CN115124533A - Tetracyclic derivative, preparation method and medical application thereof - Google Patents

Tetracyclic derivative, preparation method and medical application thereof Download PDF

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Publication number
CN115124533A
CN115124533A CN202110323652.9A CN202110323652A CN115124533A CN 115124533 A CN115124533 A CN 115124533A CN 202110323652 A CN202110323652 A CN 202110323652A CN 115124533 A CN115124533 A CN 115124533A
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alkyl
pharmaceutically acceptable
groups
compound
heteroaryl
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Inventor
陈友喜
龚亮
向清
毛文涛
赵雯雯
赵伟峰
程超英
叶成
钱文建
陈磊
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Priority to CN202110323652.9A priority Critical patent/CN115124533A/en
Priority to PCT/CN2021/141061 priority patent/WO2022199170A1/en
Priority to CN202180062608.5A priority patent/CN116113416A/en
Publication of CN115124533A publication Critical patent/CN115124533A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention relates to tetracyclic derivatives, a preparation method thereof and application thereof in medicines. Specifically, the invention relates to tetracyclic derivatives shown in a general formula (I), a preparation method thereof, pharmaceutically acceptable salts thereof, and application thereof as a therapeutic agent, in particular as a KRas G12D inhibitor, wherein the definitions of all substituents in the general formula (I) are the same as those in the specification.

Description

Tetracyclic derivative, preparation method and medical application thereof
Technical Field
The invention relates to a tetracyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular as a KRas G12D inhibitor.
Background
RAS represents a group of closely related monomeric globular proteins (21kDa molecular weight) of 189 amino acids that are associated with the plasma membrane and bind GDP or GTP. Under normal developmental or physiological conditions, RAS is activated upon receipt of growth factors and various other extracellular signals, and is responsible for regulating functions such as cell growth, survival, migration and differentiation. RAS functions as a molecular switch, with the on/off state of the RAS protein being determined by nucleotide binding, with the active signaling conformation binding GTP and the inactive conformation binding GDP. When the RAS comprises bound GDP, it is in a dormant or quiescent or off state and is "inactive". RAS is induced to convert bound GDP to GTP when cells are exposed to certain growth-promoting stimuli to respond. With GTP bound, RAS is "on" and is able to interact with and activate other proteins (their "downstream targets"). The RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP and thereby turn itself off. Switching RAS off requires exogenous proteins called Gtpase Activating Proteins (GAPs), which interact with RAS and greatly facilitate conversion of GTP to GDP. Any mutation in the RAS that affects its ability to interact with GAPs or convert GTP back to GDP will result in prolonged activation of the protein and thus produce a prolonged signal to the cell that tells it to continue growing and dividing. These signals can therefore allow cells to grow and divide, and overactivated RAS signal transduction may ultimately lead to cancer.
Structurally, RAS proteins contain a G domain responsible for the enzymatic activity of RAS-guanine nucleotide binding and hydrolysis (gtpase reaction). It also includes a C-terminal extension containing a so-called CAAX box, which can be post-translationally modified and targets the protein to the membrane. The G domain is approximately 21-25kDa in size and contains a phosphate binding loop (P-loop). The P-loop represents the capsular bag of bound nucleotides in the protein, and this is a rigid part of the domain with conserved amino acid residues that are essential for nucleotide binding and hydrolysis (glycine 12, threonine 26 and lysine 16). The G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), which are both dynamic parts of the protein, often denoted as "spring-loaded" mechanisms due to the ability of the dynamic part to switch between resting and loaded states. The major interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the gamma-phosphate of GTP, which maintains the switch I and switch II regions in their active conformations, respectively. After hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.
Among RAS family members, oncogenic mutations are most common in KRAS (85%), whereas NRAS (12%) and HRAS (3%) are less common. KRAS mutations are prevalent in three major cancer types in the united states: pancreatic (95%), colorectal (45%) and lung (25%), KRAS mutations were also found in other cancer types including multiple myeloma, uterine, cholangiocarcinoma, gastric, bladder, diffuse large B-cell lymphoma, rhabdomyosarcoma, squamous cell carcinoma of the skin, cervical, testicular germ cell carcinoma, etc., while rarely (< 2%) in breast, ovarian and brain cancers. In non-small cell lung cancer (NSCLC), KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D. In non-small cell lung cancer, the increase in frequency of specific allelic mutations is mostly due to classical smoking-induced canonical mutations (G: C to T: a substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutations.
Large genomics studies indicate that lung cancer KRAS mutations, including G12C, are mutually exclusive from other known driver oncogenic mutations in NSCLC, including EGFR, ALK, ROS1, RET, and BRAF, indicating the uniqueness of KRAS mutations in lung cancer. At the same time, KRAS mutations often occur simultaneously with certain co-mutations, such as STK11, KEAP1 and TP53, which cooperate with the mutated RAS to transform cells into highly malignant and aggressive tumor cells.
The three RAS oncogenes constitute the most frequently mutated gene family in human cancers. Disappointingly, despite over thirty years of research efforts, there is still no clinically effective anti-RAS therapy, and the use of small molecules to target this gene is a challenge. Thus, there is an urgent need in the art for small molecules for targeting and utilizing the RAS (e.g., K-RAS, H-RAS and/or N-RAS) to treat a variety of diseases, such as cancer.
At present, the clinical development competition of the KRas G12D inhibitor is intense at home and abroad, wherein the KRas G12D inhibitor MRTX-1133 developed by Mirati Therapeutics Inc. enters the preclinical stage and is used for treating diseases such as large intestine tumor, non-small cell lung cancer, pancreatic cancer and the like. There are a few patent applications for KRas G12D inhibitors, including WO2021041671, by Mirati Therapeutics Inc. Although research and application of KRas G12D inhibitors have advanced to some extent, there is still a great deal of room for improvement and there is still a need to continue research and development of new KRas G12D inhibitors.
Disclosure of Invention
The invention aims to provide a tetracyclic derivative shown as a general formula (I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:
Figure BDA0002993764680000021
wherein:
ring A is selected from aryl, heteroaryl or fused ring; preferably phenyl, naphthyl, pyridyl, benzothiazolyl or benzopyrazolyl;
x and Y are each independently selected from N or CR a ；
R a Selected from hydrogen atoms, halogens, alkyl or alkoxy groupsA group; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, alkyl or alkoxy; r is a Preferably halogen, more preferably fluorine or chlorine;
R 1 identical or different, each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group or an alkoxy group, preferably an alkyl group;
or, two R 1 Together with the atoms to which they are attached form a cycloalkyl or heterocyclyl group;
R 2 selected from hydrogen atoms, alkyl groups or deuterated alkyl groups, preferably alkyl groups or deuterated alkyl groups, more preferably methyl groups or deuterated methyl groups;
R 3 selected from aryl or heteroaryl; wherein said aryl or heteroaryl is optionally further substituted with one or more R A Substituted; r 3 Preferably a heteroaryl group;
R A selected from alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Substituted with a substituent of (a); wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 6 or-S (O) r R 5 Substituted with the substituent(s);
R 4 identical OR different, are each independently selected from hydrogen atoms, alkyl groups, alkynyl groups, halogens, nitro groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, ═ O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Substituted with the substituent(s); wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Substituted with the substituent(s);
R 5 selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with the substituent(s);
R 6 and R 7 Each independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with the substituent(s);
or, R 6 And R 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group containing one or more of N, O or S (O) r And said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with the substituent(s);
R 8 、R 9 and R 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;
m is selected from 0,1, 2,3 or 4;
n is selected from 0,1, 2,3 or 4;
r is selected from 0,1 or 2.
