3 -C 12 Cycloalkyl or 4-12 membered heterocycloalkyl;
when Cy 2 Or Cy 3 When a heterocycloalkyl group containing an S or P atom is included, optionally the S or P atom can be oxidized to-S (O) 2 -S (O) (NRa) -or-P (O) Ra-;
R 6 each independently selected from: hydrogen, halogen, oxo, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 Cycloalkyl) - (C) 0 -C 6 Alkylene) (4-8 membered heterocycloalkyl), - (C) 0 -C 6 Alkylene) ORa,-(C 0 -C 6 Alkylene) SRa, - (C) 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) C (O) Ra, - (C) 0 -C 6 Alkylene) OC (O) NRaRa', - (C) 0 -C 6 Alkylene) NRaC (O) ORa', - (C) 0 -C 6 Alkylene) NRaC (O) NRaRa', - (C) 0 -C 6 Alkylene) C (O) ORa, - (C 0 -C 6 Alkylene) C (O) NRaRa', - (C) 0 -C 6 Alkylene) S (O) 2 Ra、-P(O)RaRa’、-(C 0 -C 6 ) Alkylene CN, or Cy 2 Two R's on the same C atom 6 A spiro, bridged or fused ring may be formed, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; or Cy 2 Two R's on two adjacent ring atoms 6 May form a fused ring with the two ring atoms, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; or Cy 2 Two R's on two ring atoms not adjacent to each other 6 A bridged ring can be formed with the two ring atoms, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; and optionally, the spiro, parallel or bridged ring may contain 0, 1, 2 or 3 unsaturated bonds;
R 6 ' each independently selected from: hydrogen, halogen, oxo, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene group) (C) 3 -C 8 Cycloalkyl) - (C) 0 -C 6 Alkylene) (4-8 membered heterocycloalkyl), - (C) 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) SRa, - (C) 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) C (O) Ra, - (C) 0 -C 6 Alkylene) OC (O) NRaRa', - (C) 0 -C 6 Alkylene) NRaC (O) ORa', - (C) 0 -C 6 Alkylene) NRaC (O) NRaRa', - (C) 0 -C 6 Alkylene) C (O) ORa, - (C 0 -C 6 Alkylene) C (O) NRaRa', - (C) 0 -C 6 Alkylene) S (O) 2 Ra, or- (C) 0 -C 6 ) An alkylene group CN;or Cy 3 Two R's on the same C atom 6 ' may form a spiro, bridged or fused ring, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; or Cy 3 Two R's on two adjacent ring atoms 6 ' may form a fused ring with the two ring atoms, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; or Cy 3 Two R's on two ring atoms not adjacent to each other 6 ' may form a bridged ring with the two ring atoms, which ring may optionally contain 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S; and optionally, the spiro, parallel or bridged ring may contain 0, 1, 2 or 3 unsaturated bonds;
or R is 6 And R is R 6 ' may be in conjunction with L 2 Forming a 4-8 membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O, S;
R 7 、R 7 ' each independently selected from hydrogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) C 3 -C 8 Cycloalkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, - (C 1 -C 6 Alkylene) ORa, - (C 1 -C 6 Alkylene) SRa, - (C) 1 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) C 6 -C 12 Aromatic radical, - (C) 0 -C 6 Alkylene) (5-12 membered heteroaryl), - (C) 0 -C 6 Alkylene) NRaC (O) Ra', - (C) 0 -C 6 Alkylene) C (O) NRaRa', - (C) 0 -C 6 Alkylene) C (O) Ra or- (C) 0 -C 6 Alkylene) C (O) ORa, wherein said C 6 -C 12 Optionally, the aryl or 5-12 membered heteroaryl group may be substituted with 0, 1, 2 or 3 groups selected from halogen, C 1 -C 6 Alkyl, C 3 -C 8 Substituted by a cycloalkyl radical or R 7 And R is R 7 ' the N atom to which it is attached forms a 4-8 membered ring, said 4-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O, P or S; when R is 7 、R 7 ' is a ring containing S or P atoms, or R 7 And R is R 7 Where the' formed ring contains S or P atoms, the S or P atoms may optionally be oxidized to-S (O) 2 -S (O) (NRa) -or-P (O) Ra-;
wherein p represents 0, 1, 2, 3 or 4;
q represents 0, 1 or 2;
m, n each independently represent 0, 1, 2, 3 or 4;
ra, ra' each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 4-8 membered heterocycloalkyl; wherein when Ra, ra 'are attached to the same N atom, the Ra and Ra' together with the commonly attached N atom may form a 4-8 membered ring, which 4-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;
the alkyl, cycloalkyl, heterocycloalkyl, alkylene groups each independently may be substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.
