CN117751116A - Fused ring compounds as KRas G12D inhibitors - Google Patents
Fused ring compounds as KRas G12D inhibitors Download PDFInfo
- Publication number
- CN117751116A CN117751116A CN202280047839.3A CN202280047839A CN117751116A CN 117751116 A CN117751116 A CN 117751116A CN 202280047839 A CN202280047839 A CN 202280047839A CN 117751116 A CN117751116 A CN 117751116A
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- Prior art keywords
- alkyl
- membered
- independently
- compound
- heteroaryl
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- C—CHEMISTRY; METALLURGY
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Abstract
A class of fused ring compounds as KRas G12D inhibitors. In particular to a compound shown in a general formula (1) and a preparation method thereof, and application of the compound shown in the general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as KRAS G12D inhibitors. The compound and various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof can be used for preparing medicaments for treating or preventing related diseases mediated by KRAS G12D.
Description
The present application claims priority from chinese patent application 2021107672086, whose application date is 2021, 7. The present application refers to the entirety of the above-mentioned chinese patent application.
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a condensed-cyclic compound with KRAS G12D protein inhibition effect, a preparation method thereof and application of the compound in preparing medicines for treating, regulating or preventing related diseases mediated by KRAS G12D.
KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) is a class of GTPases and is also a member of the oncogene Ras family. In cells, kras proteins have a GDP-bound form (inactive form) and a GTP-bound form (active form), which are converted to each other to signal activation of upstream tyrosine kinases to downstream effector proteins, which regulate a range of important physiological functions, such as cell proliferation.
Recent thirty years of research have shown that KRas protein in its activated form plays a key role in tumorigenesis. About 20% of all cancers are associated with abnormal expression of KRas protein. Oncogenic KRas mutations stabilize GTP binding to KRas muteins, resulting in sustained activation of KRas protein and downstream signaling pathways. There are studies reporting that up to 25-30% of cases in lung adenocarcinoma have such KRas mutations. KRAS G12D mutation is the most common KRAS mutation. Studies have shown that KRas G12D mutations are present in 25% of pancreatic ductal carcinoma patients, 13.3% of colon adenocarcinoma patients, 10.1% of rectal adenocarcinoma patients, 4.1% of non-small cell lung carcinoma patients, and 1.7% of small cell lung carcinoma patients.
The important role of KRas in carcinogenesis and the discovery of common KRas mutations in numerous tumors makes KRas a very attractive target. Although a great deal of research has been conducted in recent 30 years to find KRas inhibitors, no other KRas inhibitors have been shown to have outstanding efficacy and safety in clinical trials, except for the therapeutic effects observed in clinical trials with KRas G12C irreversible inhibitors.
Thus, the development of specific high activity KRas G12D small molecule inhibitors would be of great clinical value for the treatment of tumors with KRas G12D mutations.
Disclosure of Invention
The invention provides a compound shown in a general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
in the general formula (1):
R 1 is-H, -OH, halogen, (C1-C3) alkyl, nitrile substituted (C1-C3) alkyl, hydroxy substituted (C1-C3) alkyl, HC (=O) -, -CO 2 R 5 、-CO 2 N(R 5 ) 2 Or (5-6 membered) heteroaryl;
y is O or NR 5 ;
Ring A is phenyl, (5-7 membered) heteroaryl, (C5-C7) cycloalkyl or (5-7 membered) heterocycloalkyl;
each R 2 independently-H, halogen, (C1-C3) alkyl(C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 membered) heteroaryl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 membered) heteroaryl may each independently optionally be substituted with 1,2,3 or 4R 6 Substitution;
each R 3 independently-H, halogen, -OH, (C1-C3) alkyl, hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (5-7 membered) heteroaryl, -CN, -SO 2 F、 NHC(O)R 8 、-N(R 5 ) 2 、 -CH 2 OC(O)N(R 5 ) 2 、-CH 2 NHC(O)OR 7 、-CH 2 NHC(O)N(R 5 ) 2 、-CH 2 NHC(O)R 7 、-CH 2 NHS(O) 2 R 7 、-CH 2 OC(O)R 8 、-OC(O)N(R 5 ) 2 、-OC(O)NH(CH 2 ) m OR 7 、-OC(O)NH(CH 2 ) m O(CH 2 ) n R 8 、-OC(O)R 8 、-CH 2 R 8 Wherein the (C1-C3) alkyl, hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy or (5-7 membered) heteroaryl groups may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 7 And R is 8 The method comprises the steps of carrying out a first treatment on the surface of the Or when two R 3 Is connected at the same timeWhen on one atom, two R 3 An oxo group may be formed;
q is a bond or O;
ring B is (C5-C7) cycloalkyl, phenyl, (5-7 membered) heteroaryl or (5-7 membered) heterocycloalkyl;
each R 4 Independently is-H, -D, halogen, R 9 、-OH、-(CH 2 ) n OR 9 、-(CH 2 ) n NR 9 R 10 、-OR 9 、-NR 9 R 10 、-CN、-C(O)NR 9 R 10 、-NR 10 C(O)R 9 、-NR 10 S(O) 2 R 9 、-S(O) p R 9 、-S(O) 2 NR 9 R 10 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 7 、-OH、-(CH 2 ) n OR 7 、-(CH 2 ) n N(R 7 ) 2 、-OR 7 、-N(R 7 ) 2 、-CN、-C(O)N(R 7 ) 2 、-NR 7 C(O)R 7 、-NR 7 S(O) 2 R 7 、-S(O) p R 7 and-S (O) 2 N(R 7 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the Or when two R 4 When attached to the same atom, two R' s 4 An oxo group may be formed;
each R 5 Independently is-H or (C1-C3) alkyl;
R 6 is-H, halogen, -OH, -CN, -OR 7 、-S-R 7 (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl(5-7 membered) heteroaryl, (C1-C4) haloalkyl, (C1-C4) alkoxy, -CH 2 C(=O)N(R 5 ) 2 、-N(R 5 ) 2 Or (C3-C6) cycloalkyl, wherein the (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (5-7 membered) heteroaryl, (C1-C4) haloalkyl, (C1-C4) alkoxy or (C3-C6) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -D, halogen, -OH, -NH 2 -CN and R 7 ;
Each R 7 Independently (C1-C6) alkyl, (C1-C6) haloalkyl or (C1-C3) alkoxy;
each R 8 Independently is a (5-7 membered) heterocycloalkyl, (5-7 membered) heteroaryl or phenyl, wherein said (5-7 membered) heterocycloalkyl, (5-7 membered) heteroaryl or phenyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -OH, -CN, -C (O) H, - (CH) 2 ) n OR 7 And- (CH) 2 ) n N(R 7 ) 2 ;
R 9 And R is 10 Each independently is-H, (C1-C6) alkyl or (C3-C7) cycloalkyl, or R on the same nitrogen atom 9 And R is 10 Together with the N atom to which they are attached can constitute a (3-7 membered) heterocycloalkyl group, which heterocycloalkyl group can be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, (C1-C3) alkyl, (C3-C5) cycloalkyl or (C1-C3) alkoxy; and
p is an integer of 0, 1 or 2, r is an integer of 1,2,3 or 4, s is an integer of 0, 1,2,3 or 4, t is an integer of 0, 1,2,3 or 4, n is an integer of 0, 1,2 or 3, and m is an integer of 1,2 or 3.
In another preferred embodiment, wherein R in the general formula (1) 1 is-H, -OH, -F, HC(=O)-、-CO 2 CH 3 or-CO 2 N(CH 3 ) 2 。
In another preferred embodiment, wherein in the general formula (1), Y is O, NH or NCH 3 。
In another preferred embodiment, wherein in the general formula (1), ring A is phenyl, 6 membered heteroaryl, cyclohexyl or (5-6 membered) heterocycloalkyl.
