CN117586256A - Substituted heterocyclic compounds - Google Patents

Substituted heterocyclic compounds Download PDF

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CN117586256A
CN117586256A CN202311013149.9A CN202311013149A CN117586256A CN 117586256 A CN117586256 A CN 117586256A CN 202311013149 A CN202311013149 A CN 202311013149A CN 117586256 A CN117586256 A CN 117586256A
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diazaspiro
methyl
cancer
nonan
alkyl
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袁保昆
陈坤成
白云
许新合
刘志华
陈曦
任仁
雷永珂
段小伟
李红娟
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Capital Pharmaceutical Holdings Beijing Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The application relates to a substituted heterocyclic compound with biological inhibition activity shown in a formula (I), and a preparation method and application thereof, wherein the application comprises the application of the compound in the formula (I) in preparing medicines for treating diseases related to MLL. In the preparation process, the preparation method comprises the steps of substitution, cyclization and deprotectionAnd (3) carrying out a series of reactions to obtain the compound.

Description

Substituted heterocyclic compounds
Technical Field
The present invention relates generally to novel substituted heterocyclic compounds having a Menin-MLL interaction inhibitory activity, processes for their preparation, pharmaceutical compositions thereof, and to the use of such compounds and pharmaceutical compositions thereof for the treatment of diseases benefiting from the inhibition of Menin-MLL interactions, e.g. for the treatment of acute leukemia.
Background
Acute leukemia is usually caused by acquired mutations in hematopoietic progenitor cells. In these leukemia diseases, chromosomal abnormalities are often a discrete mutational signature. Many chromosomal abnormalities are due to the formation of fusion genes that become drivers of tumorigenesis as a result of specific translocations.
Acute leukemias in both adults and children are likely to be caused by a rearrangement of the MLL gene located on chromosome 11q23, which results in a chimeric gene encoding an oncogenic fusion protein fused from the N-terminus of MLL to the C-terminus of one of 80 known fusion partners (Meyer et al, 2018). The MLL fusion protein binds to DNA/chromatin, and induces leukemia transformation of hematopoietic stem cells and progenitor cells by deregulating transcription of the fusion protein target gene. Depending on the progenitor cells of origin, MLLr can manifest as Acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), or a minority Mixed Phenotype Acute Leukemia (MPAL). In addition, MLL translocation can also be observed in-33% of treatment-related acute leukemias, usually after treatment with topoisomerase II inhibitors (windows 2017).
MLL gene rearrangement occurs in 5-10% of acute leukemias, and is more prevalent (up to 70% of cases) in infants in particular (Krivtsov 2007). The incidence of MLLr-ALL has a peak in the first 2 years, decreases in childhood and adolescence, and then steadily increases with age. Similar patterns were observed for MLLr AML patients, which were seen in 9 other cases, except for the postnatal peak (Meyer 2018) that was seen for infant ALL. The MLLr leukemic sub-type is characterised by invasive, resistant to treatment and has a high frequency of early relapse even after initial complete remission (Armstrong 2002;Krivtsov 2007;Pieters 2007; muntan 2012; sanjuan Pla, 2015). MLLr of pediatric ALL is a powerful predictor of poor outcome (Inaba 2013; zhang 2019). In the Interface-06 study, the 6 year Event Free Survival (EFS) of MLLr ALL infants was 36.4% (Pieters 2019). In a large cohort of pediatric AML patients with various MLL rearrangements, the 5-year EFS and Overall Survival (OS) were worse (38% EFS and 58% OS) (Guest 2016) (zwain 2015) compared to pediatric AML population (55% EFS and 70% OS). Due to the high risk classification of MLLr leukemia, clinical chemotherapy regimens are aggressive, with significant short-term toxicity and severe long-term health effects on surviving patients. The acute leukemia of MLLr in children is a disease with poor prognosis, and new treatment methods are urgently needed to improve prognosis.
The Menin protein is encoded by a multiple endocrine tumor (MEN) gene, is a widely expressed nuclear protein, and interacts with DNA processing and repair proteins, chromatin modification proteins, and various transcription factors. Binding of the Menin to the MLL fusion proteins is mediated by amino acid residues 9-13 at the N-terminus of MLL1, and binding of the Menin localizes these fusions to chromatin, which is essential for the oncogenic activity of the MLL fusion proteins (Yokoyama 2005; casilini 2007). This association has been demonstrated to constitutively up-regulate expression of HOX and MESI oncogenes and impair proliferation and differentiation of hematopoietic cells, leading to the development of leukemia. Since Menin is a common oncogenic cofactor in MLL-related leukemia, the interaction of Menin and MLL fusion proteins or MLL is a potential therapeutic target.
Recent studies have shown that nucleophosmin 1 (NPM 1 c) cells also rely on the interaction of Menin with wtMLL to sustain the onset of this leukemia, and that these cells are very sensitive to blockade of Menin-MLL binding (Uckelmann 2020). MLLr and NPM1c are targeted in the same manner, since the MLL fusion protein and wt-MLL share one N-terminal domain. Thus NPM1c acute myeloid leukemia is also an important point in the clinical development program of acute leukemia in adults.
The inhibitor of the Menin-MLL interaction shows activity in a range of cells containing MLLr fusion, disrupting the interaction between the Menin and the MLL1 fusion protein required for leukemia forming activity, thereby affecting the expression of key oncogenes, leading to growth arrest and inhibition of cell proliferation. The inhibitor has strong single dose activity in various leukemia xenograft models, and has good survival benefit after oral administration in a non-clinical model (Cierpicki 2014; bojin 2015). Taken together, these data indicate that drug inhibition of the menu-MLL interaction is a potential targeting strategy for the treatment of MLLr acute leukemia.
No messenger-MLL inhibitors have yet been approved for sale, and three inhibitors have recently entered the clinical research stage. Inhibitors of Syndax SNDX-5613 were first entered into phase I/II clinical studies (NCT 04065399) at 8.22.2019 for Acute Myeloid Leukemia (AML), acute Lymphoblastic Leukemia (ALL), mixed Lineage Acute Leukemia (MLAL), mixed Phenotype Acute Leukemia (MPAL), and unknown lineage acute leukemia (ALAL) with MLL rearrangement or NPM1 mutation. Following the Kura inhibitor KO-539, a phase I/II clinical study (NCT 04067336) was initiated at 8.26.2019 for advanced malignancy, AML, mixed Lineage Leukemia (MLL), MLAL, MPAL, ALAL. A recent clinical phase I study of JNJ-75276617 (NCT 04065399) was initiated on month 3 and 21 of 2021 by Janssen, directed to acute leukemia, AML, ALL. The molecular structure of the first two inhibitors has been disclosed, and the latter has not been disclosed. Bayer, agios, university of Michigan, university of pennsylvania, sumitomo, etc. have also been patented.
The inhibition of interactions between the Menin and MLL fusion proteins by small molecules has been demonstrated as a potential therapeutic strategy for the treatment of MLL-r leukemia, and has proven clinical transformation value. More effective and selective small molecule inhibitors are of vital importance for in vivo research, and we use computer-aided drug design as a means to discover novel structural compounds and achieve our intended purpose of having stronger efficacy and better drug properties through structural modification.
Disclosure of Invention
The invention provides a compound represented by a formula (I) or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites or prodrugs thereof,
a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
wherein,
x isWherein the position is as follows with SO 2 Is connected with the mother nucleus or is connected with the mother nucleus,
v is N or CH, and the R is H,
the ring A is a 7-12 membered nitrogen-containing spiro ring,
the C ring is a 3-12 membered nitrogen-containing heterocycle,
the D ring is a 3-12 membered nitrogen-containing heterocycle,
R 1 is hydrogen, halogen or C 1-6 Alkyl, or C 1-6 A haloalkyl group, a halogen atom,
R 2 each independently is hydrogen, halogen, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl、C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CF 3 、-NR 13 R 14 OR-OR 13 ，
R 3 Is a halogen, and is preferably a halogen,
R 20 and R is 21 Each independently is hydrogen or C 1-6 An alkyl group, a hydroxyl group,
R 4 and R is 5 Each independently is hydrogen, halogen, CN, C 1-6 Alkyl, or C 1-6 A haloalkyl group, a halogen atom,
R 11 and R is 12 Each independently selected from H, halogen and C 1-6 Alkyl, or R 11 And R is 12 Are linked together to form a 3-5 membered carbocyclic ring,
R 41 h, C of a shape of H, C 1-6 Alkyl, - (CO) -R 15 、-(CO)-OR 13 And- (CO) -NR 13 R 14 The alkyl group may optionally be substituted with halogen, -CN, -NR 13 R 14 、-OR 13 Or 3-8 membered heterocycloalkyl,
R 42 and R is 43 Each independently selected from H, halogen, -CN and C 1-6 An alkyl group, a hydroxyl group,
R 13 and R is 14 Each independently selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen,
R 15 each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 2-6 Alkenyl and C 2-6 Alkynyl, said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl and alkynyl being optionally substituted with halogen, -CN, or C 1-6 An alkyl group is substituted and a substituent is substituted,
n is each independently 0, 1, 2, or 3,
provided that the following compounds are not included:
in some embodiments, the position is relative to the SO 2 And (5) connection.