With the proviso that the compound is excluded:
Figure BDA0002993764680000041
a compound represented by the general formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) and/or (III), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure BDA0002993764680000042
wherein: ring A, R 1 ～R 4 X, Y, m and n are defined as in claim 1.
A compound of formula (I), (II) and/or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
x is selected from N;
y is selected from CR a ；
R a Selected from hydrogen, halogen, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, alkyl or alkoxy; r a Preferably halogen, more preferably fluorine or chlorine;
a compound of formula (I), (II) and/or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
x is selected from CR a ；
Y is selected from N;
R a selected from hydrogen atoms, halogens, alkyl groups or alkoxy groups; wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, alkyl or alkoxy; r a Preferably halogen, more preferably fluorine or chlorine.
A compound of formula (I), (II) and/or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 Selected from alkyl or deuterated alkyl, preferably methyl or deuterated methyl.
A compound of formula (I), (II) and/or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is 3 Selected from:
Figure BDA0002993764680000051
wherein:
R j selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, alkyl, alkoxy, haloalkyl or haloalkoxy, preferably alkyl, more preferably methyl, ethyl or isopropyl;
k is selected from 0,1, 2 or 3.
A compound of formula (I), (II) and/or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: r 3 Selected from:
Figure BDA0002993764680000052
a compound of formula (I), (II) and/or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R 4 selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, alkynyl or cycloalkyl, wherein said alkyl, alkoxy, alkynyl or cycloalkyl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, alkyl or alkoxy.
A compound of formula (I), (II) and/or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R 4 selected from fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, trifluoromethyl, ethynyl or cyclopropyl, preferably hydroxy, fluoro or ethynyl.
A compound of formula (I), (II) and/or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
Figure BDA0002993764680000053
selected from the group consisting of:
Figure BDA0002993764680000054
typical compounds of the invention include, but are not limited to:
Figure BDA0002993764680000061
Figure BDA0002993764680000071
Figure BDA0002993764680000081
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Note: if there is a difference between a drawn structure and a given name for that structure, the drawn structure will be given more weight.
The present invention provides a process for the preparation of a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:
Figure BDA0002993764680000082
carrying out coupling reaction on the compound of the general formula (IA) and the compound of the general formula (IB) under the action of a palladium catalyst, and further removing a protecting group to obtain a compound of the general formula (I);
wherein:
X 1 selected from halogen or-Sn (R) 14 ) 3 (ii) a Wherein the halogen is preferably chlorine;
R 14 selected from alkyl, preferably methyl;
m is selected from-B (OH) 2 、-BF 3 K、
Figure BDA0002993764680000083
Or halogen;
PG is a protecting group, preferably tert-butoxycarbonyl;
ring A, R 1 ～R 4 X, Y, m and n are as defined in formula (I).
Further, the present invention provides a process for the preparation of a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which comprises:
Figure BDA0002993764680000091
reacting the compound of the general formula (IC) with a compound of the general formula (ID), and further removing a protecting group to obtain a compound of the general formula (I); wherein:
X 2 is halogen, preferably iodine;
R 2 is alkyl or deuterated alkyl, preferably methyl or deuterated methyl;
PG is a protecting group, preferably tert-butoxycarbonyl;
ring A, R 1 、R 3 、R 4 X, Y, m and n are as defined in formula (I).
Furthermore, the invention provides a compound of general formula (IA) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
Figure BDA0002993764680000092
wherein:
X 1 selected from halogen or-Sn (R) 14 ) 3 (ii) a Wherein the halogen is preferably chlorine;
R 14 selected from alkyl, preferably methyl;
PG is selected from protecting groups, preferably tert-butoxycarbonyl;
R 1 ～R 3 x, Y and n are as defined in formula (I).
Typical compounds of formula (IA) include, but are not limited to:
Figure BDA0002993764680000093
Figure BDA0002993764680000101
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a compound of the general formula (IC) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure BDA0002993764680000102
wherein:
PG is selected from protecting groups, preferably tert-butoxycarbonyl;
ring A, R 1 、R 3 、R 4 X, Y, m and n are as defined in formula (I).
Typical compounds of formula (IC) include, but are not limited to:
Figure BDA0002993764680000111
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
In another aspect, the present invention provides a method of inhibiting KRas G12D enzyme, wherein the method comprises administering to a patient a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.
The invention also provides an application of the compound of the general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating diseases mediated by the mutation of KRas G12D, wherein the diseases mediated by the mutation of KRas G12D are selected from cancers, and the cancers are selected from cardiac myxoma, lung cancer, gastric cancer, large intestine tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, skin squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphocytic leukemia or glioblastoma; wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
In another aspect, the present invention provides a use of a compound of formula (I), (II) or (III), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a KRas G12D inhibitor.
Another aspect of the present invention relates to a method for preventing and/or treating KRas G12D mutation mediated diseases, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), (II) or (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
The invention also provides an application of the compound of the general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating cancers, wherein the cancers are selected from cardiac myxoma, lung cancer, gastric cancer, large intestine tumor, rectal cancer, pancreatic cancer, prostatic cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, skin squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphocytic leukemia or glioblastoma; wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
The pharmaceutical formulations of the present invention may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcortically, or by inhalation. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
The formulations of the present invention are suitably presented in unit-dose form and may be prepared by any of the methods well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that produces a therapeutic effect.
Dosage forms for topical or transdermal administration of the compounds of the present invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
When the compounds of the present invention are administered to humans and animals as pharmaceuticals, the compounds can be provided alone or in pharmaceutical compositions containing the active ingredient in combination with a pharmaceutically acceptable carrier, e.g., from 0.1% to 99.5% (more preferably, from 0.5% to 90%) of the active ingredient.
Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a phosphate buffer solution; (21) cyclodextrins, e.g., targeting ligands attached to the nanoparticle, e.g., accurins (tm); and (22) other non-toxic compatible materials used in pharmaceutical formulations, such as polymer-based compositions.
Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Solid dosage forms (e.g., capsules, dragee pills, dragees, powders, granules, and the like) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binding agents, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) humectants, such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
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 oxyhydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Ointments, pastes, creams and gels may also contain, in addition to the active compound, excipients, for example animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can also contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of the aforementioned substances. The spray may contain other conventional propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"chemical bond" means that the indicated substituent is absent and the two end portions of the substituent are directly connected to form a bond.
"alkyl" when taken as a group or part of a group means including C 1 -C 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethylN-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be optionally substituted or unsubstituted.
"alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and can be straight or branched. Preferred is that C 2 -C 10 Alkynyl of (2), more preferably C 2 -C 6 Alkynyl, most preferably C 2 -C 4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.