In another preferred embodiment, wherein in the general formula (1), the ring a is: and one end of the label is attached to the nitrogen atom.
In another preferred embodiment, wherein in the general formula (1), each R 2 independently-H, -F, -Cl, -Br, -I, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 membered) heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 membered) heteroaryl groups may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CN, -OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCF 3 、-OCHF 2 、-OCH 2 CF 3 、-SCH 3 、-SCH 2 CH 3 、-N(CH 3 ) 2 、-NH 2 、-NH(CH 3 )、 -SCF 3 、
In another preferred embodiment, wherein in the general formula (1), the structural unitThe method comprises the following steps:
in another preferred embodiment, wherein in the general formula (1), each R 3 Independently is-H, -OH, -F-Cl, -Br, -I (C1-C3) alkyl, hydroxy-substituted (C1-C3) alkyl (C1-C3) haloalkyl, (C1-C3) alkoxy, (5-6 membered) heteroaryl, -CN,NHC(O)R 8 、-N(R 5 ) 2 、-CH 2 OC(O)N(R 5 ) 2 、-CH 2 NHC(O)OR 7 、-CH 2 NHC(O)N(R 5 ) 2 、-CH 2 NHC(O)R 7 、-CH 2 NHS(O) 2 R 7 、-CH 2 OC(O)R 8 、-OC(O)N(R 5 ) 2 、-OC(O)NH(CH 2 ) m OR 7 、-OC(O)NH(CH 2 ) m O(CH 2 ) n R 8 、-OC(O)R 8 、-CH 2 R 8 Wherein the (C1-C3) alkyl group, hydroxy groupSubstituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy or (5-6 membered) heteroaryl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -CH 3 、-OCH 3 or-CH 2 CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Or when two R 3 When attached to the same atom, two R' s 3 An oxo group may be formed.
In another preferred embodiment, wherein in the general formula (1), each R 3 Independently is: -H, -OH, -F, -Cl, -Br, -I, -CN, -SO 2 F、-OCH 3 、-CF 3 、
In another preferred embodiment, wherein in the general formula (1), the ring B is a (C5-C6) cycloalkyl group, a phenyl group, a (5-6 membered) heteroaryl group or a (5-6 membered) heterocycloalkyl group.
In another preferred embodiment, wherein in the general formula (1), the ring B is:
and one end of the label is attached to the nitrogen atom.
In another preferred embodiment, wherein in the general formula (1), each R 4 Is independently-H, -D, -F,-Cl、-Br、-I、-OH、-CH 2 OR 9 、-CH 2 NR 9 R 10 、-OR 9 、-NR 9 R 10 、-CN、-C(O)NR 9 R 10 、-NR 10 C(O)R 9 、-NR 10 S(O) 2 R 9 、-SR 9 、-S(O) 2 R 9 、-S(O) 2 NR 9 R 10 (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH 3 、-N(CH 3 ) 2 and-CN; or when two R 4 When attached to the same atom, two R' s 4 An oxo group may be formed.
In another preferred embodiment, wherein in the general formula (1), each R 4 Independently is: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-CH 2 N(CH 3 ) 2 、-OCH 3 、-OCF 3 、-N(CH 3 ) 2 、-CN、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)N(CH 3 ) 2 、-NHC(O)CH 3 、-N(CH 3 )-C(O)CH 3 、-NHS(O) 2 CH 3 、-NCH 3 S(O) 2 CH 3 、-SCH 3 、-S(O) 2 CH 3 and-S (O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 N(CH 3 ) 2 、 Or when two R 4 When attached to the same atom, two R' s 4 An oxo group may be formed.
In another preferred embodiment, wherein in the general formula (1), the structural unitThe method comprises the following steps:
in another preferred example, wherein the general formula (1) has a structure as shown in the general formula (1 a) or the general formula (1 b):
wherein R is 1 、R 2 、R 3 、R 4 The definitions of Y, B, r, s and t are as described above and illustrated in the examples.
In another preferred example, wherein the general formula (1) has a structure as shown in general formula (2 a) -general formula (2 d):
wherein R is 1 、R 2 、R 3 、R 4 The definitions of Y, r, s and t are as described above and illustrated in the examples.
In various embodiments, the compound of formula (1) has one of the following structures:
it is another object of the present invention to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, as an active ingredient.
A further object of the present invention is to provide the use of a compound represented by the general formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition described above for the preparation of a medicament for treating, modulating or preventing a KRas G12D-related disease; the disease is preferably cancer, which is hematological cancer and solid tumors.
Still another object of the present invention is to provide a method for treating, modulating or preventing a disease associated with KRas G12D mediation comprising administering to a subject a therapeutically effective amount of a compound of formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof; the disease is preferably cancer, which is hematological cancer and solid tumors.
Through synthesis and careful study of a variety of novel compounds involved in the inhibition of the KRAS G12D protein, the inventors have found that among the compounds of formula (1), the compounds unexpectedly have very potent KRAS G12D inhibitory activity.
It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
Synthesis of Compounds
The process for preparing the compound of the general formula (1) of the present invention is specifically described below, but these specific processes do not constitute any limitation on the present invention.
The compounds of formula (1) described above may be synthesized using standard synthetic techniques or well known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials for the synthesis of the compounds may be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 4 th ed., vols.A and B (Plenum 2000, 2001), green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general method of preparation of the compounds may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.
In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as the reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the explanation below. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound represented by the general formula (1) can be prepared by the following general reaction scheme 1 or general reaction scheme 2:
general reaction scheme 1
Embodiments of compounds of formula (1) may be prepared according to general scheme 1, wherein R 1 、R 2 、R 3 、R 4 The Y and B rings are as defined hereinabove, H represents hydrogen, N represents nitrogen, S represents sulfur, O represents oxygen, X represents nitrogen or carbon. As shown in general reaction scheme 1, compounds 1-1 and 1-2 undergo substitution reaction under alkaline conditions to produce compounds 1-3, compounds 1-3 undergo European Union reaction with 1-4 or 1-5 to produce compounds 1-6, compounds 1-6 undergo reaction under acidic conditions to produce 1-7, compounds 1-7 and 1-8 undergo reaction to produce compounds 1-9, compounds 1-9 and POCl 3 Reaction to produce compound 1-10, substitution reaction between compound 1-10 and compound 1-11 to produce compound 1-12, substitution reaction between compound 1-12 and compound 1-13 to produce compound 1-14, and acid reaction between compound 1-14Deprotection under sexual conditions yields 1-15.
General reaction scheme 2
Embodiments of compounds of formula (1) may be prepared according to general scheme 2, wherein R 1 、R 2 、R 3 、R 4 The Y and B rings are as defined above, H represents hydrogen, N represents nitrogen, S represents sulfur, and O represents oxygen. As shown in general reaction scheme 2, compounds 2-1 and 2-2 undergo substitution reaction under alkaline conditions to produce compound 2-3, compound 2-3 undergoes substitution reaction with 2-4 to produce compound 2-5, compound 2-5 undergoes selective deprotection under acidic conditions to produce 2-6, compound 2-6 undergoes coupling reaction with compound 2-7 or 2-8 to produce compound 2-9, and compound 2-9 undergoes deprotection under acidic conditions to produce 2-10.
Further forms of the compounds
By "pharmaceutically acceptable" is meant herein a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and which is relatively non-toxic, e.g., administration of a material to an individual does not cause an undesired biological effect or interact in a deleterious manner with any of the components thereof in which it is contained.
The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered, and does not abrogate the biological activity and properties of the compound. In certain specific aspects, the pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and other organic acids, and an acidic amino acid, e.g., aspartic acid, glutamic acid.
References to pharmaceutically acceptable salts are understood to include solvent-added forms or crystalline forms, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (1) are conveniently prepared or formed in accordance with the methods described herein. For example, the hydrate of the compound of formula (1) is conveniently prepared by recrystallisation from a mixed solvent of water/organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, solvated forms are considered to correspond to unsolvated forms.