In some embodiments, the D ring is a 7-12 membered nitrogen containing spiro ring
In some embodiments, the C-ring is a 3-6 membered nitrogen containing heterocycle.
In some embodiments, V is N.
In some embodiments, n is each independently 0 or 1, preferably 0.
In some embodiments, R 1 Is hydrogen or C 1-6 Alkyl is preferably hydrogen.
In some embodiments, R 2 Each independently is hydrogen, halogen, CN, NO 2 、-OH、-NH 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CF 3 、-NH-C 1-6 Alkyl, or-O-C 1-6 An alkyl group.
In some embodiments, R 3 Is fluorine.
In some embodiments, R 11 And R is 12 Is hydrogen.
In some embodiments, R 13 And R is 14 Each independently selected from hydrogen and C 1-6 Alkyl, preferably hydrogen and C 1-3 An alkyl group;
in some embodiments, R 15 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, preferably C 1-6 An alkyl group.
In some embodiments, R 42 And R is 43 H.
In some embodiments, R 41 Is C 1-6 Alkyl, - (CO) -R 15 、-(CO)-OR 13 And- (CO) -NR 13 R 14 The alkyl group may optionally be substituted with halogen, -CN, -NR 13 R 14 、-OR 13 Or 3-8 membered heterocycloalkyl, R 13 And R is 14 As defined above.
In another aspect, the invention provides a compound, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof,
in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and optionally a pharmaceutically acceptable carrier.
In another aspect, the invention provides a method of treating a disease associated with MLL activity, comprising administering to a subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention; in some embodiments, the disease associated with MLL activity is a cancer, preferably an acute leukemia (including MLL acute leukemia, MLL partial tandem repeat acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gall bladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorionic epithelial tumors, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, ewing sarcoma, ewing's sarcoma, cartilage sarcoma, soft tissue sarcoma, or skin sarcoma.
A compound of the invention or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, for use in combination with at least one different agent, wherein the different agent is at least one agent selected from the group consisting of an antitumor alkylating agent, an antitumor antibiotic, a plant-derived antitumor drug, an antitumor platinum coordination compound, an antitumor camptothecin derivative, an antitumor tyrosine kinase inhibitor, an antitumor serine/threonine kinase inhibitor, an antitumor phospholipid kinase inhibitor, an antitumor monoclonal antibody, an interferon, a biological response modifier, a hormonal preparation, an angiogenesis inhibitor, an immune checkpoint inhibitor, an epigenetic related molecular inhibitor, a protein post-translational modification inhibitor, a proteasome inhibitor and other antitumor drugs.
In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of a disease associated with MLL activity; in some embodiments, the disease associated with MLL activity is a cancer, preferably an acute leukemia (including MLL acute leukemia, MLL partial tandem repeat acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gall bladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorionic epithelial tumors, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, ewing sarcoma, ewing's sarcoma, cartilage sarcoma, soft tissue sarcoma, or skin sarcoma.
Detailed Description
In the following detailed description of the invention, exemplary embodiments are set forth that utilize the principles of the present invention. The features and advantages of the present invention may be better understood by reference to the following summary.
It is to be understood that the scope of the various aspects of the invention is defined by the claims, and methods and structures within the scope of these claims, as well as equivalent methods and structures, are within the scope of the claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter of the invention. The use of the singular also includes the plural unless specifically stated otherwise. The use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
Certain chemical terms
The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, the optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ) Fully substituted (e.g.: -CF 2 CF 3 ) Monosubstituted (e.g.: -CH 2 CH 2 F) Or any level between mono-and full-substitution (e.g.: -CH 2 CHF 2 、-CF 2 CH 3 、-CFHCHF 2 Etc.). As will be appreciated by those skilled in the artFor any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or synthetic.
Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectrometry, and pharmacological methods are employed. Unless specifically defined otherwise, the relevant terms and experimental procedures and techniques herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
The terms "group", "chemical group" as used herein refer to a particular moiety or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded or attached to a molecule.
Some of the chemical groups named herein may be represented by shorthand notations for the total number of carbon atoms. For example, C 1 -C 6 Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by the shorthand notation does not include carbon atoms on a possible substituent.
The term "halogen", "halo" or "halide" refers to bromine, chlorine, fluorine or iodine.
The terms "aromatic", "aromatic ring", "aromatic ring" as used herein refer to a planar ring or ring portion of multiple rings having a delocalized electron conjugated system of 4n+2 electrons, where n is an integer. The aromatic ring may be formed from 5, 6, 7, 8, 9 or more than 9 atoms. The aromatic compound may be optionally substituted and may be monocyclic or polycyclic with fused rings. The term aromatic compounds includes all carbocycles (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different from one another.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
The term "alkyl" as used herein alone or as part of another component (e.g., a monoalkylamino group) refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.
The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having one or more c=c double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bond in these groups may be cisOr trans-conformation, and should be understood to include both of the isomers. Examples include, but are not limited to, vinyl (ch=ch 2 ) 1-propenyl (CH) 2 CH＝CH 2 ) Isopropenyl (C (CH) 3 )＝CH 2 ) Butenyl, and 1, 3-butadienyl, and the like. Alkenyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkenyl "or" C 2-6 Alkenyl "refers to alkenyl groups that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkenyl groups herein are also intended to cover instances where no numerical range is specified.
The term "alkynyl", as used herein alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having one or more c≡c triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Alkynyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkynyl "or" C 2-6 Alkynyl "refers to an alkynyl group that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl herein also encompasses cases where no numerical range is specified.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, which has 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C and having a fully conjugated pi-electron system. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.
The term "cycloalkyl", as used herein, alone or in combination, refers to a stable monovalent non-aromatic monocyclic or multicyclic hydrocarbon group containing only carbon and hydrogen atoms, possibly including fused, spiro, or bridged ring systems, containing from 3 to 15 ring carbon atoms, preferably from 3 to 10 ring carbon atoms, more preferably from 3 to 8 ring carbon atoms, and which may be saturated or unsaturated, attached to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The terms "heterocyclyl", "heterocycloalkyl", "heterocycle", as used herein alone or as part of another ingredient, refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of this application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic monocyclic ring or bicyclic ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuryl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
The term "carbocycle" refers to a structure covalently closed by a carbon, which may be saturated or partially unsaturated. Carbocycles may be formed from 3, 4, 5, 6, 7, 8, 9 or more than 9 atoms. The distinction between the terms carbocycle and heterocycle is that the ring backbone of a heterocycle contains at least one atom different from carbon. "carbocycles" herein may be monocyclic or polycyclic, and polycyclic carbocycles include spiro, fused and bridged rings. The carbocycle may be optionally substituted. "carbocycle" herein preferably comprises about 5 to about 20 or 5 to 10 or 5-8 or 5-6 backbone ring atoms.
The term "polymorph" or "polymorphism" as used herein means that the compounds of the present invention have a variety of lattice morphologies. Some compounds of the invention may have more than one crystal form, and the invention encompasses all polymorphs or mixtures thereof.
Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.
Unless otherwise specified, olefinic double bonds contained in the compounds of the present invention include the E and Z isomers.
The compounds of the invention include compounds having one or more isotopic substitution, and references to a particular element include within their scope all isotopes of that element. For example, reference to hydrogen includes within its scope 1 H、 2 H (D) and 3 h (T). Similarly, references to carbon and oxygen include within their scope, respectively 12 C、 13 C and C 14 C, C and C 16 O and 18 O。
it will be appreciated that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. Some of the compounds of the present invention may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It is to be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by performing or modifying known methods, such as chromatography techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
The term "pharmaceutically acceptable salt" as used herein includes both acid and base addition salts.
"pharmaceutically acceptable salts of acids" refers to those salts that retain the biological effectiveness and properties of the free base of the compound, are not biologically or otherwise undesirable, are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, and the like. By "pharmaceutically acceptable salts of bases" is meant those salts which retain the biological effectiveness and properties of the free acid of the compound, are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
The organic bases forming salts include, but are not limited to, primary, secondary, tertiary, cyclic amines and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, caffeine and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Crystallization often yields solvates of the compounds of the present invention. The term "solvate" as used herein refers to a complex of one or more molecules of a compound of the invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may only occasionally retain water or a mixture of water with some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "pharmaceutical composition" as used herein refers to a formulation that is mixed with a compound of the present invention and a medium that is generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. Such a medium comprises all pharmaceutically acceptable carriers.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a related disease or condition in a mammal, particularly a human, including
(i) Preventing a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition, from developing the corresponding disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
Preparation of the Compounds of the invention
The following specific examples are put forth so as to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. Those skilled in the art will appreciate that: there are other synthetic routes to form the compounds of the present invention, and the following non-limiting examples are provided.
All operations involving readily oxidizable or hydrolyzable feedstocks are performed under nitrogen protection. Unless otherwise indicated, the starting materials used in the present invention are all commercially available and used without further purification.