An "alkylene" is a divalent alkyl group. Preferably C 1 -C 10 Alkylene, more preferably C1-C6 alkylene, particularly preferably C 1 -C 4 An alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, -CH (CH) 3 ) 2 N-propylene, and the like. The alkylene group may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings. Preferably C 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like, with cyclopropyl, cyclobutyl and the like preferredA hexenyl group. Cycloalkyl groups may be optionally substituted or unsubstituted.
"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures with single rings sharing a single carbon atom (called the spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spiro, di-spiro, or multi-spiro cycloalkyl groups, preferably mono-spiro and di-spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused cyclic alkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls depending on the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl groups. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl or tetradecaphenanthryl.
"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s,4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s,5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1r,5r) -bicyclo [3.3.2] decyl.
"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, fused, bridged, and spiro rings. Preferably having a 5 to 7 membered monocyclic ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1, 1-dioxothiomorpholinyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which contains 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) r (wherein r is selected from 0,1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a single spiroheterocyclic group, a double spiroheterocyclic group or a multiple spiroheterocyclic group, preferably a single spiroheterocyclic group and a double spiroheterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5]]Decyl, 2-oxa-7-azaspiro [4.4]]Nonyl, 7-oxaspiro [3.5]]Nonyl and 5-oxaspiro [2.4]]And a heptyl radical.
"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) r (wherein r is selected from 0,1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably7 to 10 yuan. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3,4-c]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1,4]Dioxins (dioxines).
"bridged heterocyclyl" means a 5-to 14-membered, 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) r (wherein r is selected from 0,1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl and 2-azabicyclo [3.3.2]A decyl group.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C 6 -C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. The aryl group may be substituted or unsubstituted.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which can contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Preferred examples of bicyclic heteroaryls, "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyrimidyl, or,
Figure BDA0002993764680000161
Heteroaryl groups may be substituted or unsubstituted.
"fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a completely conjugated pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more selected from nitrogen, oxygen, or S (O) r (wherein r is selected from 0,1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14, more preferably 8 to 10. Examples of "fused rings" include, but are not limited to:
Figure BDA0002993764680000162
Figure BDA0002993764680000171
"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C 1 -C 6 Alkoxy groups of (4) are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"haloalkyl" refers to an alkyl group optionally further substituted with one or more halogens, wherein alkyl is as defined herein.
"deuterated alkyl" refers to an alkyl group optionally further substituted with one or more deuterium atoms, wherein alkyl is as defined herein. "deuterated alkyl" is preferably deuterated methyl, including: mono-, di-and tri-deuterated methyl, preferably tri-deuterated methyl.
"hydroxyalkyl" refers to a group wherein the alkyl group is optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.
"haloalkoxy" means a group in which the alkyl group of (alkyl-O-) is optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"amino" means-NH 2 。
"cyano" means-CN.
"nitro" means-NO 2 。
"benzyl" means-CH 2 -phenyl.
"carboxy" refers to-C (O) OH.
"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
"DMSO" refers to dimethyl sulfoxide.
"BOC" refers to tert-butoxycarbonyl.
"Ts" refers to p-toluenesulfonyl.
"T3P" refers to propyl phosphoric anhydride.
"DPPA" refers to diphenylphosphoryl azide.
"DEA" refers to diethylamine.
"TFA" refers to trifluoroacetic acid.
“CaCl 2 "refers to calcium chloride.
“MgCl 2 "refers to magnesium chloride.
"KCl" refers to potassium chloride.
"NaCl" refers to sodium chloride.
"Glucose" refers to Glucose.
"HEPES" means N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid.
"EGTA" refers to ethylene glycol bis (2-aminoethyl ether) tetraacetic acid.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, ═ O, -c (O) R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Substituted with the substituent(s);
R 5 selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (O, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with the substituent(s);
R 6 and R 7 Each independently selected from hydrogen, hydroxyl, halogen,Alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with the substituent(s);
or, R 6 And R 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group containing one or more of N, O or S (O) r And said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with the substituent(s);
R 8 、R 9 and R 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;
r is 0,1 or 2.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Unless otherwise indicated, the structures described herein also include all isomers (e.g., diastereomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms) of such structures, e.g., the R and S configurations of the various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds of formula (I) may be metal salts, amine salts with suitable acids.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the invention relates to a preparation method of a compound shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which comprises the following steps:
Figure BDA0002993764680000191
carrying out coupling reaction on the compound of the general formula (IA) and the compound of the general formula (IB) under the action of a palladium catalyst, and further removing a protecting group to obtain a compound of the general formula (I);
wherein:
X 1 selected from halogen or-Sn (R) 14 ) 3 (ii) a Wherein the halogen is preferably chlorine;
R 14 selected from alkyl, preferably methyl;
m is selected from-B (OH) 2 、-BF 3 K、
Figure BDA0002993764680000192
Or halogen;
PG is a protecting group, preferably tert-butoxycarbonyl;
ring A, R 1 ～R 4 X, Y, m and n are as defined in formula (I).
Further, the present invention provides a process for preparing a compound of the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure BDA0002993764680000201
reacting the compound of the general formula (IC) with a compound of the general formula (ID), and further removing a protecting group to obtain a compound of the general formula (I); wherein:
X 2 is halogen, preferably iodine;
R 2 is alkyl or deuterated alkyl, preferably methyl or deuterated methyl;
PG is a protecting group, preferably tert-butoxycarbonyl;
ring A, R 1 、R 3 、R 4 X, Y, m and n are as defined in formula (I).
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Examples
The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention. 1 HNMR spectra were obtained using a Bruker instrument (400MHz) and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used. 1 HNRepresentation method of MR: s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. When coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, the starting materials and reagents are commercially available or synthesized according to known methods, and are used without further purification, unless otherwise indicated, commercially available manufacturers include, but are not limited to, shanghai haohnhong biomedical science and technology limited, shanghai shaoshimo reagents limited, shanghai beide medical science and technology limited, saen chemical technology (shanghai) limited, shanghai ling medical science and technology limited, and the like.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
Purifying the compound using an eluent system for column chromatography and thin layer chromatography, wherein the system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane and ethyl acetate system, D: dichloromethane and ethanol system, E: tetrahydrofuran and petroleum ether system, F: tetrahydrofuran and methanol, wherein the volume ratio of the solvent is different according to the polarity of the compound, or a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for carrying out the conditions.
Example 1
(2R,4aR)-10-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -10- (2-amino-7-fluoropheno [ d ] thiazol-4-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
Figure BDA0002993764680000211
Figure BDA0002993764680000221
First step of
6-chloro-5-fluoro-2- ((2-isopropylpropyl-4-methylpyridin-3-yl) amino) nicotinic acid 6-chloro-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinic acid
Dissolving 2-isopropyl-4-methylpyridin-3-amine 1d (21.46g,142.86mmol) in 200mL tetrahydrofuran, cooling to-78 ℃, dropwise adding lithium bis (trimethylsilyl) amide (1.0M,238.11mL) under the protection of nitrogen, stirring for 15 minutes at 78 ℃, and then dropwise adding a tetrahydrofuran (100mL) solution of 2, 6-dichloro-5-fluoronicotinic acid 1a (20g,95.24 mmol). After 1 hour at-78 ℃ the reaction was continued for 3 hours at 25 ℃. After completion of the reaction, the reaction mixture was poured into 100mL of ice-water, and methyl t-butyl ether (100mL) was added. The aqueous phase was adjusted to pH 4 with 2M dilute hydrochloric acid, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-chloro-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinic acid 1b (15g,46.33mmol), yield: 48.65 percent.