In other specific embodiments, the compounds of formula (1) are prepared in different forms including, but not limited to, amorphous, crushed and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.
In another aspect, the compounds of formula (1) may have chiral centers and/or axial chiralities and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric forms, and cis-trans isomeric forms. Each chiral center or axial chiral will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The compounds of the invention may be present in one or more of the precursors constituting the compoundThe child contains an unnatural proportion of atomic isotopes. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) And C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For another example, deuterium can be substituted for a hydrogen atom to form a deuterated compound, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, and generally deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, prolonging in vivo half-life of drugs, and the like, compared to non-deuterated drugs. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Terminology
The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. It must be noted that, in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. 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.
Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, particularly alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH 3 、CH 3 CH 2 、CF 3 、CHF 2 、CF 3 CH 2 、CF 3 (CH 3 )CH、 i Pr、 n Pr、 i Bu、 n Bu or t Bu。
Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.
Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, and includes straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl are preferred.
Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, for example ethynyl, 1-propynyl or 1-butynyl.
Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), a partially unsaturated cycloalkyl may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, pinyl, carenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexane, and the like.
Unless otherwise specified, "alkoxy" refers to bonding to the remainder of the molecule through an ether oxygen atomIs a hydrocarbon group. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from OCH 3 、OCF 3 、CHF 2 O、CF 3 CH 2 O、 i- PrO、 n- PrO、 i- BuO、 n- BuO or t- BuO。
Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, an aryl group being monocyclic or polycyclic, e.g., a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the remainder of the molecule through an ether oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.
Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrylene.
Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), heteroaryl being monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, pyrrolopyrimidinyl, 1H-pyrrole [3,2-b ] ]Pyridyl, 1H-pyrrole [2,3-c ]]Pyridyl, 1H-pyrrole [3,2-c ]]Pyridyl, 1H-pyrrole [2,3-b ]]A pyridyl group,
Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.
Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl group contains at least one triple bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form oxo or thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains from 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are benzo derivatives having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, thienyl, or the like. The heterocycloalkyl group containing the fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro [5.5 ] ]Undecyl, 1-oxa-8-azaspiro [4.5 ]]Decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3, 4-tetrahydroquinolinyl, tropanyl,4,5,6, 7-tetrahydrothiazolo [5,4-c]Pyridyl, 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyllactam, valerolactam, imidazolone, hydantoin, dioxolanyl, phthalimido, pyrimidine-2, 4 (1H, 3H) -dione, 1, 4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S, S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro [3.3 ]]Heptyl, indolinyl, and,
Unless otherwise specified, "oxo" refers to =o; for example, a group formed by substitution of carbon with an oxo group is a "carbonyl group"; the group formed by substitution of sulfur by an oxo group being "sulfinyl", the group formed by substitution of sulfur with two oxo groups is a" sulfonyl group”。
Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted with F, cl, br or I, preferably F or Cl, in any combination.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Substituent "-O-CH 2 -O- "means that two oxygen atoms in the substituent are attached to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, such as:
when the number of one linking group is 0, such as- (CH) 2 ) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in X-L-Y represents a bond, it is indicated that the structure is in fact X-Y.
The term "membered ring" includes any cyclic structure. The term "meta" is meant to indicate the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings and cyclopentyl, pyrrolyl, furanyl and thiophenyl are five-membered rings.
The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.
Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keys And straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key
Unless otherwise indicated, use ofRepresents a single bond or a double bond.
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 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 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.
"active ingredient" refers to a compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the invention may contain one or more asymmetric centers (chiral centers or axial chiralities) and thus appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The terms "compound", "composition", "agent" or "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).
The term "administration (administered, administering or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a prodrug (pro), derivative (derivative), or analog (analog) of the active compound, and the like.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.
Unless defined otherwise herein, the meanings of scientific and technical terms used herein are the same as commonly understood by one of ordinary skill in the art. Furthermore, as used in this specification, the singular noun encompasses the plural version of the noun without conflict with the context; plural nouns as used also encompasses singular versions of the noun.
Therapeutic use
The compounds of formula (1) or pharmaceutical compositions provided herein are generally useful for inhibiting KRas G12D protein and thus are useful for treating one or more conditions associated with KRas G12D protein activity. Thus, in certain embodiments, the present invention provides a method for treating a KRas G12D protein-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.
In some embodiments, there is provided a method for treating cancer, the method comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancer is mediated by KRas G12D protein. In other embodiments, the cancer is hematologic and solid tumors, including, but not limited to, leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastasis.
Route of administration
The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
"pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soya oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agents (e.g. tween ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present invention. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. Various changes and modifications to the present invention will become apparent to those skilled in the art upon reading the present description, and such equivalents fall within the scope of the present application.
In all of the embodiments described herein, the present invention, 1 H-NMR was recorded on a Varian Mercury 400 Nuclear magnetic resonance apparatus, chemical shifts being expressed as delta (ppm); the silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.
The invention adopts the following abbreviations: ac (Ac) 2 O represents acetic anhydride; (Boc) 2 O represents di-tert-butyl dicarbonate; CDCl 3 Represents deuterated chloroform; CO represents carbon monoxide; cs (cells) 2 CO 3 Represents cesium carbonate; csF represents cesium fluoride; etOAc represents ethyl acetate; hexane represents n-Hexane; HPLC means high performance liquid chromatography; meCN or CH 3 CN represents acetonitrile; DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; dioxane represents 1, 4-Dioxane; DMF represents N, N-dimethylformamide; DMAP represents 4- (dimethylamino) pyridine; DMSO represents dimethylsulfoxide; dichloroo (p-cymene) ruthenium (II) dimer represents Dichloro (p-methylisopropylene) ruthenium (II) dimer; DPPA represents diphenyl azide phosphate; etOH stands for ethanol; hr represents hours; k (K) 2 CO 3 Represents potassium carbonate; KOAc represents potassium acetate; k (K) 3 PO 4 Represents potassium phosphate; liAlH 4 Represents lithium aluminum hydride; liHMDS represents lithium bis (trimethylsilyl) amide; min represents minutes; meOH represents methanol; MS stands for mass spectrum; MOMCl represents chloromethyl methyl ether; MOM represents methoxymethyl; MTBE stands for tert-butyl methyl ether; naHCO (NaHCO) 3 Represents sodium bicarbonate; na (Na) 2 SO 4 Represents sodium sulfate; n-BuLi represents n-butyllithium; NMR stands for Nuclear magnetismResonance; NIS stands for iodinated succinimide; pd/C represents palladium on carbon; pd (dppf) Cl 2 Represents [1,1' -bis (diphenylphosphine) ferrocene ]Palladium (II) dichloride; pd (PPh) 3 ) 2 Cl 2 Represents bis triphenylphosphine palladium dichloride; PE represents petroleum ether; POCl (Point of care testing) 3 Represents phosphorus oxychloride; psi stands for pound force per square inch; SOCl 2 Represents thionyl chloride; t-BuOH represents tert-butanol; TEA represents triethylamine; TFA represents trifluoroacetic acid; tf (Tf) 2 O represents trifluoromethanesulfonic anhydride; THF represents tetrahydrofuran; TIPS represents triisopropylsilyl; tolene or Tol represents Toluene; xantPhos represents 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; TLC stands for thin layer chromatography; XPhos stands for 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl.