Column chromatography was performed on silica gel (200-300 mesh) produced by Qingdao chemical Co., ltd. Thin layer chromatography was performed using prefabricated plates (silica gel 60PF254,0.25 mm) manufactured by e.merck company. Chiral compound isolation and enantiomeric excess value (ee) determination Agilent LC 1200series (column: CHIRALPAK AD-H,x 250 mm, 5 microns, 30 ℃). Nuclear magnetic resonance chromatography (NMR) was measured using a Varian VNMRS-400 NMR; liquid chromatography-mass spectrometry (LC/MS) using FINNIGAN Thermo LCQ Advantage MAX Agilent LC 1200series (column: waters Symmetry C, 18,) >x 50 mm, 5 μm, 35 ℃) using ESI (+) ion mode。
Experimental part
Intermediate 1:2- ((4-chloropyridin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Synthesized according to the procedure described for intermediate 41 in WO 2017214367.
Intermediate 2:2- ((4- (2, 7-diazaspiro [ 3.5)]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-NN-di Isopropyl benzamide
Synthesized according to the procedure for the same intermediate as in example 6A of patent WO 2017214367.
Intermediate 3:5-fluoro-N, N-diisopropyl-2- ((4- (7- (piperidin-4-ylmethyl) -2, 7-diazaspiro [ 3.5)] Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
Step 1:4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester
2- ((4- (2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide (883 mg), tert-butyl 4-formylpiperidine-1-carboxylate (427 mg) and acetic acid (24 mg) were added to 1, 2-dichloroethane (10 mL), stirred at room temperature for 1 hour, sodium triacetoxyborohydride (1.24 g) was further added, stirred at room temperature overnight, quenched with saturated aqueous sodium bicarbonate solution, reacted with stirring, filtered, the filtrate was extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to give the title compound (930 mg). MS m/z [ LC-MS ]:639.40[ M+1].
Step 2: 5-fluoro-N, N-diisopropyl-2- ((4- (7- (piperidin-4-ylmethyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
The product (920 mg) of step 1 was added to a 4mol/L hydrogen chloride dioxane solution (15 mL), stirred at room temperature for 2 hours, diethyl ether (50 mL) was added, stirred for 1 hour, filtered, and the filter cake was rinsed with diethyl ether and dried to give the objective compound (910 mg). MS m/z [ LC-MS ]:539.35[ M+1].
Intermediate 4:4- ((2, 7-diazaspiro [ 3.5)]Nonan-7-yl) methyl) piperidine-1-carboxylic acid benzyl ester hydrochloride
Step 1:7- ((1- ((benzyloxy) carbonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
Referring to the procedure of step 1 in intermediate 3, the title compound is obtained starting from benzyl 4-formylpiperidine-1-carboxylate and tert-butyl 2, 7-diazaspiro [3.5] nonane-2-carboxylate. MS m/z [ LC-MS ]:458.30[ M+1].
Step 2:4- ((2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidine-1-carboxylic acid benzyl ester hydrochloride
Referring to the method of the step 2 in the intermediate 3, the target compound is obtained by taking the product of the step 1 as a raw material. MS m/z [ LC-MS ]:358.25[ M+1].
Intermediate 5:5-fluoro-N, N-diisopropyl-2- ((5- (7- (piperidin-4-ylmethyl) -2, 7-diazaspiro [ 3.5) ] Nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
Step 1:4- ((2- (3, 6-dichloro-1, 2, 4-triazin-5-yl) pyrrolidin-3-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidine-1-carboxylic acid benzyl ester
Intermediate 4 (860 mg) and diisopropylethylamine (1.03 g) were added to tetrahydrofuran (20 mL), cooled to 0 ℃, 3,5, 6-trichloro-1, 2, 4-triazine (369 mg) was added, and after slowly warming to room temperature, the mixture was stirred for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the objective compound (1.10 g) which was used directly in the next step. MS m/z [ LC-MS ]:505.19[ M+1].
Step 2:4- ((2- (3-chloro-6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidine-1-carboxylic acid benzyl ester
The product of step 1 (1.10 g), 5-fluoro-2-hydroxy-N, N-diisopropylbenzamide (720 mg) and potassium carbonate (550 mg) were added to 1, 4-dioxane (15 mL) and refluxed for 12 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 20:1) to give the objective compound (1.13 g). MS m/z [ LC-MS ]:708.34[ M+1].
Step 3: 5-fluoro-N, N-diisopropyl-2- ((5- (7- (piperidin-4-ylmethyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
The product of step 2 (1.13 g) and 10% palladium on carbon hydroxide (230 mg) were added to methanol (20 mL), the air in the reactor was replaced with hydrogen, and the mixture was stirred at 60℃for 8 hours under a hydrogen pressure of 3 atmospheres. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 10:1) to give the objective compound (770 mg). MS m/z [ LC-MS ]:540.35[ M+1].
Intermediate 6:7- (chlorosulfonyl) -2, 7-diazaspiro [3.5]]Nonane-2-carboxylic acid tert-butyl ester
Tert-butyl 2, 7-diazaspiro [3.5] nonane-2-carboxylate (460 mg) and triethylamine (410 mg) were added to dichloromethane (10 mL), cooled to 0℃and sulfonyl chloride (300 mg) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction mixture was washed with 1mol/L dilute hydrochloric acid, water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate, 4:1) to give the objective compound (540 mg). MS m/z [ LC-MS ]:325.10[ M+1].
Intermediate 7:6- (sulfamoyl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate. MS m/z [ LC-MS ]:297.07[ M+1].
Intermediate 8:5-fluoro-2- ((4- (7- ((4-fluoropiperidin-4-yl) methyl) -2, 7-diazaspiro [ 3.5)]Nonane-2- Group) pyrimidin-5-yl) oxy) -N, N-diisopropylbenzamide hydrochloride
Step 1:4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester
Referring to the procedure of step 1 in intermediate 3, starting from 2- ((4- (2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate the title compound was obtained. MS m/z [ LC-MS ]:657.39[ M+1].
Step 2: 5-fluoro-2- ((4- (7- ((4-fluoropiperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -N, N-diisopropylbenzamide hydrochloride
Referring to the method of step 2 in the intermediate 3, the target compound is obtained by taking the product of step 1 as a raw material. MS m/z [ LC-MS ]:557.34[ M+1].
Intermediate 9:(R) - (3- (pyrrolidin-3-ylmethyl) -3-azaspiro [ 5.5)]Undecan-9-yl) carbamic acid benzyl ester Ester hydrochloride
Step 1:9- (((benzyloxy) carbonyl) amino) -3-azaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester
Tert-butyl 9-amino-3-azaspiro [5.5] undecane-3-carboxylate (500 mg) and diisopropylethylamine (300 mg) were added to methylene chloride (10 mL), and benzyl chloroformate (360 mg) was added dropwise under ice-cooling, followed by stirring at room temperature for 2 hours after completion of the dropwise addition. The reaction mixture was quenched with saturated aqueous sodium hydrogencarbonate solution, the aqueous phase was separated, and the organic phase was washed with 1mol/L dilute hydrochloric acid, water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether/ethyl acetate, 4:1) to give the objective compound (610 mg). MS m/z [ LC-MS ]:403.26[ M+1].
Step 2: (3-azaspiro [5.5] undecan-9-yl) carbamic acid benzyl ester hydrochloride
Referring to the method of step 2 in the intermediate 3, the target compound is obtained by using the product of step 1 as a raw material. MS m/z [ LC-MS ]:303.21[ M+1].
Step 3: (S) -3- ((9- (((benzyloxy) carbonyl) amino) -3-azaspiro [5.5] undec-3-yl) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Referring to the method of step 1 in intermediate 3, the product of step 2 is used as a raw material to obtain the target compound. MS m/z [ LC-MS ]:486.33[ M+1].
Step 4: (R) - (3- (pyrrolidin-3-ylmethyl) -3-azaspiro [5.5] undecan-9-yl) carbamic acid benzyl ester hydrochloride
Referring to the method of step 2 in the intermediate 3, the target compound is obtained by using the product of step 3 as a raw material. MS m/z [ LC-MS ]:386.28[ M+1].
Intermediate 10:(S) -2- ((5- (3- ((9-amino-3-azaspiro [5.5 ])]Undec-3-yl) methyl) pyrrolidines 1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1: (S) - (3- ((1- (3, 6-dichloro-1, 2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -3-azaspiro [5.5] undecan-9-yl) carbamic acid benzyl ester
Referring to the procedure of step 1 in intermediate 5, the objective compound is obtained starting from intermediate 9. MS m/z [ LC-MS ]:533.22[ M+1].
Step 2: (S) - (3- ((1- (3-chloro-6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -3-azaspiro [5.5] undec-9-yl) carbamic acid benzyl ester
Referring to the method of step 2 in intermediate 5, the product of step 1 is used as a raw material to obtain the target compound. MS m/z [ LC-MS ]:736.38[ M+1].