MS m/z(ESI):323.8[M+1] +
Second step of
ethyl
3-(6-chloro-5-fluoro-2-((2-isopropyl-4-methylpyridin-3-yl)amino)pyridin-3-yl)-2-nitro-3-oxopropanoate
3- (6-chloro-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) pyridin-3-yl) -2-nitro-3-oxopropanoic acid ethyl ester
6-chloro-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinic acid 1b (5g,15.44mmol) was dissolved in N, N-dimethylformamide (50mL), and potassium carbonate (6.40g,46.33mmol) and ethyl 2-nitroacetate (6.17g,46.33mmol) were added, followed by 2-chloro-1-methylpyridine iodide (7.89g,30.89mmol), followed by reaction at 25 ℃ for 3 hours. 10mL of ethyl acetate and 10mL of saturated brine were added, the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (eluent: E system) to obtain ethyl 3- (6-chloro-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) pyridin-3-yl) -2-nitro-3-oxopropanoate 1c (2.3g,5.24mmol), yield: 33.94 percent.
MS m/z(ESI):438.9[M+1] +
The third step
7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridine-2,4(1H,3H)-dione
7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1, 8-naphthyridine-2, 4(1H,3H) -dione
Ethyl 3- (6-chloro-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) pyridin-3-yl) -2-nitro-3-oxopropanoate 1c (2.3g,5.24mmol) was dissolved in N, N-dimethylformamide (20mL), cesium carbonate (2.56g,7.86mmol) was added and the reaction stirred at 50 ℃ for 16 h. After completion of the reaction, it was cooled to 25 ℃ and 10mL of ethyl acetate and 10mL of saturated brine were added, followed by liquid separation, drying of the organic phase over anhydrous sodium sulfate, filtration and concentration under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (eluent: E system-F system) to give 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1, 8-naphthyridine-2, 4(1H,3H) -dione 1E (1.7g,4.33mmol), yield: 82.58 percent.
MS m/z(ESI):393.0[M+1] +
The fourth step
4, 7-dichoro-6-fluoro-1- (2-isoproyl-4-methylpyridin-3-yl) -3-nitro-1,8-naphthyridin-2(1H) -one4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1,8-naphthyridin-2(1H) -one
7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1, 8-naphthyridine-2, 4(1H,3H) -dione 1e (400mg,1.02mmol) was dissolved in phosphorus oxychloride (3mL) and reacted at 90 ℃ for 1 hour. LC-MS monitored the progress of the reaction. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (eluent: system E) to give 4,7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1,8-naphthyridin-2(1H) -one 1f (350mg,851.14 μmol), yield: 83.58 percent.
MS m/z(ESI):410.8[M+1] +
The fifth step
1-(tert-butyl)3-methyl
(3R,6R)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate
(3R,6R) -1-N-tert-Butoxycarbonyl-4- (7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylic acid methyl ester
4,7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1,8-naphthyridin-2(1H) -one 1f (1.3g,3.16mmol) was dissolved in acetonitrile (15mL), and (3R,6R) -1-N-tert-butoxycarbonyl-6-methylpiperazine-3-carboxylic acid methyl ester 1j (1.63g,6.32mmol) was added and reacted at 80 ℃ for 16 hours. LC-MS monitored the progress of the reaction. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (eluent: system E) to give 1g (1g,1.58mmol) of methyl (3R,6R) -1-N-tert-butoxycarbonyl-4- (7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylate, yield: 49.97 percent.
MS m/z(ESI):633.0[M+1] +
The sixth step
1-(tert-butyl)3-methyl
(3R,6R)-4-(3-amino-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate
(3R,6R) -1-N-tert-Butoxycarbonyl-4- (3-amino-7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylic acid methyl ester
Methyl (3R,6R) -1-N-tert-butoxycarbonyl-4- (7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylate 1g (1g,1.58mmol) and Raney's nickel (10mg, 157.96. mu. mol) were dissolved in tetrahydrofuran (10mL) and reacted with hydrogen for 2 hours at 25 ℃ with hydrogen substitution 3 times. Filtration and concentration of the filtrate under reduced pressure gave crude (3R,6R) -1-N-tert-butoxycarbonyl-4- (3-amino-7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylic acid methyl ester for 1h (0.83g,1.38mmol) which was used directly in the next reaction. Yield: 87.13 percent.
MS m/z(ESI):603.3[M+1] +
Step seven
tert-butyl
(2R,4aR)-10-chloro-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
(3R,6R) -1-N-tert-butoxycarbonyl-4- (3-amino-7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylic acid methyl ester 1h (0.83g,1.38mmol) and potassium carbonate (570.64mg,4.13mmol) were dissolved in N, N-dimethylformamide (10mL) and reacted at 50 ℃ for 1 hour. After the reaction was completed, 10mL of ethyl acetate and 10mL of saturated brine were added, liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude (2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 1k (0.7g,1.23mmol), which was used directly in the next reaction.
MS m/z(ESI):571.0[M+1] +
The eighth step
tert-butyl
(2R,4aR)-10-chloro-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
Reacting (2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4, 5)]Pyrazino [2,3-c ] s][1,8]Naphthyridine-3-carboxylic acid tert-butyl ester 1k (0.7g,1.23mmol), iodomethane (521.98mg,3.68mmol) and potassium carbonate (508.27mg,3.68mmol) were dissolved in N, N-dimethylformamide (10mL) and reacted at 25 ℃ for 16 hours. Adding 10mL of ethyl acetate and 10mL of water, separating, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the obtained residue with flash silica gel column chromatography (eluent: E system) to obtain (2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5]Pyrazino [2,3-c ] s][1,8]1m (0.45g, 769.14. mu. mol) of t-butyl naphthyridine-3-carboxylate, yield: 62.74 percent. MS M/z (ESI) 585.0[ M + 1]] +
The ninth step
tert-butyl
(2R,4aR)-10-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR) -10- (2- ((tert-butoxycarbonyl) amino) -7-fluoropheno [ d ] thiazol-4-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
(2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 1m (0.12g, 205.10. mu. mol), (2- ((tert-butoxycarbonyl) amino) -7-fluoropheno [ d ] thiazol-4-yl) boronic acid 1p (192.05mg, 615.31. mu. mol), tetrakis (triphenylphosphine) palladium (23.70mg, 20.51. mu. mol) and potassium phosphate (217.68mg,1.03mmo) were dissolved in 0.2mL water and 1mL1, in a mixed solvent of 4-dioxane, nitrogen gas was replaced 3 times, and the reaction was carried out at 100 ℃ for 16 hours under a nitrogen atmosphere. LC-MS monitored the progress of the reaction. After the reaction was completed, concentration was performed under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (eluent: system E) to obtain (2R,4aR) -10- (2- ((tert-butoxycarbonyl) amino) -7-fluoropheno [ d ] thiazol-4-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 1n (0.1g,122.41 μmol), yield: and (5) 59.68%.