Preparation example 1 Synthesis of intermediate Int_A-1
Step 1: synthesis of Compound int_A-1-2
Int-A-1-1 hydrochloride (31 g,178.13 mmol) was dissolved in water (500 mL) and NaHCO was added at room temperature 3 (37.41 g,445.34 mmol) and acetic anhydride (20.00 g,195.95mmol,18.35 mL) were added to the reaction solution after stirring for 30 minutes, and the reaction solution was stirred at room temperature for another 4 hours to precipitate a white solid. LC-MS detection showed complete reaction. Filtration gives a filter cake which is washed with water (50 ml X2) and dried to give the crude product. The crude product was slurried with MTBE (300 ml) at room temperature for 30 minutes, filtered to give a cake and dried to give a white solid (18 g, yield: 56.3%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=6.40(br s,1H),5.06-4.97(m,1H),4.05-3.98 (m,1H),3.95-3.89(m,1H),3.87-3.81(m,3H),2.15-2.06(m,3H)
Step 2: synthesis of Compound int_A-1-4
Int_A-1-2 (17.01 g,94.74 mmol) and Int_A-1-3 (10 g,72.87 mmol) were dissolved in acetonitrile (100 mL), and a solution of DIPEA (9.42 g,72.87mmol,12.69 mL) in acetonitrile (100 mL) was added dropwise at 0deg.C, and after the mixture was stirred at room temperature for 16 hours, LC-MS detection showed complete reaction. To the reaction solution was added 3mL of water and stirring was continued for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=10/1 to 0/1) to give a yellow oil (10 g, yield: 60.4%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=6.80-6.33(m,1H),4.74-4.57(m,1H),3.76(d,J=2.0Hz,3H),2.48-2.08(m,5H),2.07-1.99(m,4H),1.95-1.76(m,2H),1.63-1.54(m,1H)
Step 3: synthesis of Compound int_A-1-5
Int_A-1-4 (10 g,44.00 mmol) was dissolved in 10% hydrochloric acid (320.88 g,880.06mmol,314.59 mL) and after the mixture was allowed to react at 80℃for 3 hours, LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (8 g, yield: 95.9%).
Step 4: synthesis of Compound int_A-1-6
Int_A-1-5 (8 g,52.23 mmol) and Pd/C (3 g,5.22mmol,10% purity) were dissolved in ethanol (200 mL) and the mixture was hydrogenated at 15psi for 16 hours, and the LC-MS detection showed complete reaction. Filtering to obtain filtrate, and concentrating the filtrate under reduced pressure to obtain crude product. The crude product was used directly in the next reaction (8 g, yield: 98.7%).
Step 5: synthesis of Compound int_A-1-7
Int_A-1-6 (7 g,45.10 mmol) was dissolved in methanol (200 mL) and SOCl was slowly added dropwise at 20deg.C 2 (10.73 g,90.21mmol,6.54 mL) and the reaction was stirred at room temperature for 16 hours and the LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (8 g, yield: 105%).
Step 6: synthesis of Compound int_A-1-8
Int_A-1-6 (8 g,47.3 mmol) was dissolved in dichloromethane (200 mL) and TEA (23.92 g,236mmol,32.9 mL) and Boc were added at room temperature 2 O (12.38 g,56.73mmol,13.03 mL) and the reaction was stirred at room temperature for 16 hours and then detected by LC-MS to indicate completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=4/1) to give a colorless oil (10 g, yield: 78.5%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=4.46-4.12(m,2H),3.77-3.68(m,3H),2.75-2.63(m,1H),2.49-2.33(m,1H),2.04-1.86(m,2H),1.84-1.73(m,2H),1.51-1.34(m,11H)
Step 7: synthesis of Compound int_A-1-10
Int_A-1-8 (9.1 g,33.79 mmol) was dissolved in THF (160 mL), liHMDS (1M, 54.06 mL) was slowly added dropwise at-60℃and after stirring the reaction solution at-60℃for 1 hour, int_A-1-9 (7.98 g,50.68mmol,4.99 mL) was added to the reaction solution, the reaction solution continued to be stirred at-60℃for 1 hour, and then allowed to react to room temperature for 2 hours, and LC-MS detection showed complete reaction. To the reaction solution were added 10mL of a saturated aqueous ammonium chloride solution and 20mL of water, the aqueous phase was extracted with ethyl acetate (30 mL X3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=100/1 to 15/1) to give a yellow gum (6 g, yield: 51.3%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=4.41-4.09(m,1H),3.76-3.69(m,3H),3.66-3.49(m,2H),2.85-2.65(m,1H),2.40-2.24(m,1H),2.21-2.06(m,1H),2.05-1.63(m,8H),1.55-1.37(m,11H)
Step 8: synthesis of Compound int_A-1-11
Int_A-1-10 (6 g,17.35 mmol) was dissolved in dichloromethane (10 mL), dioxane hydrochloride solution (4M, 43.37 mL) was slowly added dropwise at a temperature below 10℃and the reaction mixture was stirred at room temperature for 3 hours, and LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (5 g, yield: 117%).
Step 9: synthesis of Compound int_A-1-12
Int_A-1-11 hydrochloride (5 g,17.72 mmol) was dissolved in methanol (150 mL) and K was added at room temperature 2 CO 3 (7.35 g,53.15 mmol) and the reaction stirred at room temperature for 16 hours, LC-MS detection showed complete reaction. Filtering the reaction solution to obtainThe filtrate was concentrated under reduced pressure to give a crude product. The crude product was subjected to column chromatography (SiO 2, DCM/meoh=10/1) to give a yellow oil (2.5 g, yield: 67.4%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=3.76-3.69(m,3H),3.30-3.24(m,1H),3.14(td,J=6.9,11.1Hz,1H),2.88-2.80(m,1H),2.70-2.58(m,1H),2.24-2.16(m,2H),2.14-2.05(m,1H),1.94-1.36(m,10H)
Step 10: synthesis of Compound int_A-1
Int_A-1-12 (2.3 g,10.99 mmol) was dissolved in THF (50 mL), liAlH4 (284 mg,21.98 mmol) was added at 0deg.C, and the reaction was stirred at room temperature for 2 hours and showed complete reaction by LC-MS detection. 10.H2O.Na2SO4 (20 g) was added to the reaction mixture at 0℃and the reaction mixture was allowed to warm to room temperature with stirring for half an hour. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was suspended in methylene chloride (10 mL), and the filtrate was again filtered to give a yellow oil (1.5 g, yield: 75.3%) by concentrating the filtrate under reduced pressure.
1 H NMR:(400MHz,CHLOROFORM-d)δ=3.31-3.20(m,2H),3.18-3.11(m,1H),2.92-2.77(m,2H),2.69-2.57(m,1H),2.04-1.91(m,2H),1.80(dd,J=7.2,12.9Hz,1H),1.76-1.44(m,12H)
Preparation example 2 Synthesis of intermediate int_A-2
Step 1: synthesis of Compound int_A-2-2
Int_A-2-1 hydrochloride(75 g,430.97 mmol) was dissolved in water (1000 mL) and NaHCO was added at room temperature 3 (90.51 g,1.08 mol) and acetic anhydride (48.40 g,474.07mmol,44.40 mL) were added to the reaction solution after stirring for 30 minutes, and the reaction solution was stirred at room temperature for another 4 hours to precipitate a white solid. LC-MS detection showed complete reaction. Filtration gives a filter cake which is washed with water (50 ml X2) and dried to give the crude product. The crude product was slurried with MTBE (500 ml) at room temperature for 30 minutes, filtered to give a cake and dried to give a white solid (40 g, yield: 51.7%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=6.41(br s,1H),5.08-4.99(m,1H),4.03-3.97(m,1H),3.96-3.89(m,1H),3.84(s,3H),2.10(s,3H)
Step 2: synthesis of Compound int_A-2-4
Int_A-2-2 (25 g,182.19mmol,26.57 mL) and Int_A-2-3 (39.27 g,218.62 mmol) were dissolved in acetonitrile (300 mL), and a solution of DIPEA (23.55 g,182.19mmol,31.73 mL) in acetonitrile (300 mL) was added dropwise at 0deg.C, and after the mixture was stirred at room temperature for 16 hours, LC-MS detection showed complete reaction. To the reaction solution was added 3mL of water and stirring was continued for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=10/1 to 0/1) to give a yellow oil (24 g, yield: 57.9%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=6.82-6.37(m,1H),4.74-4.55(m,1H),3.76(d,J=2.0Hz,3H),2.49-2.32(m,2H),2.31-2.00(m,9H),1.94-1.78(m,2H),1.64-1.54(m,1H)
Step 3: synthesis of Compound int_A-2-5
Int-A-2-4 (25 g,110.01 mmol) was dissolved in 10% hydrochloric acid (401.10 g,1.10mol,393.23 mL) and the mixture was allowed to react at 80℃for 3 hours, after which LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (18 g, crude).