Step 3: (S) -2- ((5- (3- ((9-amino-3-azaspiro [5.5] undecan-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the method of step 3 in intermediate 5, the product of step 2 is used as a raw material to obtain the target compound. MS m/z [ LC-MS ]:568.38[ M+1].
Intermediate 11:(S) -2- ((5- (3- ((9-amino-3-azaspiro [5.5 ])]Undec-3-yl) methyl) pyrrolidines 1-yl) -1,2, 4-triazin-6-yl) oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide
Step 1: (S) - (3- ((1- (3-chloro-6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -3-azaspiro [5.5] undec-9-yl) carbamic acid benzyl ester
Referring to the method of step 2 in intermediate 5, the target compound is obtained using benzyl (S) - (3- ((1- (3, 6-dichloro-1, 2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -3-azaspiro [5.5] undecan-9-yl) carbamate and N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide as starting materials. MS m/z [ LC-MS ]:722.36[ M+1].
Step 2: (S) -2- ((5- (3- ((9-amino-3-azaspiro [5.5] undecan-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide
Referring to the method of the step 3 in the intermediate 5, the target compound is obtained by using the product of the step 1 as a raw material. MS m/z [ LC-MS ]:554.36[ M+1].
Intermediate 12:(S) -5-fluoro-N, N-diisopropyll-2- ((4- (3- ((9-oxo-3-azaspiro [5.5 ])]Undecane- 3-yl) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) benzamide
Step 1: (S) -3- ((9-oxo-3-azaspiro [5.5] undecane-3-) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3-azaspiro [5.5] undecan-9-one hydrochloride (611 mg), (R) -3- (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (840 mg) and potassium carbonate (1242 mg) were added to acetonitrile (30 mL), heated to 80℃and stirred for 6 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 20:1) to give the objective compound (530 mg). MS m/z [ LC-MS ]:351.27[ M+1].
Step 2: (R) -3- (pyrrolidin-3-ylmethyl) -3-azaspiro [5.5] undecan-9-one hydrochloride
Referring to the method of step 2 in the intermediate 3, the target compound is obtained by using the product of step 1 as a raw material. MS m/z [ LC-MS ]:251.21[ M+1].
Step 3: (S) -5-fluoro-N, N-diisopropyl-2- ((4- (3- ((9-oxo-3-azaspiro [5.5] undecan-3-yl) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) benzamide
Intermediate 1 (704 mg), (R) -3- (pyrrolidin-3-ylmethyl) -3-azaspiro [5.5] undecan-9-one hydrochloride (646 mg) and diisopropylethylamine (903 mg) were added to isopropanol (10 mL), heated to 80℃and stirred for 12 hours, cooled to room temperature, concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to give the title compound (980 mg). MS m/z [ LC-MS ]:566.35[ M+1].
Intermediate 13:(S) -2- ((4- (3- ((9-amino-3-azaspiro [5.5 ])]Undec-3-yl) methyl) pyrrolidines 1-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Intermediate 12 (565 mg) and amine acetate (154 mg) were added to 1, 2-dichloroethane (10 mL), stirred at room temperature for 1 hour, further sodium triacetoxyborohydride (636 mg) was added, stirred at room temperature overnight, quenched with saturated aqueous sodium bicarbonate solution, filtered, the filtrate extracted with dichloromethane, the extract dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure was separated by silica gel column chromatography (dichloromethane/methanol, 12:1) to give the title compound (450 mg). MS m/z [ LC-MS ]:567.38[ M+1].
Intermediate 14:5-fluoro-N, N-diisopropyl-2- ((4- (7- ((1, 2,3, 6-tetrahydropyridin-4-yl) methyl) -2, 7-diazaspiro [3.5]]Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
Step 1:4- (((methylsulfonyl) oxy) methyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Tert-butyl 4- (hydroxymethyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (426 mg), diisopropylethylamine (774 mg) were added to dichloromethane (10 mL), cooled to-5℃and a solution of trifluoromethanesulfonic anhydride (620 mg) in dichloromethane (5 mL) was slowly added dropwise. After the completion of the dropwise addition, stirring was carried out at-5℃to 0℃for 1 hour, and the reaction solution was washed with 0.5mol/L dilute hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated by silica gel column chromatography (petroleum ether/ethyl acetate, 4:1) to give the objective compound (495 mg). MS m/z [ LC-MS ]:292.12[ M+1].
Step 2:4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
The product of step 1 (437 mg), 2- ((4- (2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide (660 mg) and potassium carbonate (620 mg) were added to acetonitrile (10 mL), heated to 60℃and stirred for 4 hours, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to give the title compound (763 mg). MS m/z [ LC-MS ]:637.39[ M+1].
Step 3: 5-fluoro-N, N-diisopropyl-2- ((4- (7- ((1, 2,3, 6-tetrahydropyridin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
Referring to the method of step 2 in the intermediate 3, the target compound is obtained by using the product of step 2 as a raw material. MS m/z [ LC-MS ]:537.34[ M+1].
Intermediate 15:(1- (chlorosulfonyl) azetidin-3-yl) carbamic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl azetidin-3-ylcarbamate. MS m/z [ LC-MS ]:271.05[ M+1].
Intermediate 16:5-fluoro-N, N-diisopropyl-2- ((3- (methylamino) -5- (7- (piperidin-4-ylmethyl) -2,7- Diazaspiro [3.5]Nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
Step 1:4- ((2- (6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -3- (methylamino) -1,2, 4-triazin-5-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidine-1-carboxylic acid benzyl ester
Benzyl 4- ((2- (3-chloro-6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidine-1-carboxylate (283 mg), methylamine hydrochloride (125 mg) and potassium carbonate (410 mg) were added to isopropanol (5 mL) and reacted at microwave 150℃for 12 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to give the title compound (195 mg). MS m/z [ LC-MS ]:703.41[ M+1].
Step 2: 5-fluoro-N, N-diisopropyl-2- ((3- (methylamino) -5- (7- (piperidin-4-ylmethyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
The product (190 mg) of step 1 and 10% palladium on carbon hydroxide (38 mg) were added to methanol (10 mL), the air in the reactor was replaced with hydrogen, reacted at 60℃for 8 hours under a hydrogen pressure of 3 atmospheres, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 10:1) to give the objective compound (130 mg). MS m/z [ LC-MS ]:569.37[ M+1].
Intermediate 17:(S) -5-fluoro-N, N-diisopropyll-2- ((4- (7- (pyrrolidin-3-ylmethyl) -2, 7-diaza) Spiro [3.5]]Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
Step 1: (R) -3- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Referring to the procedure of step 1 in intermediate 3, starting from 2- ((4- (2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide and tert-butyl (S) -3-formylpyrrolidine-1-carboxylate the title compound was obtained. MS m/z [ LC-MS ]:625.39[ M+1].
Step 2: (S) -5-fluoro-N, N-diisopropyl-2- ((4- (7- (pyrrolidin-3-ylmethyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
Referring to the method of step 2 in the intermediate 3, the target compound is obtained by using the product of step 1 as a raw material. MS m/z [ LC-MS ]:525.34[ M+1].
Intermediate 18:6- (sulfamoyl) -2, 6-diazaspiro [3.4]]Octane-2-carboxylic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate. MS m/z [ LC-MS ]:311.08[ M+1].
Intermediate 19:6- (chlorosulfonyl) -2, 6-diazaspiro [3.5]]Nonane-2-carboxylic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl 2, 6-diazaspiro [3.5] nonane-2-carboxylate. MS m/z [ LC-MS ]:325.10[ M+1].
Intermediate 20:(S, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid hydrochloride
Synthesized according to the procedure of example 1 in patent CN 201810440934.5.
Intermediate 21:(R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid hydrochloride
Synthesized according to the procedure of example 3 in patent CN 201810440934.5.
Intermediate 22:2- ((4- (2, 7-diazaspiro [ 3.5)]Nonan-2-yl) pyrimidin-5-yl) oxy) -N-ethyl-5- fluoro-N-isopropylbenzamide
Synthesized according to the procedure described for intermediate 41f in WO 2017214367.
Intermediate 23:N-ethyl-5-fluoro-N-isopropyl-2- ((4- (7- ((4-methoxypiperidin-4-yl) methyl) -2,7- Diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
Step 1:4- ((2- (5- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester
Referring to the procedure of step 1 in intermediate 3, starting from intermediate 22 and tert-butyl 4-methoxy-4- (((methylsulfonyl) oxy) methyl) piperidine-1-carboxylate, the title compound is obtained. MS m/z [ LC-MS ]:655.40[ M+1].
Step 2: N-ethyl-5-fluoro-N-isopropyl-2- ((4- (7- ((4-methoxypiperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
Referring to the method of step 2 in the intermediate 3, the target compound is obtained by taking the product of step 1 as a raw material. MS m/z [ LC-MS ]:555.35[ M+1].
Intermediate 24:3- ((chlorosulfonyl) amino) azetidine-1-carboxylic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl 3-aminoazetidine-1-carboxylate. MS m/z [ LC-MS ]:271.05[ M+1].