MS m/z(ESI):817.4[M+1] +
The tenth step
(2R,4aR)-10-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -10- (2-amino-7-fluoropheno [ d ] thiazol-4-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
(2R,4aR) -10- (2- ((tert-butoxycarbonyl) amino) -7-fluoropheno [ d ] thiazol-4-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 1n (0.1g, 122.41. mu. mol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (300mg,2.63mmol) was added, and the reaction was carried out at 20 ℃ for 16 hours. Concentration under reduced pressure gave crude (2R,4aR) -10- (2-amino-7-fluoropheno [ d ] thiazol-4-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione 1(100mg, 136.85. mu. mol).
MS m/z(ESI):617.5[M+1] +
Example 2
(2R,4aR)-10-(6-amino-3-chloropyridin-2-yl)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -10- (6-amino-3-chloropyridin-2-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
Figure BDA0002993764680000261
First step of
tert-butyl
(2R,4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-10-(trimethylstannyl)-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxyl
ate
(2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-10- (trimethylstannane)
Base) -1,2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
Reacting (2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5]Pyrazino [2,3-c ] s][1,8]1m (0.1g, 170.92. mu. mol) of t-butyl naphthyridine-3-carboxylate, hexamethylditin (139.99mg, 427.30. mu. mol), and tetrakis (triphenylphosphine) palladium (19.75mg, 17.09. mu. mol) were dissolved in 1, 4-dioxane (1mL), and reacted under nitrogen at 110 ℃ for 16 hours while displacing nitrogen three times. Concentrating under reduced pressure, separating and purifying the obtained residue with flash silica gel column chromatography (eluent: E system) to obtain (2R,4aR) -11-Fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-10- (trimethylstannyl) -1,2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5]Pyrazino [2,3-c ] s][1,8]Naphthyridine-3-carboxylic acid tert-butyl ester 2a (95mg,133.16 μmol), yield: 77.91 percent. MS m/z (ESI): 714.8[ M + 1]] +
Second step of
tert-butyl
(2R,4aR)-10-(6-amino-3-chloropyridin-2-yl)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR) -10- (6-amino-3-chloropyridin-2-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
(2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-10- (trimethylstannyl) -1,2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 2a (40mg, 56.07. mu. mol), 6-bromo-5-chloropyridine-2-amine 2b (13.96mg, 67.28. mu. mol), cuprous iodide (1.07mg, 5.61. mu. mol) and tetrakis (triphenylphosphine) palladium (3.24mg, 2.80. mu. mol) were dissolved in 1, 4-dioxane (0.5mL), the nitrogen gas was replaced three times, and the reaction was carried out at 100 ℃ for 16 hours under a nitrogen atmosphere. Concentration under reduced pressure and separation and purification of the obtained residue by flash column chromatography on silica gel (eluent: system E) gave (2R,4aR) -10- (6-amino-3-chloropyridin-2-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 2c (15mg,22.15 μmol), yield: 39.51 percent.
MS m/z(ESI)：677.3[M+1] +
The third step
(2R,4aR)-10-(6-amino-3-chloropyridin-2-yl)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -10- (6-amino-3-chloropyridin-2-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
(2R,4aR) -10- (6-amino-3-chloropyridin-2-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 2c (30mg, 44.30. mu. mol) was dissolved in dichloromethane (3mL), trifluoroacetic acid (1g,8.77mmol) was added, and the reaction was carried out at 20 ℃ for 16 hours. Concentration under reduced pressure gave (2R,4aR) -10- (6-amino-3-chloropyridin-2-yl) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione 2(30mg, 51.99. mu. mol).
MS m/z(ESI)：577.0[M+1] +
Example 3
(2R,4aR)-11-fluoro-10-(3-hydroxynaphthalen-1-yl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -11-fluoro-10- (3-hydroxynaphthalen-1-yl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
Figure BDA0002993764680000281
First step of
tert-butyl
(2R,4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(3-methoxynaphthalen-1-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -10- (3-methoxynaphthalen-1-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
(2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 1m (100mg, 170.92. mu. mol), (3-methoxynaphthalen-1-yl) boronic acid 3a (103.58mg, 512.76. mu. mol), tetrakis (triphenylphosphine) palladium (19.75mg, 17.09. mu. mol) and potassium phosphate (181.40mg, 854.60. mu. mol) were dissolved in a mixed solvent of 0.3mL of water and 1.5mL of 1, 4-dioxane, nitrogen was replaced 3 times, the reaction was carried out at 100 ℃ for 16 hours under nitrogen atmosphere. LC-MS monitored the progress of the reaction. Concentration under reduced pressure and separation and purification of the obtained residue by flash column chromatography on silica gel (eluent: system E) to give (2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -10- (3-methoxynaphthalen-1-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 3b (0.1g,141.48 μmol), yield: 82.78 percent.
MS m/z(ESI):707.7[M+1] +
Second step of
(2R,4aR)-11-fluoro-10-(3-hydroxynaphthalen-1-yl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -11-fluoro-10- (3-hydroxynaphthalen-1-yl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
(2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -10- (3-methoxynaphthalen-1-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 3b (70mg, 99.04. mu. mol) was dissolved in 5mL of dichloromethane, boron tribromide (1.40g,5.59mmol) was added, and the reaction was carried out at 20 ℃ for 16 hours. The reaction was quenched by the addition of 10mL of methanol, concentrated under reduced pressure, diluted with 20mL of water, washed with ethyl acetate (20mL × 2), the aqueous phase collected and lyophilized to give (2R,4aR) -11-fluoro-10- (3-hydroxynaphthalen-1-yl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione 3(100mg,168.73 μmol).
MS m/z(ESI):593.4[M+1] +
Example 4
(2R,4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-10-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-10- (5-methyl-1H-indazol-4-yl) -2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
Figure BDA0002993764680000291
First step of
tert-butyl
(2R,4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-10-(5-methyl-1H-indazol-4-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-10- (5-methyl-1H-indazol-4-yl) -5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
(2R,4aR) -10-chloro-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 1m (50mg, 85.46. mu. mol), (5-methyl-1H-indazol-4-yl) boronic acid 4a (45.12mg, 256.38. mu. mol), tetrakis (triphenylphosphine) palladium (9.88mg, 8.55. mu. mol) and potassium phosphate (54.42mg, 256.38. mu. mol) were dissolved in 0.3mL of a mixed solvent of water and 1.5mL of 1, 4-dioxane, the nitrogen gas was replaced 3 times, and the reaction was carried out at 100 ℃ for 16 hours under a nitrogen atmosphere. LC-MS monitored the progress of the reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (eluent: system E) to obtain (2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-10- (5-methyl-1H-indazol-4-yl) -5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 4b (10mg,14.69 μmol), yield: 17.19 percent.