Step 4: synthesis of Compound int_A-2-6
Int_A-2-5 (15 g,97.93 mmol) and Pd/C (1.5 g,10% purity) were dissolved in ethanol (40 mL) and the mixture was hydrogenated at 15psi for 16 hours, and LC-MS detection showed complete reaction. Filtering to obtain filtrate, and concentrating the filtrate under reduced pressure to obtain crude product. The crude product was used directly in the next reaction (15 g, crude).
Step 5: synthesis of Compound int_A-2-7
Int-A-2-6 (15 g,96.65 mmol) was dissolved in methanol (200 mL) and SOCl was slowly added dropwise at 20deg.C 2 (23.00 g,193.31mmol,14.02 mL) and stirring of the reaction mixture was continued at room temperature for 16 hours, and LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (16 g, crude).
Step 6: synthesis of Compound int_A-2-8
Int_A-2-6 (16 g,94.55 mmol) was dissolved in dichloromethane (200 mL) and TEA (61.10 g,472.76mmol,82.35 mL) and Boc were added at room temperature 2 O (30.95 g,141.83mmol,32.58 mL) and the reaction was stirred at room temperature for 16 hours, and the LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate=4/1) to give a colorless oil (16 g, yield: 62.83%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=4.47-4.13(m,2H),3.82-3.71(m,3H),2.76-2.63(m,1H),2.49-2.34(m,1H),2.04-1.87(m,2H),1.87-1.66(m,3H),1.61(s,4H),1.57- 1.34(m,10H)
Step 7: synthesis of Compound int_A-2-10
Int_A-2-8 (16 g,59.41 mmol) was dissolved in THF (300 mL), liHMDS (1M, 89.11 mL) was slowly added dropwise at-60℃and after stirring the reaction solution at-60℃for 1 hour, int_A-2-9 (14.03 g,89.11mmol,8.77 mL) was added to the reaction solution, the reaction solution continued to be stirred at-60℃for 1 hour, and then the reaction was allowed to proceed to room temperature for 2 hours, and LC-MS detection showed complete reaction. To the reaction solution were added 100mL of a saturated aqueous ammonium chloride solution and 100mL of water, the aqueous phase was extracted with ethyl acetate (150 mL. Times.3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=100/1 to 15/1) to give a yellow gum (17 g, yield: 82.7%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=4.34-4.10(m,1H),3.78-3.70(m,3H),3.66-3.49(m,2H),2.82-2.70(m,1H),2.37-2.24(m,1H),2.21-2.07(m,1H),2.04-1.56(m,10H),1.53-1.38(m,11H)
Step 8: synthesis of Compound int_A-2-11
Int_A-2-10 (17 g,49.15 mmol) was dissolved in dichloromethane (50 mL), dioxane hydrochloride solution (4M, 122.88 mL) was slowly added dropwise at a temperature below 10℃and the reaction mixture was stirred at room temperature for 3 hours, and LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (12 g, yield: 99.35%).
Step 9: synthesis of Compound int_A-2-12
Int_A-2-11 (12 g,48.83 mmol) was dissolved in methanol (200 mL) and K was added at room temperature 2 CO 3 (20.25 g,146.49 mmol) and the reaction stirred at room temperature for 16 hours, LC-MS detection showed complete reaction. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO 2, DCM/meoh=10/1) to give a yellow oil (7 g, yield: 68.50%).
1 H NMR:(400MHz,CHLOROFORM-d)δ=3.76-3.69(m,3H),3.30-3.24(m,1H),3.14(td,J=6.9,11.1Hz,1H),2.88-2.80(m,1H),2.70-2.58(m,1H),2.24-2.16(m,2H),2.14-2.05(m,1H),1.94-1.36(m,10H)
Step 10: synthesis of Compound int_A-2
Int-A-2-12 (7 g,33.45 mmol) was dissolved in THF (150 mL), liAlH4 (2.54 g,66.89 mmol) was added at 0deg.C and the reaction stirred at room temperature for 2 hours and the LC-MS detection showed complete reaction. 10.H2O.Na2SO4 (50 g) was added to the reaction mixture at 0℃and the reaction mixture was allowed to warm to room temperature with stirring for half an hour. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was suspended in methylene chloride (10 mL), and the filtrate was obtained by filtration again, and the filtrate was concentrated under reduced pressure to give a yellow oil (5 g, yield: 82.5%).
Preparation example 3 Synthesis of intermediate Int_B-1
Step 1: synthesis of Compound int_B-1-3
Int_B-1-1 (25 g,156 mmol), int_B-1-2 (49 g,188 mmol), dichloro (p-cymene) ruthenium (II) dimer (9.5 g,15.6 mmol) and potassium acetate (30.6 g,312 mmol) were dissolved in dioxane (300 mL), and the reaction mixture was reacted at 110℃for 12 hours, and the LC-MS detection showed the reaction to be complete. To the reaction solution was added 500mL of water, the aqueous phase was extracted with ethyl acetate (500 mL X3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=3/1) to give a product (46 g, yield: 86.7%).
ESI-MS m/z:341[M+H] + .
Step 2: synthesis of Compound int_B-1-4
Int_B-1-3 (90 g,264.5 mmol) and DIPEA (103 g,0.8mol,138 mL) were dissolved in methylene chloride (800 mL), MOMCl (31.9 g,396.5mmol,30.1 mL) was added at 0deg.C, and the reaction mixture was reacted at 0deg.C for half an hour, and the LC-MS detection showed that the reaction was complete. 600mL of water was added to the reaction mixture, the aqueous phase was extracted with methylene chloride (300 mL. Times.3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=3/1) to give a product (51 g, yield: 50.5%).
1 H NMR(400MHz,CHLOROFORM-d)δ=9.26(s,1H),7.70(dd,J=0.8,8.0Hz,1H),7.50(dd,J=1.2,7.2Hz,1H),7.32(dd,J=7.2,8.4Hz,1H),6.99(d,J=2.4Hz,1H),6.78(d,J=2.4Hz,1H),5.28(s,2H),3.52(s,3H),1.20-1.16(m,21H).
Step 3: synthesis of Compound int_B-1-5
Int_B-1-4 (100 g,260 mmol) and DIPEA (101 g,0.78mol,136 mL) were dissolved in dichloromethane (1200 mL) and Tf was added at-40 ℃ 2 O (110 g,390mmol,64.5 mL) and reaction at-40℃for half an hour, LC-MS detection showed complete reaction. To the reaction mixture was added 800mL of water to quench the reaction, the aqueous phase was extracted with methylene chloride (500 mL. Times.3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=5/1) to give a product (115 g, yield: 85.8%).
Step 4: synthesis of Compound int_B-1
Int_B-1-5 (115 g,222.5 mmol), int_B-1-6 (113 g,445 mmol), pd (dppf) Cl 2 (16.3 g,23 mmol) and potassium acetate (76 g,0.78 mol) were dissolved in toluene (800 mL), and the reaction was reacted at 110℃for 3 hours under nitrogen protection, and the reaction was complete by LC-MS detection. To the reaction solution was added 500mL of water, the aqueous phase was extracted with ethyl acetate (500 mL X3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=20/1) to give a product (56 g, yield: 50.9%).