Intermediate 25:3- (((chlorosulfonyl) (methyl) amino) methyl) azetidine-1-carboxylic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl 3- ((methylamino) methyl) azetidine-1-carboxylate. MS m/z [ LC-MS ]:299.08[ M+1].
Intermediate 26:8- (chlorosulfonyl) -5-oxa-2, 8-diazaspiro [3.5]]Nonane-2-carboxylic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl 5-oxa-2, 8-diazaspiro [3.5] nonane-2-carboxylate. MS m/z [ LC-MS ]:327.08[ M+1].
Intermediate 27:8- (chlorosulfonyl) -2, 8-diazaspiro [4.5]]Decane-2-carboxylic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl 2, 8-diazaspiro [4.5] decane-2-carboxylate. MS m/z [ LC-MS ]:339.11[ M+1].
Intermediate 28:(R) -2- (pyrrolidin-3-ylmethyl) -2, 7-diazaspiro [3.5]Nonane-7-carboxylic acid benzyl ester hydrochloride Salt
Step 1:2, 7-diazaspiro [3.5] nonane-7-carboxylic acid benzyl ester hydrochloride
Referring to the procedure of step 2 in intermediate 3, the title compound was obtained starting from 7-benzyl 2- (tert-butyl) 2, 7-diazaspiro [3.5] nonane-2, 7-dicarboxylic acid ester. MS m/z [ LC-MS ]:261.16[ M+1].
Step 2: (S) -2- ((1- (tert-Butoxycarbonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid benzyl ester
Referring to the procedure of step 1 in intermediate 3, the title compound was obtained starting from benzyl 2, 7-diazaspiro [3.5] nonane-7-carboxylate hydrochloride. MS m/z [ LC-MS ]:444.29[ M+1].
Step 3: (R) -2- (pyrrolidin-3-ylmethyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid benzyl ester hydrochloride
Referring to the procedure of step 2 in intermediate 3, starting from benzyl (S) -2- ((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate, the title compound was obtained. MS m/z [ LC-MS ]:344.23[ M+1].
Intermediate 29:(S) -2- ((5- (3- ((2, 7-diazaspiro [3.5 ])]Nonan-2-yl) methyl) pyrrolidin-1-yl) 1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1: (S) -2- ((1- (3, 6-dichloro-1, 2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid benzyl ester
Referring to the procedure of step 1 in intermediate 5, the starting intermediate 28 is used to obtain the desired compound. MS m/z [ LC-MS ]:491.17[ M+1].
Step 2: (S) -2- ((1- (3-chloro-6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid benzyl ester
Referring to the method of step 2 in intermediate 5, the product of step 1 is used as a raw material to obtain the target compound. MS m/z [ LC-MS ]:694.33[ M+1].
Step 3: (S) -2- ((5- (3- ((2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in intermediate 5, starting from benzyl (S) -2- ((1- (3-chloro-6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate, the title compound was obtained. MS m/z [ LC-MS ]:526.33[ M+1].
Intermediate 30:(R) - (1- (chlorosulfonyl) piperidin-3-yl) carbamic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl (R) -piperidin-3-ylcarbamate. MS m/z [ LC-MS ]:299.08[ M+1].
Intermediate 31:3- ((chlorosulfonyl) (methyl) amino) azetidine-1-carboxylic acid tert-butyl ester
Referring to the procedure in intermediate 6, the target compound was obtained starting from tert-butyl 3- (methylamino) azetidine-1-carboxylate. MS m/z [ LC-MS ]:285.07[ M+1].
Example 1:(E) -4- ((1S, 4S) -5- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) Yl) pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 5-diaza-bis Ring [2.2.1]Heptane-2-yl) -4-oxo-but-2-enoic acid ethyl ester
Step 1: (1S, 4S) -5- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
Intermediate 3 (130 mg), diisopropylethylamine (155 mg) was added to dichloromethane (5 mL), cooled to 0 ℃, tert-butyl (1 s,4 s) -5- (chlorosulfonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (150 mg) was added, slowly warmed to room temperature and stirred for 2 hours, then refluxed for 12 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to give the objective compound (128 mg). MS m/z [ LC-MS ]:799.43[ M+1].
Step 2:2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The product (125 mg) of step 1 was added to a 4mol/L hydrogen chloride dioxane solution (5 mL), stirred at room temperature for 2 hours, diethyl ether (30 mL) was added, stirred for 1 hour, filtered, and the filter cake was rinsed with diethyl ether and dried to give the objective compound (120 mg). MS m/z [ LC-MS ]:699.38[ M+1].
Step 3: (E) -4- ((1S, 4S) -5- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -4-oxobut-2-enoic acid ethyl ester
The product of step 2 (60 mg) and diisopropylethylamine (78 μl) were added to dichloromethane (3 mL), cooled to 0 ℃, and (E) -4-chloro-4-oxo-but-2-enoic acid ethyl ester (15 μl) was added, slowly warmed to room temperature, stirred for 2 hours, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to give the objective compound (30 mg). MS m/z [ LC-MS]：825.41[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.34(s，1H)，7.74(s，1H)，7.20(d，J＝15.2Hz，0.3H)，7.04(d，J＝15.2Hz，0.7H)，6.95-6.99(m，2H)，6.85-6.89(m，1H)，6.73-6.77(m，1H)，4.97(s，0.7H)，4.68(s，0.3H)，4.44(s，0.7H)，4.42(s，0.3H)，4.21-4.28(m，1H)，3.64-4.02(m，8H)，3.57(dd，J＝9.2Hz，2.0Hz，0.7H)，3.43-3.51(m，1.7H)，3.31-3.37(m，1.3H)，3.22(d，J＝9.2Hz，0.3H)，2.69(t，J＝11.6Hz，2H)，2.18-2.38(m，3H)，2.10(d，J＝6.8Hz，2H)，1.68-2.06(m，10H)，1.52(d，J＝6.4Hz，3H)，1.46(d，J＝7.2Hz，3H)，1.28-1.33(m，3H)，1.14-1.21(m，2H)，1.11(d，J＝6.87Hz，3H)，1.07(d，J＝6.8Hz，3H)。
Example 2:2- ((5- (7- ((1- ((2-propenoyl-2, 7-diazaspiro [3.5 ]))]Nonan-7-yl) sulfonyl Piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) -1,2, 4-triazin-6-yl-oxy) -5-fluoro-N, N-di Isopropyl benzamide
Step 1:7- ((4- ((2- (6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 5 and intermediate 6, to give the target compound. MS m/z [ LC-MS ]:828.46[ M+1].
Step 2:2- ((5- (7- ((1- ((2, 7-diazaspiro [3.5] nonan-7-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:728.41[ M+1].
Step 3:2- ((5- (7- ((1- ((2-propenoyl-2, 7-diazaspiro [3.5] nonan-7-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：782.42[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.44(s，1H)，7.22-7.25(m，1H)，7.06-7.11(m，1H)，6.94(dd，J＝7.6Hz，3.2Hz，1H)，5.33(dd，J＝17.2Hz，2.0Hz，1H)，6.17(dd，J＝17.2Hz，10.4Hz，1H)，5.67(dd，J＝10.4Hz，2.0Hz，1H)，4.46(d，J＝10.0Hz，1H)，4.27(d，J＝10.0Hz，1H)，3.82-3.91(m，4H)，3.72-3.80(m，3H)，3.62-3.69(m，2H)，3.34-3.41(m，1H)，3.11-3.24(m，4H)，2.73(td，J＝12.0Hz，2.0Hz，2H)，2.20-2.43(m，3H)，2.12(d，J＝7.2Hz，2H)，1.68-1.86(m，11H)，1.52-1.63(m，1H)，1.48(d，J＝6.8Hz，3H)，1.37(d，J＝6.4Hz，3H)，1.11-1.21(m，2H)，1.06(d，J＝6.8Hz，3H)，0.70(d，J＝6.4Hz，3H)。
Example 3:2- ((5- (7- ((1- ((6-acryloyl-2, 6-diazaspiro [3.3 ]))]Heptane-2-yl) sulfonyl group Piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) -1,2, 4-triazin-6-yl-oxy) -5-fluoro-N, N-di Isopropyl benzamide
Step 1:6- ((4- ((2- (6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 5 and intermediate 7, to give the target compound. MS m/z [ LC-MS ]:800.43[ M+1].
Step 2:2- ((5- (7- ((1- ((2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:700.38[ M+1].