2. The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof of claim 1, wherein R 1 Represent C 1 -C 6 Alkyl, - (C) 1 -C 6 Alkylene) - (C 3 -C 8 Cycloalkyl) or- (C) 1 -C 6 Alkylene) - (4-8 membered heterocycloalkyl); preferably, R 1 Represent C 1 -C 6 An alkyl group; more preferably, R 1 Represent C 1 -C 3 An alkyl group.
3. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R 2 Represent C 1 -C 6 Alkyl optionally substituted with 0, 1 or 2-ORa substituents; preferably, R 2 Representation ofStill more preferably, R 2 Representation->More preferably, R 2 Representation ofWherein, is R 2 A site linked to the site linked thereto in formula (I).
4. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R 3 Represents hydrogen or-O (C) 1 -C 6 ) Alkyl, -O (C) 0 -C 6 Alkylene group) (C) 3 -C 8 ) Cycloalkyl, -O (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, which may be optionally substituted with 0 or 1 substituents selected from: ORa, -SRa, or NRaRa'.
5. A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims wherein Cy 1 Represent C 3 -C 8 Cycloalkyl or 4-8 membered heterocycloalkyl.
6. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R 4 Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) SRa, - (C) 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) CONRaRa', - (C 0 -C 6 Alkylene) NRaCORa', - (C 0 -C 6 Alkylene) oconra' - (C) 0 -C 6 Alkylene) CN, - (C) 0 -C 6 Alkylene) (5-12 memberedHeteroaryl), or Cy 1 R on two C atoms of (C) 4 Together with the C atom to which it is attached and the atoms between the two C atoms may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or Cy 1 Two R's on the same C atom 4 Together with the C atom to which it is attached, may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.
7. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R 4 Each independently represents hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) CONRaRa', - (C 0 -C 6 Alkylene) (5-12 membered heteroaryl), or Cy 1 R on two C atoms of (C) 4 Together with the C atom to which it is attached and the atoms between the two C atoms may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or Cy 1 Two R's on the same C atom 4 Together with the C atom to which it is attached, may form a 3-8 membered ring, which 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.
8. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R 5 、R 5 ' each independently represents hydrogen or C 1 -C 6 An alkyl group; more preferably, R 5 、R 5 ' each independently represents hydrogen or methyl.
9. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein L 1 、L 2 Each independently represents- (C) 0 -C 3 ) Alkylene-, which optionally may be substituted with 0, 1, 2 or 3C' s 1 -C 3 Alkyl substituted, or two C atoms on the same C atom 1 -C 3 The alkyl substituents may form a 3-4 membered ring.
10. A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims wherein Cy 2 Selected from C 3 -C 12 Cycloalkyl, 4-12 membered heterocycloalkyl, more preferably Cy 2 Is 4-12 membered heterocycloalkyl, and Cy 2 Can be spiro, bridged, and fused.
11. The compound of any one of claims 1-9 having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein Cy 2 Selected from C 6 -C 12 Aryl or 5-12 membered heteroaryl, more preferably Cy 2 Is a 5-12 membered heteroaryl, and Cy 2 Can be spiro, bridged, and fused.
12. A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims wherein Cy 3 Is 4-12 membered heterocycloalkyl, and Cy 3 Can be spiro, bridged, and fused.
13. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R 6 Each independently selected from: hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, - (C 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) OC (O) NRaRa', - (C) 0 -C 6 Alkylene) NRaC (O) ORa ', -P (O) RaRa', - (C) 0 -C 6 Alkylene) C (O) Ra, - (C) 0 -C 6 ) Alkylene CN, or as claimed in claim 1, two R 6 A spiro, bridged or fused ring can be formed, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S and optionally containing 0, 1, 2 or 3 unsaturated bonds; when two R 6 When a ring containing an unsaturated bond is formed, the ring is preferably an aromatic heterocycle.
14. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R 6 ' each independently selected from: hydrogen, halogen, C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl- (C 0 -C 6 Alkylene) ORa, - (C 0 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) OC (O) NRaRa', - (C) 0 -C 6 Alkylene) NRaC (O) ORa', - (C) 0 -C 6 Alkylene) C (O) Ra, - (C) 0 -C 6 ) Alkylene CN, or as claimed in claim 1, two R 6 ' may form a spiro, bridged or fused ring, optionally containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O, S, and optionally containing 0, 1, 2 or 3 unsaturated bonds; when two R 6 When the ring containing an unsaturated bond is formed, preferably, the ring is an aromatic heterocycle.
15. A compound of formula (I) or formula (II) as claimed in any preceding claim or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein R 7 、R 7 ' each independently selected from C 1 -C 6 Alkyl, - (C) 0 -C 6 Alkylene) (4-8 membered) heterocycloalkyl, - (C 1 -C 6 Alkylene) ORa, - (C 1 -C 6 Alkylene) SRa, - (C) 1 -C 6 Alkylene) nra' - (C) 0 -C 6 Alkylene) (5-12 membered heteroaryl), - (C) 0 -C 6 Alkylene) NRaC (O) Ra' or- (C) 0 -C 6 Alkylene) C (O) NRaRa', wherein the 5-12 membered heteroaryl optionally may be substituted with 0, 1, 2 or 3 groups selected from halogen, C 1 -C 6 Substituted by alkyl radicals or R 7 And R is R 7 ' the N atom to which it is attached forms a 4-8 membered ring, said 4-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O, P or S; when R is 7 、R 7 ' is a ring containing S or P atoms, or R 7 And R is R 7 Where the' formed ring contains S or P atoms, the S or P atoms may optionally be oxidized to-S (O) 2 -, -S (O) (NRa) -or-P (O) Ra-.
16. A compound of formula (I) or formula (II) as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein p is preferably 0, 1 or 2; or q is preferably 0 or 1; or m, n are each independently preferably 0, 1 or 2.
17. The compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein,comprising at least one secondary amine or tertiary amine; preferably, at least one tertiary amine is included; wherein>A site linked to the site linked thereto in formula (I).
18. A compound of formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims wherein R 7 、R 7 At most one of which is a hydrogen atom.
19. The compound of any one of the preceding claims having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof, wherein-Cy in formula (I) 1 -(R 4 ) The structure of p is selected from the following:
wherein, represents-Cy 1 -(R 4 ) p is attached to the site of the linkage site in formula (I).
20. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein the structure in formula (I)Selected from the following:
wherein, representA site linked to the site linked thereto in formula (I).
21. A compound of formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims, wherein the structure in formula (II) Selected from the following:
wherein, representA site linked to a site linked thereto in the formula (II).
22. A compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof as claimed in any one of the preceding claims wherein the compound of formula (I) has the structure of formula (III) and the compound of formula (II) has the structure of formula (IV):
23. a compound having the structure:
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24. a pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer thereof.
25. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer or a pharmaceutical composition according to claim 24 for the manufacture of a medicament for the prevention and/or treatment of cancer, tumour, inflammatory disease, autoimmune disease or immune mediated disease.
26. A method of preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-23 or a pharmaceutically acceptable salt, isotopic derivative, stereoisomer, and/or a pharmaceutical composition of claim 24.
CN202311516025.2A 2022-11-29 2023-11-15 pan-KRAS inhibitor compound Pending CN117534684A (en)

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CN202211508623 2022-11-29

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