MS m/z(ESI):681.1[M+1] +
Second step of
(2R,4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-10-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-10- (5-methyl-1H-indazol-4-yl) -2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
(2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-10- (5-methyl-1H-indazol-4-yl) -5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 4b (10mg, 14.69. mu. mol) was dissolved in 2mL of 1, 4-dioxane, 4M dilute hydrochloric acid (36.72. mu.L) was added dropwise, and the reaction was carried out at 25 ℃ for 2 hours. LC-MS monitored the progress of the reaction. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product of (2R,4aR) -11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-10- (5-methyl-1H-indazol-4-yl) -2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione 4(10mg,17.22 μmol).
MS m/z(ESI):581.2[M+1] +
Example 5
(2R,4aR)-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -11-chloro-10- (2-fluoro-6-hydroxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-6- (methyl-d 3) -2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
Figure BDA0002993764680000301
Figure BDA0002993764680000311
First step of
2, 5-dichloro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid
2,5, 6-trichloronicotinic acid 5a (20g,88.32mmol) and (2-fluoro-6-methoxyphenyl) boronic acid (30.02g,176.64mmol) were dissolved in 1, 4-dioxane (200mL) and water (40mL), tetrakis (triphenylphosphine) palladium (2.00g,1.73mmol) and sodium carbonate (28.08g,264.97mmol) were added, and the mixture was heated to 100 ℃ under argon protection and allowed to react overnight. After the reaction was completed, it was cooled, 100mL of water was added, extraction was performed with ethyl acetate (100mL × 2), the organic phases were combined, the aqueous phase was made acidic with 1M diluted hydrochloric acid, extraction was performed with ethyl acetate (100mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, 2, 5-dichloro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid 5b (27g,85.41mmol), yield: 96.71 percent.
MS m/z(ESI)：315.8[M+1] +
Second step of
2, 5-dichloro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid methyl ester
2, 5-dichloro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid 5b (26g,82.25mmol) was dissolved in methanol (200mL), and thionyl chloride (19.57g,164.50mmol,11.93mL) was added dropwise with stirring at room temperature, and the mixture was heated to 90 ℃ to react for 6 hours. After the reaction was completed, it was cooled, concentrated under reduced pressure, added with 200mL of water, adjusted to alkaline by dropwise addition of a saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with a saturated saline solution (100 mL. times.3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System A) to give methyl 2, 5-dichloro-6- (2-fluoro-6-methoxyphenyl) nicotinate 5c (17.16g,51.98mmol), yield: 63.20 percent.
MS m/z(ESI)：329.8[M+1] +
1 H NMR(400MHz,CDCl 3 -d)δ8.28-8.23(m,1H),7.42-7.36(m,1H),6.82-6.77(m,2H),3.99(s,3H),3.78(s,3H).
The third step
5-chloro-6- (2-fluoro-6-methoxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinic acid methyl ester
methyl
5-chloro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinate
Dissolving methyl 2, 5-dichloro-6- (2-fluoro-6-methoxyphenyl) nicotinate 5c (16.8G,50.89mmol) and 2-isopropyl-4-methylpyridin-3-amine 1d (8.41G,55.98mmol) in anhydrous 1, 4-dioxane (200mL), adding cesium carbonate (49.74G,152.66mmol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1, 1' -biphenyl Ruphos (4.75G,10.18mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) RuPhos Pd G3(4.26G,5.09mmol), under the protection of argon, the reaction was heated to 100 ℃ and allowed to react overnight. After the reaction was completed, 250mL of water was added to the system, extraction was performed with ethyl acetate (200mL), the organic phase was washed with saturated brine (100m × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain methyl 5-chloro-6- (2-fluoro-6-methoxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinate 5d (7.4g,16.67mmol), yield: 32.76 percent. MS m/z (ESI): 443.9[ M +1] +
The fourth step
5-chloro-6- (2-fluoro-6-methoxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinic acid
5-chloro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid
Methyl 5-chloro-6- (2-fluoro-6-methoxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinate 5d (15g,33.79mmol) was dissolved in a mixed solvent of methanol (50mL) and water (10mL), and lithium hydroxide monohydrate (7.09g,168.96mmol) was added, and the mixture was heated to 90 ℃ and reacted overnight. After the reaction was completed, it was cooled, concentrated under reduced pressure to remove methanol, added with 100mL of water, extracted with 100mL of ethyl acetate, and the organic phase was washed with saturated ammonium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 5-chloro-6- (2-fluoro-6-methoxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinic acid 5e (11.4g,26.52mmol), yield: 78.48 percent.
MS m/z(ESI)：429.9[M+1] +
The fifth step
6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridine-2,4(1H,3H)-dione
6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1, 8-naphthyridine-2, 4(1H,3H) -dione
5-chloro-6- (2-fluoro-6-methoxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinic acid 5e (3g,6.98mmol), ethyl 2-nitroacetate (2.79g,20.94mmol) and potassium carbonate (2.89g,20.94mmol) were dissolved in 30mL of N, N-dimethylformamide, and 2-chloro-1-methylpyridine iodide (3.57g,13.96mmol) was added and reacted at room temperature for 16 hours. After the reaction was completed, 100mL of water was added, extraction was performed with ethyl acetate (100mL × 2), the organic phases were combined, the organic phase was washed with saturated brine (100mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give 6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1, 8-naphthyridine-2, 4(1H,3H) -dione 5f (800mg,1.60mmol), yield: 22.9 percent.
MS m/z(ESI)：499.0[M+1] +
The sixth step
4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one
4, 6-dichloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1,8-naphthyridin-2(1H) -one
6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1, 8-naphthyridine-2, 4(1H,3H) -dione 5f (800mg,1.60mmol) was dissolved in phosphorus oxychloride (18g,117.39mmol), heated to 100 ℃ and reacted for 3 hours. After the reaction was completed, the reaction solution was poured into 100mL of ice water, extracted with dichloromethane (100mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain 5g (550mg,1.1mmol) of the product 4, 6-dichloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1,8-naphthyridin-2(1H) -one: 68.75 percent.
MS m/z(ESI)：517.0[M+1] +
Step seven
(3R,6R) -1-N-tert-Butoxycarbonyl-4- (6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylic acid methyl ester 1- (tert-butyl)3-methyl
(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate
5g (550mg,1.1mmol) of 4, 6-dichloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-1,8-naphthyridin-2(1H) -one and methyl (3R,6R) -1-N-tert-butoxycarbonyl-6-methylpiperazine-3-carboxylate 1j (458.33mg,1.77mmol) were dissolved in acetonitrile (10mL) and reacted at 90 ℃ for 16 hours under argon protection. After the reaction was completed, 100mL of water was added, extraction was performed with ethyl acetate (100mL × 2), the organic phases were combined, the organic phase was washed with saturated brine (100mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give the product (3R,6R) -1-N-tert-butoxycarbonyl-4- (6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylic acid methyl ester 5h (400mg,541.13 μmol), yield: 49.28 percent.