Step 3:2- ((5- (7- ((1- ((6-propenoyl-2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：754.39[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.43(s，1H)，7.21-7.25(m，1H)，7.06-7.11(m，1H)，6.94(dd，J＝8.0Hz，2.8Hz，1H)，6.31(dd，J＝16.8Hz，1.6Hz，1H)，6.12(dd，J＝16.8Hz，10.4Hz，1H)，5.68(dd，J＝10.4Hz，1.6Hz，1H)，4.45(d，J＝10.4Hz，1H)，4.25-4.29(m，3H)，4.17(s，2H)，3.94-4.00(m，4H)，3.66-3.90(m，5H)，3.34-3.40(m，1H)，.70(td，J＝12.0Hz，2.0Hz，2H)，2.22-2.43(m，3H)，2.12(d，J＝7.2Hz，2H)，1.68-1.90(m，7H)，1.52-1.61(m，1H)，1.48(d，J＝6.4Hz，3H)，1.36(d，J＝6.8Hz，3H)，1.10-1.20(m，2H)，1.06(d，J＝6.8Hz，3H)，0.69(d，J＝6.4Hz，3H)。
Example 4:2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -4- (dimethylamino) but-2-enoyl) -2, 5-dio-ne) Azabicyclo [2.2.1]Heptane-2-yl) sulfonyl-4-fluoropiperidin-4-yl) methyl-2, 7-diazaspiro [3.5]Nonane-2- Group) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1: (1S, 4S) -5- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -4-fluoropiperidin-1-yl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 8, to give the target compound. MS m/z [ LC-MS ]:817.42[ M+1].
Step 2:2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) sulfonyl) -4-fluoropiperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:717.37[ M+1].
Step 3:2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -4- (dimethylamino) but-2-enoyl) -2, 5-diazabicyclo [2.2.1] heptane-2-yl) sulfonyl) -4-fluoropiperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the title compound was obtained starting from the product of step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride. MS m/z [ LC-MS ]：828.44[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，6.90-7.00(m，3H)，6.74-6.77(m，1H)，6.29(d，J＝15.2Hz，0.3H)，6.12(d，J＝15.2Hz，0.7H)，4.97(s，0.7H)，4.65(s，0.3H)，4.42(s，0.7H)，4.40(s，0.3H)，3.73-4.01(m，5H)，3.22-3.66(m，7H)，2.98-3.11(m，4H)，2.38-2.48(m，4H)，2.27(s，1.8H)，2.25(s，4.2H)，1.56-2.02(m，12H)，1.53(d，J＝6.8Hz，3H)，1.47(d，J＝6.8Hz，3H)，1.12(d，J＝6.8Hz，3H)，1.08(d，J＝6.8Hz，3H)。
Example 5:(S) -5-fluoro-N, N-diisopropyll-2- ((5- (3- ((9- ((5-methylpyrimidin-2-yl) amino) -3-) Azaspiro [5.5 ]]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
Intermediate 10 (57 mg), 2-bromo-5-methylpyrimidine (21 mg), cuprous iodide (6 mg), and cesium carbonate (98 mg) were added to dioxane (3 mL) under nitrogen, and refluxed for 24 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 12:1) to give the objective compound (30 mg). MS m/z [ LC-MS]：660.42[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.49(s，1H)，8.09(s，2H)，7.19-7.25(m，1H)，7.06-7.12(m，1H)，6.93-6.96(m，1H)，4.91(d，J＝8.4Hz，1H)，3.46-3.96(m，5H)，3.26-3.42(m，2H)，1.55-2.72(m，22H)，1.48(d，J＝6.4Hz，3H)，1.18-1.36(m，5H)，1.07-1.08(m，3H)，0.70-0.76(m，3H)。
Example 6:(S) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (3- ((9- ((3, 4,5, 6-tetrahydropyridine) -2 ] Group) amino) -3-azaspiro [5.5]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) benzyl Amides and their use
Intermediate 11 (55 mg), diisopropylethylamine (65 mg) and 6-chloro-2, 3,4, 5-tetrahydropyridine (0.1 mmol) were added to acetonitrile (3 mL), heated to 60 ℃ and stirred for 4 hours. Filtration, concentration of the filtrate under reduced pressure and separation by silica gel column chromatography (dichloromethane/methanol, 10:1) gave the title compound (28 mg). MS m/z [ LC-MS]：635.42[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.80-8.98(brs，0.3H)，8.51(s，0.7H)，7.09-7.29(m，2H)，6.95-7.04(m，1H)，3.75-4.62(m，3H)，2.74-3.69(m，10H)，2.65-2.72(m，0.6H)，2.49-2.56(m，1.4H)，2.28-2.46(m，1H)，1.46-2.14(m，22H)，0.99-1.14(m，6H)，0.70-0.82(m，3H)。
Example 7:(S) -5-fluoro-N, N-diisopropyll-2- ((5- (3- ((9- ((3, 4,5, 6-tetrahydropyridin-2-yl) ammonia) Radical) -3-azaspiro [5.5]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
Referring to the method in example 6, the objective compound was obtained starting from intermediate 10. MS m/z [ LC-MS]：649.44[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.89-9.08(s，0.3H)，8.51(s，0.7H)，7.19-7.30(m，1H)，7.08-7.16(m，1H)，6.90-6.97(m，1H)，3.96-4.73(m，2H)，2.74-3.90(m，13H)，2.64-2.73(m，0.6H)，2.48-2.56(m，1.4H)，2.26-2.45(m，1H)，1.52-2.18(m，19H)，1.42-1.50(m，3H)，1.29-1.33(m，3H)，1.06-1.11(m，3H)，0.68-0.75(m，3H)。
Example 8:(S) -2- ((4- (3- ((9- ((1, 2, 4-triazin-5-yl) amino) -3-azaspiro [ 5.5)]Undecane- 3-yl) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1: (S) -2- ((4- (3- ((9- ((3, 6-dichloro-1, 2, 4-triazin-5-yl) amino) -3-azaspiro [5.5] undecan-3-yl) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 1 in intermediate 5, starting from intermediate 13 and 3,5, 6-trichloro-1, 2, 4-triazine, the target compound is obtained. MS m/z [ LC-MS ]:714.32[ M+1].
Step 2: (S) -2- ((4- (3- ((9- ((1, 2, 4-triazin-5-yl) amino) -3-azaspiro [5.5] undecan-3-yl) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the method of step 3 in intermediate 5, the product of step 1 is used as a raw material to obtain the target compound. MS m/z [ LC-MS]：646.40[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.72(s，1H)，8.55(s，1H)，8.43(s，0.5H)，8.42(s，0.5H)，7.85(s，1H)，6.92-7.01(m，2H)，6.67-6.70(m，0.5H)，6.52-6.55(m，0.5H)，3.41-4.10(m，6H)，2.58-3.18(m，8H)，2.14-2.26(m，1H)，1.56-2.06(m，14H)，1.50-1.53(m，3H)，1.45(d，J＝7.2Hz，3H)，1.12-1.19(m，6H)。
Example 9:(S) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (3- ((9- ((1, 4,5, 6-tetrahydropyrimidine-2-)) Group) amino) -3-azaspiro [5.5]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) benzyl Amides and their use
Reference implementationThe procedure described in example 6 gave the title compound starting from 2-chloro-1, 4,5, 6-tetrahydropyrimidine. MS m/z [ LC-MS]：636.42[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.48(s，1H)，7.96(s，1H)，7.88(s，1H)，7.09-7.30(m，2H)，6.96-7.03(m，1H)，3.24-4.52(m，12H)，2.66-3.17(m，8H)，2.24-2.34(m，1H)，1.53-1.92(m，12H)，1.30-1.48(m，2H)，1.02-1.12(m，6H)，0.70-0.80(m，3H)。
Example 10:2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -4- (dimethylamino) but-2-enoyl) -2, 5-) Diazabicyclo [2.2.1]Heptane-2-yl) sulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1: (1S, 4S) -5- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -3, 6-dihydropyridin-1 (2H) -yl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 14, to give the target compound. MS m/z [ LC-MS ]:797.42[ M+1].
Step 2:2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) sulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:697.37[ M+1].
Step 3:2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -4- (dimethylamino) but-2-enoyl) -2, 5-diazabicyclo [2.2.1] heptane-2-yl) sulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the title compound was obtained starting from the product of step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride. MS m/z [ LC-MS]：808.43[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.34(s，1H)，7.74(s，1H)，6.89-7.00(m，3H)，6.74-6.78(m，1H)，6.31(d，J＝15.2Hz，0.3H)，6.12(d，J＝15.2Hz，0.7H)，5.53(s，1H)，4.96(s，0.7H)，4.65(s，0.3H)，4.43(s，0.7H)，4.40(s，0.3H)，3.62-4.05(m，8H)，3.42-3.53(m，2.3H)，3.21-3.37(m，3.7H)，3.07-3.11(m，2H)，2.80(s，2H)，1.80-2.36(m，14H)，1.69-1.78(m，4H)，1.52(d，J＝6.8Hz，3H)，1.46(d，J＝6.8Hz，3H)，1.11(d，J＝6.8Hz，3H)，1.07(d，J＝6.8Hz，3H)。
Example 11:5-fluoro-N, N-diisopropyll-2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -4- (piperidine-1-)) p-packet) Group) but-2-enoyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-di Azaspiro [3.5]]Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide
2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [ 2.2.1))]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride (50 mg), diisopropylethylamine (48 mg), (E) -4- (piperidin-1-yl) but-2-enoic acid (16 mg) and 2- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (35 mg) were added to N, N-dimethylformamide (2 mL), and heated to 60℃and stirred for 2 hours. The reaction solution was poured into water (20 mL), extracted with ethyl acetate, and the extracts were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 10:1) to give the objective compound (22 mg). MS m/z [ LC-MS ]：850.48[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.37(s，1H)，7.64-7.90(brs，1H)，7.05-7.10(m，1H)，6.90-7.01(m，2H)，6.64-6.76(m，1.4H)，6.39(d，J＝15.2Hz，0.6H)，4.84(s，0.6H)，4.70(s，0.4H)，3.93-4.54(m，6H)，3.56-3.72(m，5H)，3.14-3.54(m，9H)，2.63-2.94(m，8H)，1.72-2.32(m，14H)，1.43(d，J＝6.0Hz，3H)，1.33(d，J＝6.0Hz，3H)，1.20-1.30(m，2H)，1.09(d，J＝6.0Hz，3H)，0.94(d，J＝6.0Hz，3H)。
Example 12:2- ((5- (7- ((1- ((3-acrylamidoazetidin-1-yl) sulfonyl) piperidin-4-yl) Methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) -1,2, 4-triazin-6-yl-oxy) -5-fluoro-N, N-diisopropylbenzene Amides and their use
Step 1: (1- ((4- ((2- (6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) azetidin-3-yl) carbamic acid tert-butyl ester
The objective compound was obtained by the method of step 1 in example 1 starting from intermediate 5 and intermediate 15. MS m/z [ LC-MS ]:774.41[ M+1].