1 H NMR(400MHz,CHLOROFORM-d)δ=7.71-7.66(m,2H),7.47(d,J=2.4Hz,1H),7.39-7.32(m,2H),5.28(s,2H),3.52(s,3H),1.43(s,12H),1.19-1.15(m,21H).
EXAMPLE 1 Synthesis of Compound 2
Step 1: synthesis of Compound int_2-2
Int_2-1 (60 g, 323 mmol), TEA (103.5 g,1.03mol,142.6 mL), t-butanol (336.7 g,4.53mol,433 mL) and DPPA (26 g,0.26 mol) were dissolved in toluene (400 mL), and the reaction mixture was reacted at 110℃for 6 hours under nitrogen atmosphere, and the LC-MS detection showed that the reaction was complete. 600mL of water was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (500 mL. Times.3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography (SiO 2, petroleum ether/Ethyl acetate=100/1 to 5/1) to give a product (59 g, yield: 69.7%).
1 H NMR(400MHz,methanol-d4)δ=8.11(t,J=5.6Hz,1H),7.99(d,J=5.6Hz,1H),1.52(s,9H).
Step 2: synthesis of Compound int_2-3
Int_2-2 (0.95 g,3.85 mmol) was dissolved in dichloromethane (6 mL) and TFA (3 mL) was slowly added dropwise at a controlled temperature below 10deg.C, and the reaction was allowed to react at room temperature for 6 hours, and LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (564 mg, yield: 100%).
1 H NMR(400MHz,CHLOROFORM-d):δ=7.82(d,J=5.4Hz,1H),6.60(t,J=5.8Hz,1H),4.38(br s,2H).
Step 3: synthesis of Compound int_2-4
Int_2-3 (10.7 g,73 mmol) and NIS (19.7 g,87.6 mmol) were dissolved in acetonitrile (50 mL), p-toluenesulfonic acid (0.7 g,3.65 mmol) was added at room temperature and the reaction mixture was stirred at 70℃for 16 hours and LC-MS detection showed complete reaction. To the reaction solution was added 50mL of water, the aqueous phase was extracted with ethyl acetate (50 mL X3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was directly used in the next reaction (18 g, yield: 90.9%).
Step 4: synthesis of Compound int_2-5
Int_2-4 (7.8 g,28.8 mmol), pd (PPh) 3 ) 2 Cl 2 (2 g,2.88 mmol) and TEA (10.5 g,0.1mol,14.5 mL) were dissolved in ethanol (200 mL) and the reaction was reacted at 80℃for 16 hours under CO atmosphere (15.0 psi) and LC-MS detection showed the reaction was complete. To the reaction solution was added 100mL of water, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography to give the product (5.3 g, yield: 84.1%).
1 H NMR(400MHz,dmso-d6)δ=8.36(s,1H),7.49-7.42(m,2H),4.31(q,J=7.2Hz,2H), 1.31(t,J=7.2Hz,3H).
Step 5: synthesis of Compound int_2-7
Int_2-5 (10 g,36.5 mmol) was dissolved in THF (30 mL) and Int_2-6 (10 g,55mmol,6.5 mL) was slowly added dropwise at a controlled temperature below 10deg.C, and the reaction was allowed to react at room temperature for 1 hour, and LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (13.7 g, yield: 92.5%).
Step 6: synthesis of Compound int_2-8
Int_2-7 (10 g,21 mmol) was dissolved in methanol (100 mL), and a methanol solution of ammonia (10 mL,20% purity) was slowly added dropwise to the solution, and the reaction solution was reacted at room temperature for 1 hour, and the LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was slurried in MTBE to give the product (3.9 g, yield: 86.7%).
ESI-MS m/z:216[M+H] + .
Step 7: synthesis of Compound int_2-9
Int_2-8 (2 g,9.3 mmol) was dissolved in toluene (10 mL), phosphorus oxychloride (4.3 g,27.8mmol,2.6 mL) and DIPEA (3.6 g,27.8mmol,4.85 mL) were slowly added dropwise to the solution at 0deg.C, and the reaction mixture was warmed to 110deg.C and reacted for 5 hours, and LC-MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction (2.1 g, yield: 89.7%).
Step 8: synthesis of Compound int_2-11
Int_2-9 (1.0 g,3.961 mmol) was dissolved in DCM (25 mL), DIPEA (2.6 g,19.81 mmol) was added, a solution of Int_2-10 (841 mg,3.961 mmol) in DCM (10 mL) was added dropwise at-40℃under nitrogen protection, the reaction solution was reacted at-40℃for 0.5 hours, LC-MS detection showed completion of the reaction, 50mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL X3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give the crude product, which was directly used in the next reaction (1.65 g, 97.1%).
ESI-MS m/z:428[M+H] +
Step 9: synthesis of Compound int_2-12
Int_2-11 (500 mg,1.167 mmol) was dissolved in DMF (7 mL), and Int_A-1 (212 mg,1.169 mmol) and cesium carbonate (760 mg,2.338 mmol) were added and reacted at 80℃for 16 hours. LC-MS detection showed complete reaction, and the reaction mixture was concentrated under reduced pressure to give a crude product, which was prepared by reverse phase HPLC to give a yellow solid product (120 mg, yield: 17.1%).
ESI-MS m/z:573[M+H] +
Step 10: synthesis of Compound int_2-13
To a mixed solution of int_2-12 (120 mg,0.209 mmol) in dioxane/water (5 mL/1 mL) was added int_B-1 (104 mg,0.209 mmol), potassium carbonate (43 mg,0.314 mmol) and Ruphos-Pd-G3 (52 mg,0.062 mmol), and the reaction solution was reacted at 100℃for 16 hours under the protection thereof, and the LC-MS detection showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give a crude product, which was prepared by reversed phase HPLC to give a yellow solid product (30 mg, yield: 15.8%).
ESI-MS m/z:453[M/2+H] +
Step 11: synthesis of Compound int_2-14
Int_2-13 (30 mg,0.033 mmol) was dissolved in DMF (2 mL), cesium fluoride (50 mg,0.33 mmol) was added and the reaction was allowed to react at room temperature under nitrogen for 2 hours, and LC-MS detection showed complete reaction. To the reaction solution was added 10mL of water, the aqueous phase was extracted with ethyl acetate (10 mL X3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give a crude product, which was prepared by reverse phase HPLC to give a yellow solid product (20 mg, yield: 79.1%).
ESI-MS m/z:375[M/2+H] +
Step 12: synthesis of Compound 2
Int_2-14 (20 mg,0.026 mmol) was dissolved in methanol (1 mL), cooled to-5℃in an ice bath, 4M dioxane hydrochloride solution (2 mL) was slowly added dropwise to the reaction solution, and after the addition, the reaction solution was kept at-5℃for 2 hours, and LC-MS detection showed complete reaction. The reaction was adjusted to pH 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10 mL X3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give the crude product which was prepared as a yellow solid by reverse phase HPLC (5 mg, 31.6%).
1 H NMR(400MHz,Methanol-d4)δ=9.04(d,J=3.6Hz,1H),8.53(s,1H),7.82(d,J=8.2Hz,1H),7.51(dd,J=7.2,1.3Hz,1H),7.44-7.37(m,1H),7.33(d,J=2.6Hz,1H),7.16(dd,J=2.6,1.4Hz,1H),4.57(dd,J=17.7,12.2Hz,6H),3.79-3.65(m,3H),3.48(dd,J=3.3,1.6Hz,2H),3.14(dt,J=6.8,3.4Hz,2H),3.04-2.90(m,2H),2.38-2.27(m,1H),2.17(dq,J=11.7,6.1,5.1Hz,2H),2.00(dd,J=13.5,6.7Hz,2H),1.93-1.72(m,5H).1.70-1.50(m,2H)ESI-MS m/z:605[M+H] +
EXAMPLE 2 Synthesis of Compound 3
Step 1: synthesis of Compound int_3-1
Int_2-11 (500 mg,1.167 mmol) was dissolved in DMF (7 mL), and Int_A-2 (212 mg,1.169 mmol) and cesium carbonate (760 mg,2.338 mmol) were added and reacted at 80℃for 16 hours. LC-MS detection showed complete reaction, and the reaction mixture was concentrated under reduced pressure to give a crude product, which was prepared by reversed phase HPLC to give a yellow solid product (105 mg, yield: 15%).