MS m/z(ESI)：739.1[M+1] +
Eighth step
tert-butyl
(2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR) -11-chloro-10- (2-fluoro-6-methoxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
Methyl (3R,6R) -1-N-tert-butoxycarbonyl-4- (6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -6-methylpiperazine-3-carboxylate 5h (40mg,54.11 μmol) was dissolved in methanol (5mL), 10% palladium on carbon (16.33mg,153.45 μmol) was added, and after 3 times replacement of hydrogen gas, the reaction was carried out at room temperature for 2 hours under hydrogen protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of (2R,4aR) -11-chloro-10- (2-fluoro-6-methoxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 5i (36.5 mg).
MS m/z(ESI)：677.3[M+1] +
The ninth step
tert-butyl
(2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR) -11-chloro-10- (2-fluoro-6-methoxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-6- (methyl-d 3) -5, 7-dione-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester
(2R,4aR) -11-chloro-10- (2-fluoro-6-methoxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 5i (1.43g,2.11mmol) was dissolved in 10mLN, N-dimethylformamide and deuterated iodomethane (918.36mg,6.34mmol, 394.15. mu.L) was added dropwise and reacted at room temperature overnight. To the reaction solution, 10mL of water was added, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain the product (2R,4aR) -11-chloro-10- (2-fluoro-6-methoxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-6- (methyl-d 3) -5, 7-dione-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 5j (1g,1.44mmol), yield: 68.21 percent.
MS m/z(ESI)：694.3[M+1] +
The tenth step
(2R,4aR)-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -11-chloro-10- (2-fluoro-6-hydroxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-6- (methyl-d 3) -2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
(2R,4aR) -11-chloro-10- (2-fluoro-6-methoxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-6- (methyl-d 3) -5, 7-dione-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 5j (1.33g,1.92mmol) was dissolved in dichloromethane (15mL), cooled to 0 ℃, boron tribromide (9.60g,38.32mmol,3.69mL) was added dropwise, and the mixture was allowed to warm to room temperature for overnight reaction. The reaction solution is cooled to 0 ℃, saturated sodium bicarbonate solution is added to quench the reaction, the pH value is adjusted to 7-8 by adding saturated sodium bicarbonate solution, ethyl acetate is used for extraction (50mL is multiplied by 3), organic phases are combined, the mixture is washed by saturated brine, dried by anhydrous sodium sulfate, filtered, decompressed, concentrated and dried to obtain (2R,4aR) -11-chloro-10- (2-fluoro-6-hydroxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-6- (methyl-d 3) -2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione 5(1.11g,1.91 mmol).
MS m/z(ESI)：580.3[M+1] +
Example 6
(2R,4aR) -11-chloro-10- (7, 8-difluoro-3-hydroxynaphththalen-1-yl) -8- (2-isoproxyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6, 8-hexahydro-1H-pyrido [1',2':4,5] pyrido [2,3-c ] [1,8] naphthyridine-5,7-dione (2R,4aR) -11-chloro-10- (7, 8-difluoro-3-hydroxynaphthalene-1-yl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
Figure BDA0002993764680000351
The reaction conditions of the first and second steps of example 3 were repeated, except that in the first step, tert-butyl (2R,4aR) -10, 11-dichloro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylate 6a and (7,8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) boronic acid 6b were used as reaction raw materials to obtain (2R,4aR) -11-chloro-10- (7,8-difluoro-3-hydroxynaphthalen-1-yl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione 6.
Example 7
(2R,4aR)-11-chloro-10-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR) -11-chloro-10- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione
Figure BDA0002993764680000352
Figure BDA0002993764680000361
The reaction conditions of the first and second steps of example 3 were repeated, except that in the first step, (2R,4aR) -11-chloro-10- (8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -10, 11-dichloro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dioxo-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-3-carboxylic acid tert-butyl ester 6a and (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) boronic acid 7a were used as reaction raw materials to obtain (2R,4aR) -11-chloro-10- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-one- 1-yl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,8] naphthyridine-5,7-dione 7.
Biological evaluation
Test example 1 determination of p-ERK1/2 inhibitory Activity of Compounds of the present invention in AGS cells
The following method was used to determine the inhibitory activity of the compounds of the present invention on p-ERK1/2 in AGS cells. The method uses Advanced phosphor-ERK 1/2(Thr202/tyr204) kit (cat. 64AERPEH) from Cisbio company, and the detailed experimental operation can refer to the kit instruction. AGS cells (containing KRAS G12D mutation) were purchased from the cell resource center of shanghai life science research institute of china academy of sciences.
The experimental procedure is briefly described as follows: AGS cells were cultured in F12K complete medium containing 10% fetal bovine serum, 100U penicillin, and 100. mu.g/mL streptomycin. AGS cells were plated at 40000 cells per well in 96-well plates in complete medium and cultured overnight at 37 ℃ in a 5% CO2 incubator. Test compounds were dissolved in DMSO to prepare a 10mM stock solution, followed by dilution with F12K complete medium, 100uL of F12K complete medium containing the test compound at the corresponding concentration was added to each well, the final concentration of the test compound in the reaction system ranged from 1000nM to 0.015nM, after 3 hours of culture in a cell incubator, cell supernatant was discarded, cells were washed with ice-bath PBS, and then 50. mu.l of 1 xcell phosphate/total protein lysate buffer (Advanced phosphate-ERK 1/2 kit component) was added to each well for lysis, 96-well plates were placed on ice for half an hour for lysis, and then the lysate was assayed with reference to the Advanced phosphate-ERK 1/2(Thr202/tyr204) kit instructions. Finally, the fluorescence intensity of each well with the emission wavelength of 620nM and 665nM under the excitation wavelength of 304nM is measured on a microplate reader in TF-FRET mode, and each well is calculated665/620 fluorescence intensity ratio. The percent inhibition of the test compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO), and the IC of the compound was obtained by nonlinear regression analysis of the test compound concentration log-inhibition by GraphPad Prism 5 software 50 The value is obtained.
Preferred compounds of the invention have significant inhibitory effects on p-ERK1/2 activity in AGS cells, and IC of preferred compounds 50 <500nM, more optimized IC of the compound 50 <200nM。
Test example 2 inhibition of AsPC-1 cell proliferation by Compounds of the present invention
The following method was used to determine the effect of the compounds of the invention on AspC-1 cell proliferation. AspC-1 cells (containing KRAS G12D mutation) were purchased from the cell resource center of Shanghai Life sciences institute of Chinese academy of sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100. mu.g/mL streptomycin and 1mM Sodium Pyruvate. Cell viability by
Figure BDA0002993764680000362
The luminesent Cell Viability Assay kit (Promega, cat # G7573).
The experimental method is operated according to the steps of the kit specification, and is briefly as follows: test compounds were first prepared as 10mM stock solutions dissolved in DMSO and then diluted in culture medium to prepare test samples with compound concentrations ranging from 1000nM to 0.015 nM. Cells in logarithmic growth phase were seeded at a density of 800 cells per well in 96-well cell culture plates at 37 ℃ with 5% CO 2 The incubation was carried out overnight in an incubator, followed by addition of test compounds and further incubation for 120 hours. After the incubation was completed, 50uL volume of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes, and then Luminescence values of each well of the sample were read on a microplate reader using a Luminescence mode. Percent inhibition of compound at each concentration point was calculated by comparison to the value of control (0.3% DMSO), followed by non-linear regression analysis in GraphPad Prism 5 software as log-inhibition of compound concentration to obtain compound inhibitionIC of cell proliferation 50 The value is obtained.