Step 2:2- ((5- (7- ((1- ((3-aminoazetidin-1-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:674.36[ M+1].
Step 3:2- ((5- (7- ((1- ((3-acrylamidoazetidin-1-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：728.37[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.44(s，1H)，7.22-7.26(m，1H)，7.06-7.11(m，1H)，6.94(dd，J＝8.0Hz，3.2Hz，1H)，6.41(d，J＝7.6Hz，1H)，6.30(dd，J＝17.2Hz，1.2Hz，1H)，6.08(dd，J＝17.2Hz，10.0Hz，1H)，5.67(dd，J＝10.0Hz，1.2Hz，1H)，4.74-4.83(m，1H)，4.46(d，J＝10.0Hz，1H)，4.27(d，J＝10.0Hz，1H)，4.05(t，J＝8.0Hz，2H)，3.66-3.90(m，7H)，3.34-3.41(m，1H)，2.71(td，J＝12.0HZ，1.6Hz，2H)，1.98-2.48(m，3H)，2.12(d，J＝7.2Hz，2H)，1.68-1.87(m，7H)，1.51-1.62(m，1H)，1.49(d，J＝7.2Hz，3H)，1.37(d，J＝6.8Hz，3H)，1.10-1.22(m，2H)，1.06(d，J＝6.8Hz，3H)，0.69(d，J＝6.0Hz，3H)。
Example 13:5-fluoro-N, N-diisopropyl-2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -4- (pyrrolidin-1-)) and) Group) but-2-enoyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-di Azaspiro [3.5 ]]Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide
Reference is made to the procedure in example 11 as 2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E) -4- (pyrrolidin-1-yl) but-2-enoic acid were used as starting materials to give the target compound. MS m/z [ LC-MS]：836.47[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.44(s，1H)，7.80-7.88(s，1H)，7.11-7.15(m，1H)，6.99-7.01(m，2H)，6.78-6.88(m，1.3H)，6.50(d，J＝16.0Hz，0.7H)，4.95(s，0.7H)，4.72(s，0.3H)，4.42(s，0.3H)，4.38(s，0.7H)，4.03-4.26(m，2H)，3.18-3.91(m，14H)，2.58-2.96(m，11H)，2.30-2.44(m，2H)，1.83-2.20(m，12H)，1.49(d，J＝6.8Hz，3H)，1.38(d，J＝6.8Hz，3H)，1.16(d，J＝6.8Hz，3H)，0.95(d，J＝6.8Hz，3H)。
Example 14:(S) -5-fluoro-N, N-diisopropyll-2- ((5- (3- ((9- ((pyridin-2-yl) amino) -3-nitrogen)Impurity(s) Spiro [5.5 ]]Undecan-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
Referring to the procedure in example 5, starting from intermediate 10 and 2-bromopyridine the title compound was obtained. MS m/z [ LC-MS]：645.40[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.48(s，1H)，8.02(d，J＝4.4Hz，1H)，7.38-7.42(m，1H)，7.18-7.24(m，1H)，7.07-7.12(m，1H)，6.92-6.96(m，1H)，6.51-6.54(m，1H)，6.35(d，J＝8.8Hz，1H)，4.66-4.84(m，1H)，4.28-4.48(m，1H)，4.06-4.25(m，1H)，3.26-3.98(m，5H)，2.24-2.70(m，8H)，1.83-2.22(m，6H)，1.56-1.80(m，7H)，1.48(d，J＝6.8Hz，3H)，1.33-1.39(m，3H)，1.04-1.08(m，3H)，0.70-0.75(m，3H)。
Example 15:(S) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (3- ((9- ((pyridin-2-yl) amino) -3-nitrogen) Heterospiro [5.5 ]]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
The procedure of example 5 was followed, starting from intermediate 11 and 2-australine, to give the title compound. MS m/z [ LC-MS]：631.39[M+1]。 1 H NMR(400 MHz，CDCl 3 )：δ＝8.49(s，1H)，8.01(d，J＝4.4Hz，1H)，7.38-7.43(m，1H)，7.18-7.24(m，1H)，7.08-7.14(m，1H)，6.98-7.04(m，1H)，6.51-6.54(m，1H)，6.37(d，J＝8.4Hz，1H)，4.76-5.01(m，1H)，4.18-4.44(m，1H)，3.40-3.99(m，6H)，3.24-3.28(m，1H)，3.04-3.18(m，1H)，2.28-2.78(m，6H)，2.10-2.24(m，1H)，1.58-1.96(m，13H)，1.44-1.53(m，1H)，1.22-1.42(m，6H)，0.72-0.81(m，3H)。
Example 16:(E) 2- ((5- (7- ((1- ((3- (4- (dimethylamino) but-2-enamido) azetidine) amino) 1-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) -1,2, 4-triazin-6-yl) oxy Phenyl) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, 2- ((5- (7- ((1- ((3-aminoazetidin-1-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide salt and (E) -4- (dimethylamino) but-2-enoyl chloride are used as raw materials to obtain the target compound. MS m/z [ LC-MS]：785.43[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.44(s，1H)，7.22-7.26(m，1H)，7.06-7.11(m，1H)，6.94(dd，J＝8.0Hz，3.2Hz，1H)，6.80-6.87(m，1H)，6.25(d，J＝8.0Hz，1H)，5.95(d，J＝15.2Hz，1H)，4.72-4.82(m，1H)，4.46(d，J＝10.0Hz，1H)，4.27(d，J＝10.0Hz，1H)，4.05(t，J＝8.0Hz，2H)，3.66-3.90(m，7H)，3.34-3.41(m，1H)，3.05(d，J＝6.0Hz，2H)，2.71(td，J＝12.0Hz，2.0Hz，2H)，2.18-2.42(m，9H)，2.11(d，J＝7.2Hz，2H)，1.87-2.03(m，1H)，1.72-1.84(m，6H)，1.52-1.62(m，1H)，1.49(d，J＝6.8Hz，3H)，1.37(d，J＝6.8Hz，3H)，1.10-1.20(m，2H)，1.06(d，J＝6.8Hz，3H)，0.69(d，J＝6.8Hz，3H)。
Example 17:2- ((4- (7- ((1- ((6-acryloyl-2, 6-diazaspiro [3.3 ]))]Heptane-2-yl) sulfonyl Phenyl) -4-fluoropiperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N- Diisopropylbenzene formamide
Step 1:6- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -4-fluoropiperidin-1-yl) sulfonyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 8 and intermediate 7, to give the target compound. MS m/z [ LC-MS ]:817.42[ M+1].
Step 2:2- ((4- (7- ((1- ((2, 6-diazaspiro [3.3] heptane-2-yl) sulfonyl) -4-fluoropiperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:717.37[ M+1].
Step 3:2- ((4- (7- ((1- ((6-propenoyl-2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) -4-fluoropiperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：771.38[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.75(s，1H)，6.96-7.00(m，2H)，6.73-6.77(m，1H)，6.33(dd，J＝17.2Hz，1.6Hz，1H)，6.13(dd，J＝17.2Hz，10.4Hz，1H)，5.68(dd，J＝10.4Hz，1.6Hz，1H)，4.31(s，2H)，4.18(s，2H)，3.90-4.02(m，5H)，3.70-3.86(m，3H)，3.54-3.68(m，3H)，3.44-3.52(m，1H)，3.01-3.08(m，2H)，2.36-2.52(m，6H)，1.90-1.98(m，2H)，1.56-1.78(m，6H)，1.53(d，J＝6.8Hz，3H)，1.47(d，J＝6.8Hz，3H)，1.12(d，J＝6.4Hz，3H)，1.08(d，J＝6.4Hz，3H)。
Example 18:2- ((5- (7- ((1- (((1S, 4S) -5-propenoyl-2, 5-diazabicyclo [ 2.2.1)]Heptane- 2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) -3- (methylamino) -1,2, 4-tris Oxazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1: (1S, 4S) -5- ((4- ((2- (6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -3- (methylamino) -1,2, 4-triazin-5-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 16, to give the target compound. MS m/z [ LC-MS ]:829.46[ M+1].