ESI-MS m/z:573[M+H] +
Step 2: synthesis of Compound int_3-2
To a mixed solution of int_3-1 (105 mg, 0.183mmol) in dioxane/water (5 mL/1 mL) was added int_B-1 (91 mg, 0.183mmol), potassium carbonate (38 mg,0.275 mmol) and Ruphos-Pd-G3 (52 mg,0.062 mmol), and the reaction solution was reacted at 100℃for 16 hours under the protection of the reaction solution, and the LC-MS detection showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give a crude product, which was prepared by reversed phase HPLC to give a yellow solid product (45 mg, yield: 27.1%).
ESI-MS m/z:453[M/2+H] +
Step 3: synthesis of Compound int_3-3
Int_3-2 (45 mg,0.0497 mmol) was dissolved in DMF (2 mL), cesium fluoride (75 mg,0.497 mmol) was added and the reaction was allowed to react at room temperature under nitrogen for 2 hours, and LC-MS detection showed complete reaction. To the reaction solution was added 10mL of water, the aqueous phase was extracted with ethyl acetate (10 mL X3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give a crude product, which was prepared by reverse phase HPLC to give a yellow solid product (28 mg, yield: 75.3%).
ESI-MS m/z:375[M/2+H] +
Step 4: synthesis of Compound 3
Int_3-3 (28 mg,0.0366 mmol) was dissolved in methanol (1.5 mL), cooled to-5℃in an ice bath, 4M dioxane hydrochloride solution (3 mL) was slowly added dropwise to the reaction solution, and after the addition, the reaction solution was kept at-5℃for 2 hours, and the LC-MS detection showed that the reaction was complete. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10 mL X3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give the crude product which was prepared as a yellow solid by reverse phase HPLC (7 mg, 31.8%).
1 H NMR(400MHz,Methanol-d4)δ=9.08(d,J=4.3Hz,1H),8.47(s,1H),7.83(dd,J=8.5,1.3Hz,1H),7.51(dd,J=7.1,1.3Hz,1H),7.43–7.32(m,2H),7.16(t,J=2.2Hz,1H),4.75–4.58(m,4H),4.03–3.89(m,3H),3.83(d,J=13.3Hz,2H),3.78–3.64(m,2H),3.54–3.42(m,1H),3.18–3.07(m,1H),2.39(dd,J=13.9,8.7Hz,1H),2.34–1.79(m,11H),1.77–1.62(m,2H).
ESI-MS m/z:605[M+H] +
Examples 3-348 Synthesis of Compound 1 and Compounds 4-348
Using the above synthesis method, the target compound 1 and compounds 4 to 348 in Table 1 can be obtained using different raw materials.
TABLE 1
Example 349 Compound measurement of anti-proliferative Activity on Aspc-1 cells
Suspending human pancreatic cancer cell line Aspc-1 carrying KRAS-G12D mutant in RPMI1640 medium containing fetal bovine serum, and planting in 96-well ultra-low adsorption plate (Corning 7007) with cell amount of 2500 per well containing 5% CO 2 The cells were incubated at 37℃for 1 day in a gas incubator. The next day the gradient diluted compound was added with a final DMSO concentration of 0.3% and then mixed with 5% CO 2 Culturing at 37deg.C for 3 days, adding Cell Titer-Glo, mixing for 10 min, detecting luminescence by enzyme-labeled instrument, measuring ATP content in cells, evaluating Cell growth, and calculating IC for inhibiting Cell growth by the compound 50 . The results are shown in Table 2 below.
TABLE 2A compound of the invention was used on Aspc-1 cellsAntiproliferative activity (IC) 50 ,nM)
Compounds of formula (I) | IC 50 | Compounds of formula (I) | IC 50 | Compounds of formula (I) | IC 50 | Compounds of formula (I) | IC 50 |
1 | ++ | 2 | ++ | 3 | +++ | 4 | N.D |
5 | N.D | 6 | ++ | 7 | ++ | 8 | +++ |
9 | N.D | 10 | N.D | 11 | ++ | 12 | ++ |
13 | ++ | 14 | N.D | 15 | N.D | 16 | N.D |
17 | ++ | 18 | +++ | 19 | N.D | 20 | N.D |
21 | N.D | 22 | ++ | 23 | ++ | 24 | N.D |
25 | N.D | 26 | N.D | 27 | ++ | 28 | ++ |
29 | N.D | 30 | N.D | 31 | N.D | 32 | ++ |
33 | ++ | 34 | N.D | 35 | N.D | 36 | N.D |
37 | ++ | 38 | ++ | 43 | +++ | 44 | +++ |
45 | ++ | 46 | ++ | 47 | N.D | 48 | ++ |
49 | ++ | 50 | ++ | 51 | ++ | 52 | N.D |
53 | +++ | 54 | +++ | 55 | +++ | 56 | ++ |
57 | N.D | 58 | +++ | 59 | +++ | 60 | ++ |
61 | ++ | 62 | N.D | 63 | ++ | 64 | ++ |
75 | ++ | 76 | ++ | 77 | ++ | 78 | ++ |
79 | N.D | 80 | +++ | 81 | +++ | 82 | ++ |
83 | ++ | 84 | N.D | 85 | +++ | 86 | +++ |
87 | ++ | 88 | ++ | 89 | N.D | 90 | ++ |
91 | ++ | 92 | ++ | 93 | ++ | 94 | N.D |
95 | ++ | 96 | ++ | 97 | ++ | 98 | ++ |
99 | N.D | 100 | ++ | 101 | ++ | 102 | ++ |
103 | ++ | 104 | N.D | 105 | N.D | 106 | +++ |
107 | +++ | 108 | +++ | 109 | +++ | 110 | N.D |
129 | N.D | 130 | ++ | 131 | ++ | 132 | N.D |
++ + representing IC 50 Less than or equal to 500nM
++ means IC 50 500nM to 1000nM
+ represents IC 50 Greater than 1000nM
N.D represents activity unmeasured
As can be seen from the data in Table 2, the compounds of the present invention have potent antiproliferative activity on both Aspc-1 cells.
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.