Preferred compounds of the invention have significant inhibitory effects on AspC-1 cell proliferation, and IC of preferred compounds 50 <500nM, more optimal IC of compound 50 <200nM。

Claims (22)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure FDA0002993764670000011
wherein:
ring A is selected from aryl, heteroaryl or fused ring; preferably phenyl, naphthyl, pyridyl, benzothiazolyl or benzopyrazolyl;
x and Y are each independently selected from N or CR a ；
R a Selected from hydrogen atoms, halogens, alkyl groups or alkoxy groups; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, alkyl or alkoxy; r a Preferably halogen, more preferably fluorine or chlorine;
R 1 identical or different, each independently selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups or alkoxy groups, preferably alkyl groups;
or, two R 1 Together with the atoms to which they are attached form a cycloalkyl or heterocyclyl group;
R 2 selected from hydrogen atoms, alkyl groups or deuterated alkyl groups, preferably alkyl groups or deuterated alkyl groups, more preferably methyl groups or deuterated methyl groups;
R 3 selected from aryl or heteroaryl; wherein said aryl or heteroaryl is optionally further substituted with one or more R A Substituted; r 3 Preferably a heteroaryl group;
R A selected from alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Substituted with the substituent(s); wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 6 or-S (O) r R 5 Substituted with the substituent(s);
R 4 identical OR different, are each independently selected from hydrogen atoms, alkyl groups, alkynyl groups, halogens, nitro groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, ═ O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Substituted with the substituent(s); wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted by one OR more substituents selected from the group consisting of alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH 2 NHC(O)OR 5 、-CH 2 NR 6 R 7 or-S (O) r R 5 Substituted with the substituent(s);
R 5 selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkylHaloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with the substituent(s);
R 6 and R 7 Each independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with a substituent of (a);
or, R 6 And R 7 Together with the atoms to which they are attached form a 4-8 membered heterocyclic group containing one or more of N, O or S (O) r And said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO 2 NR 9 R 10 or-NR 9 C(O)R 10 Substituted with the substituent(s);
R 8 、R 9 and R 10 Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;
m is selected from 0,1, 2,3 or 4;
n is selected from 0,1, 2,3 or 4;
r is selected from 0,1 or 2.
With the proviso that the compound is not included:
Figure FDA0002993764670000021
2. the compound according to claim 1, which is a compound represented by general formula (II) and/or (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure FDA0002993764670000022
wherein: ring A, R 1 ～R 4 X, Y, m and n are defined as in claim 1.
3. A compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
x is selected from N;
y is selected from CR a ；
R a Selected from hydrogen atoms, halogens, alkyl groups or alkoxy groups; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, alkyl or alkoxy; r a Preferably halogen, more preferably fluorine or chlorine.
4. A compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
x is selected from CR a ；
Y is selected from N;
R a selected from hydrogen atoms, halogens, alkyl groups or alkanesAn oxy group; wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, alkyl or alkoxy; r a Preferably halogen, more preferably fluorine or chlorine.
5. A compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from alkyl or deuterated alkyl, preferably methyl or deuterated methyl.
6. The compound of claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from:
Figure FDA0002993764670000031
wherein:
R j selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, alkyl, alkoxy, haloalkyl or haloalkoxy, preferably alkyl, more preferably methyl, ethyl or isopropyl;
k is selected from 0,1, 2 or 3.
7. A compound according to claim 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 3 is selected from
Figure FDA0002993764670000032
8. A compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 4 selected from hydrogen atom, halogen, hydroxyl, amino, alkyl, alkoxy, alkynyl or cycloalkyl, wherein the alkyl, alkoxy, alkynyl or cycloalkyl is optionally further selectedSubstituted with one or more substituents selected from halogen, hydroxy, amino, alkyl or alkoxy.
9. A compound according to claim 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, trifluoromethyl, ethynyl or cyclopropyl, preferably hydroxy, fluoro or ethynyl.
10. A compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein
Figure FDA0002993764670000033
Selected from:
Figure FDA0002993764670000041
11. a compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0002993764670000042
12. a process for the preparation of a compound of general formula (I) according to claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:
Figure FDA0002993764670000051
carrying out coupling reaction on the compound of the general formula (IA) and the compound of the general formula (IB) under the action of a palladium catalyst, and further removing a protecting group to obtain a compound of the general formula (I);
wherein:
X 1 selected from halogen or-Sn (R) 14 ) 3 (ii) a Wherein the halogen is preferably chlorine;
R 14 selected from alkyl, preferably methyl;
m is selected from-B (OH) 2 、-BF 3 K、
Figure FDA0002993764670000052
Or halogen;
PG is a protecting group, preferably tert-butoxycarbonyl;
ring A, R 1 ～R 4 X, Y, m and n are defined as in claim 1.
13. A process for the preparation of a compound of general formula (I) according to claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:
Figure FDA0002993764670000053
reacting the compound of the general formula (IC) with a compound of the general formula (ID), and further removing a protecting group to obtain a compound of the general formula (I);
wherein:
X 2 is halogen, preferably iodine;
R 2 is alkyl or deuterated alkyl, preferably methyl or deuterated methyl;
PG is a protecting group, preferably tert-butoxycarbonyl;
ring A, R 1 、R 3 、R 4 X, Y, m and n are defined as in claim 1.
14. A compound of formula (IA) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,
Figure FDA0002993764670000061
wherein:
X 1 selected from halogen or-Sn (R) 14 ) 3 (ii) a Wherein the halogen is preferably chlorine;
R 14 selected from alkyl, preferably methyl;
PG is selected from protecting groups, preferably tert-butoxycarbonyl;
R 1 ～R 3 x, Y and n are defined as in claim 1.
15. A compound according to claim 14, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0002993764670000062
16. a compound of formula (IC) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,
Figure FDA0002993764670000063
wherein:
PG is selected from protecting groups, preferably tert-butoxycarbonyl;
ring A, R 1 、R 3 、R 4 X, Y, m and n are defined as in claim 1.
17. A compound according to claim 16, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is:
Figure FDA0002993764670000071
18. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
19. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the preparation of a KRas G12D inhibitor.
20. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament for the treatment of a disease mediated by the KRas G12D mutation, wherein the disease mediated by the KRas G12D mutation is selected from cancers selected from cardiac myxoma, lung cancer, stomach cancer, large intestine tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, skin squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphocytic leukemia or glioblastoma, preferably pancreatic cancer, large intestine tumor, rectal cancer and lung cancer.
21. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament for the treatment of a cancer selected from the group consisting of cardiac myxoma, lung cancer, gastric cancer, large intestine tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, skin squamous cell carcinoma, adrenoneuroblastoma, myeloid leukemia, acute lymphocytic leukemia or glioblastoma, preferably pancreatic cancer, large intestine tumor, rectal cancer and lung cancer.
22. The use according to claim 20 or 21, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
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