Claims (18)
- A compound represented by general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:in the general formula (1):R 1 is-H, -OH, halogen, (C1-C3) alkyl, nitrile substituted (C1-C3) alkyl, hydroxy substituted (C1-C3) alkyl, HC (=O) -, -CO 2 R 5 、-CO 2 N(R 5 ) 2 Or (5-6 membered) heteroaryl;y is O or NR 5 ;Ring A is phenyl, (5-7 membered) heteroaryl, (C5-C7) cycloalkyl or (5-7 membered) heterocycloalkyl;each R 2 independently-H, halogen, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 membered) heteroaryl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 membered) heteroaryl may each independently optionally be substituted with 1,2,3 or 4R 6 Substitution;each R 3 independently-H, halogen, -OH, (C1-C3) alkyl, hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (5-7 membered) heteroaryl, -CN, -SO 2 F、 NHC(O)R 8 、-N(R 5 ) 2 、 -CH 2 OC(O)N(R 5 ) 2 、-CH 2 NHC(O)OR 7 、-CH 2 NHC(O)N(R 5 ) 2 、-CH 2 NHC(O)R 7 、-CH 2 NHS(O) 2 R 7 、-CH 2 OC(O)R 8 、-OC(O)N(R 5 ) 2 、-OC(O)NH(CH 2 ) m OR 7 、-OC(O)NH(CH 2 ) m O(CH 2 ) n R 8 、-OC(O)R 8 、-CH 2 R 8 Wherein the (C1-C3) alkyl, hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy or (5-7 membered) heteroaryl groups may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 7 And R is 8 The method comprises the steps of carrying out a first treatment on the surface of the Or when two R 3 When attached to the same atom, two R' s 3 An oxo group may be formed;q is a bond or O;ring B is (C5-C7) cycloalkyl, phenyl, (5-7 membered) heteroaryl or (5-7 membered) heterocycloalkyl;each R 4 Independently is-H, -D, halogen, R 9 、-OH、-(CH 2 ) n OR 9 、-(CH 2 ) n NR 9 R 10 、-OR 9 、-NR 9 R 10 、 -CN、-C(O)NR 9 R 10 、-NR 10 C(O)R 9 、-NR 10 S(O) 2 R 9 、-S(O) p R 9 、-S(O) 2 NR 9 R 10 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 7 、-OH、-(CH 2 ) n OR 7 、-(CH 2 ) n N(R 7 ) 2 、-OR 7 、-N(R 7 ) 2 、-CN、-C(O)N(R 7 ) 2 、-NR 7 C(O)R 7 、-NR 7 S(O) 2 R 7 、-S(O) p R 7 and-S (O) 2 N(R 7 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the Or when two R 4 When attached to the same atom, two R' s 4 An oxo group may be formed;each R 5 Independently is-H or (C1-C3) alkyl;R 6 is-H, halogen, -OH, -CN, -OR 7 、-S-R 7 (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (5-7 membered) heteroaryl, (C1-C4) haloalkyl, (C1-C4) alkoxy, -CH 2 C(=O)N(R 5 ) 2 、-N(R 5 ) 2 Or (C3-C6) cycloalkyl, wherein the (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (5-7 membered) heteroaryl, (C1-C4) haloalkyl, (C1-C4) alkoxy and (C3-C6) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -D, halogen, -OH, -NH 2 -CN and R 7 ;Each R 7 Independently (C1-C6) alkyl, (C1-C6) haloalkyl or (C1-C3) alkoxy;each R 8 Independently is a (5-7 membered) heterocycloalkyl, (5-7 membered) heteroaryl or phenyl, wherein said (5-7 membered) heterocycloalkyl, (5-7 membered) heteroaryl or phenyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -OH, -CN, -C (O) H, - (CH) 2 ) n OR 7 And- (CH) 2 ) n N(R 7 ) 2 ;R 9 And R is 10 Each independently is-H, (C1-C6) alkyl or (C3-C7) ringAlkyl, or R on the same nitrogen atom 9 And R is 10 Together with the N atom to which they are attached can constitute a (3-7 membered) heterocycloalkyl group, which heterocycloalkyl group can be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, (C1-C3) alkyl, (C3-C5) cycloalkyl or (C1-C3) alkoxy; andp is an integer of 0, 1 or 2, r is an integer of 1, 2, 3 or 4, s is an integer of 0, 1, 2, 3 or 4, t is an integer of 0, 1, 2, 3 or 4, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.
- The compound according to claim 1, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 1 is-H, -OH, -F, HC(=O)-、-CO 2 CH 3 or-CO 2 N(CH 3 ) 2 。
- The compound according to claim 1 or 2, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), Y is O, NH or NCH 3 。
- A compound according to any one of claims 1 to 3, wherein in formula (1) ring a is phenyl, 6 membered heteroaryl, cyclohexyl or (5-6 membered heterocycloalkyl, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.
- A compound according to any one of claims 1 to 4, or each isomer, each crystal form, pharmaceutically acceptable thereofAn acceptable salt, hydrate or solvate, wherein in the general formula (1), ring A is And one end of the label is attached to the nitrogen atom.
- The compound of any one of claims 1-5, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R in the general formula (1) 2 independently-H, -F, -Cl, -Br, -I, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 membered) heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 membered) heteroaryl groups may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CN, -OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCF 3 、-OCHF 2 、-OCH 2 CF 3 、-SCH 3 、-SCH 2 CH 3 、-N(CH 3 ) 2 、-NH 2 、-NH(CH 3 )、
- A compound according to any one of claims 1 to 6, or each isomer, each crystal form thereofPharmaceutically acceptable salts, hydrates or solvates thereof, wherein in the general formula (1), the structural unitThe method comprises the following steps:
- the compound of any one of claims 1-7, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R in the general formula (1) 3 Independently is-H, -OH, -F-Cl, -Br, -I (C1-C3) alkyl, hydroxy-substituted (C1-C3) alkyl (C1-C3) haloalkyl, (C1-C3) alkoxy, (5-6 membered) heteroaryl, -CN,NHC(O)R 8 、-N(R 5 ) 2 、-CH 2 OC(O)N(R 5 ) 2 、-CH 2 NHC(O)OR 7 、-CH 2 NHC(O)N(R 5 ) 2 、-CH 2 NHC(O)R 7 、-CH 2 NHS(O) 2 R 7 、-CH 2 OC(O)R 8 、-OC(O)N(R 5 ) 2 、-OC(O)NH(CH 2 ) m OR 7 、-OC(O)NH(CH 2 ) m O(CH 2 ) n R 8 、-OC(O)R 8 、-CH 2 R 8 Wherein the (C1-C3) alkyl, hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy or (5-6 membered) heteroaryl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -CH 3 、-OCH 3 or-CH 2 CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Or when two R 3 When attached to the same atom, two R' s 3 An oxo group may be formed.
- The compound according to claim 8 or its individual isomers,Each crystalline form, pharmaceutically acceptable salt, hydrate or solvate, wherein in the general formula (1), each R 3 Independently is: -H, -OH, -F, -Cl, -Br, -I, -CN, -OCH 3 、-CF 3 、
- The compound of any one of claims 1-9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein in the general formula (1), ring B is (C5-C6) cycloalkyl, phenyl, (5-6 membered) heteroaryl, or (5-6 membered) heterocycloalkyl.
- The compound of claim 10, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), ring B is:and one end of the label is attached to the nitrogen atom.
- The compound of any one of claims 1-11, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R in the general formula (1) 4 Is independently-H, -D, -F, -Cl-Br, -I, -OH, -CH 2 OR 9 、-CH 2 NR 9 R 10 、-OR 9 、-NR 9 R 10 、-CN、-C(O)NR 9 R 10 、-NR 10 C(O)R 9 、-NR 10 S(O) 2 R 9 、-SR 9 、-S(O) 2 R 9 、-S(O) 2 NR 9 R 10 (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH 3 、-N(CH 3 ) 2 and-CN; or when two R 4 When attached to the same atom, two R' s 4 An oxo group may be formed.
- The compound of claim 12, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R in the general formula (1) 4 Independently is: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-CH 2 N(CH 3 ) 2 、-OCH 3 、-OCF 3 、-N(CH 3 ) 2 、-CN、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)N(CH 3 ) 2 、-NHC(O)CH 3 、-N(CH 3 )-C(O)CH 3 、-NHS(O) 2 CH 3 、-NCH 3 S(O) 2 CH 3 、-SCH 3 、-S(O) 2 CH 3 and-S (O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 N(CH 3 ) 2 、 Or when two R 4 When attached to the same atom, two R' s 4 An oxo group may be formed.
- The compound of any one of claims 1-13, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), the structural unitThe method comprises the following steps:
- the compound of any one of claims 1-14, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound has one of the following structures:
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound according to any one of claims 1 to 15, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.
- Use of a compound according to any one of claims 1 to 15, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment, modulation or prevention of KRas G12D-related diseases.
- The use of claim 17, wherein the disease is cancer, the cancer is hematological cancer and solid tumors.
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