Step 2:2- ((5- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -3- (methylamino) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:729.40[ M+1].
Step 3:2- ((5- (7- ((1- (((1S, 4S) -5-propenoyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) -3- (methylamino) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：783.41[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝7.15-7.19(m，1H)，7.00-7.05(m，1H)，6.91(dd，J＝8.0Hz，3.2Hz，1H)，6.39-6.43(m，1.3H)，6.28(dd，J＝16.8Hz，10.0Hz，0.7H)，5.71-5.74(m，1H)，4.98(s，0.7H)，4.62(s，0.3H)，4.43(s，0.7H)，4.41(s，0.3H)，4.33-4.39(m，1H)，4.14-4.21(m，1H)，3.64-3.86(m，6.7H)，3.30-3.53(m，4H)，3.22(d，J＝9.6Hz，0.3H)，2.92(d，J＝5.2Hz，3H)，2.70(t，J＝12.0Hz，2H)，2.22-2.42(m，3H)，2.12(d，J＝7.2Hz，2H)，1.54-2.07(m，10H)，1.50(d，J＝6.8Hz，3H)，1.42(d，J＝6.8Hz，3H)，1.11-1.22(m，2H)，1.05(d，J＝6.4Hz，3H)，0.83(d，J＝6.4Hz，3H)。
Example 19:2- ((5- ((S) -3- ((9- (((1S, 4S) -5-propenoyl-2, 5-diazabicyclo [ 2.2.1)] Heptane-2-sulfonamide) on the surface of the substrate3-azaspiro [5.5 ]]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl Oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1: (1S, 4S) -5- (N- (3- (((S) -1- (6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -3-azaspiro [5.5] undec-9-yl) sulfamoyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 10, to give the target compound. MS m/z [ LC-MS ]:828.46[ M+1].
Step 2:2- ((5- ((S) -3- ((9- ((1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-sulfonylamino) -3-azaspiro [5.5] undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:728.41[ M+1].
Step 3:2- ((5- ((S) -3- ((9- (((1S, 4S) -5-propenoyl-2, 5-diazabicyclo [2.2.1] heptane-2-sulfonylamino) -3-azaspiro [5.5] undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS ]:782.42[ M+1].
Example 20:2- ((4- (7- ((1- ((6-acryloyl-2, 6-diazaspiro [3.3 ]))]Heptane-2-yl) sulfonyl Phenyl) -1,2,3, 6-tetrahydropyridin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5- fluoro-N, N-diisopropylbenzamide
Step 1:6- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -3, 6-dihydropyridin-1 (2H) -yl) sulfonyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 14 and intermediate 7, to give the target compound. MS m/z [ LC-MS ]:797.42[ M+1].
Step 2:2- ((4- (7- ((1- ((2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:697.37[ M+1].
Step 3:2- ((4- (7- ((1- ((6-propenoyl-2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：751.38[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，6.95-7.00(m，2H)，6.74-6.77(m，1H)，6.29-6.34(m，1H)，6.12(dd，J＝16.8Hz，10.4Hz，1H)，5.68(dd，J＝10.4Hz，2.0Hz，1H)，5.53(m，1H)，4.30(s，1.6H)，4.17(s，1.6H)，3.90-4.01(m，5H)，3.84-3.86(m，2H)，3.71-3.80(m，4H)，3.63-3.66(m，0.8H)，3.44-3.50(m，1H)，3.31(t，J＝5.6Hz，2H)，2.80(s，2H)，2.07-2.40(m，6H)，1.70-1.76(m，4H)，1.52(d，J＝6.8Hz，3H)，1.46(d，J＝6.4Hz，3H)，1.12(d，J＝6.4Hz，3H)，1.07(d，J＝6.4Hz，3H)。
Example 21:(R) -2- ((4- (7- ((1- ((6-propenoyl-2, 6-diazaspiro [3.3 ])]Heptane-2-yl) sulfonic acid Acyl) pyrrolidin-3-yl-methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-di Isopropyl benzamide
Step 1: (R) -6- ((3- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyrrolidin-1-yl) sulfonyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 17 and intermediate 7, to give the target compound. MS m/z [ LC-MS ]:785.42[ M+1].
Step 2: (R) -2- ((4- (7- ((1- ((2, 6-diazaspiro [3.3] heptane-2-yl) sulfonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:685.37[ M+1].
Step 3: (R) -2- ((4- (7- ((1- ((6-propenoyl-2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：739.38[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.75(s，1H)，6.96-7.00(m，2H)，6.74-6.77(m，1H)，6.29-6.35(m，1H)，6.09-6.18(m，1H)，5.68(dd，J＝10.4Hz，1.6Hz，1H)，4.31(s，1.4H)，4.18(s，1.4H)，3.90-4.02(m，4.6H)，3.64-3.87(m，5H)，3.34-3.51(m，3.6H)，3.24-3.30(m，1H)，2.98-3.02(m，1H)，2.18-2.48(m，6H)，1.95-2.05(m，1H)，1.58-1.82(m，6H)，1.53(d，J＝6.8Hz，3H)，1.47(d，J＝6.4Hz，3H)，1.12(d，J＝6.4Hz，3H)，1.08(d，J＝6.4Hz，3H)。
Example 22:(E) -2- ((4- (7- ((1- ((2- (4- (dimethylamino) but-2-enoyl) -2, 7-di)Azaspiro compounds [3.5]Nonan-7-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy Phenyl) -5-fluoro-N, N-diisopropylbenzamide
Step 1:7- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 6, to give the target compound. MS m/z [ LC-MS ]:827.47[ M+1].
Step 2:2- ((4- (7- ((1- ((2, 7-diazaspiro [3.5] nonan-7-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:727.41[ M+1].
Step 3: (E) -2- ((4- (7- ((1- ((2- (4- (dimethylamino) but-2-enoyl) -2, 7-diazaspiro [3.5] nonan-7-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the title compound was obtained starting from the product of step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride. MS m/z [ LC-MS]：838.48[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.34(s，1H)，7.74(s，1H)，6.94-6.99(m，2H)，6.82-6.89(m，1H)，6.73-6.77(m，1H)，6.01(d，J＝15.6Hz，1H)，3.82-4.02(m，6H)，3.72-3.80(m，3H)，3.61-3.68(m，2H)，3.43-3.50(m，1H)，3.10-3.24(m，4H)，3.05(dd，J＝6.4Hz，1.2Hz，2H)，2.68-2.76(m，2H)，2.19-2.35(m，10H)，2.11(d，J＝7.6Hz，2H)，1.68-1.84(m，11H)，1.52(d，J＝6.8Hz，3H)，1.46(d，J＝6.4Hz，3H)，1.12-1.22(m，2H)，1.11(d，J＝6.4Hz，3H)，1.07(d，J＝6.4Hz，3H)。
Example 23:(E) -2- ((4- (7- ((1- ((6- (4- (dimethylamino) but-2-enoyl) -2, 6-diazaspiro) 1) [3.3]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy Phenyl) -5-fluoro-N, N-diisopropylbenzamide
Step 1:6- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 7, to give the target compound. MS m/z [ LC-MS ]:799.73[ M+1].
Step 2:2- ((4- (7- ((1- ((2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:699.38[ M+1].
Step 3: (E) -2- ((4- (7- ((1- ((6- (4- (dimethylamino) but-2-enoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the title compound was obtained starting from the product of step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride. MS m/z [ LC-MS]：810.45[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.75(s，1H)，6.95-6.99(m，2H)，6.82-6.88(m，1H)，6.74-6.77(m，1H)，5.98(d，J＝15.6Hz，1H)，4.29(s，2H)，4.15(s，2H)，3.90-3.99(m，5H)，3.84-3.86(m，2H)，3.74-3.80(m，1H)，3.65-3.73(m，2H)，3.44-3.51(m，1H)，3.14-3.16(m，2H)，3.06(d，J＝4.8Hz，2H)，2.67-2.74(m，2H)，2.21-2.32(m，8H)，2.11(d，J＝7.2Hz，2H)，1.69-1.82(m，6H)，1.50-1.54(m，5H)，1.47(d，J＝6.8Hz，3H)，1.13-1.20(m，2H)，1.12(d，J＝6.4Hz，3H)，1.08(d，J＝6.4Hz，3H)。
Example 24:(E) -2- ((4- (7- ((1- ((6- (2-cyano-4, 4-dimethylpent-2-enoyl) -2, 6-dinitrogen) Heterospiro [3.3]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidine-5- Group) oxy) -5-fluoro-N, N-diisopropylbenzamide
Reference is made to the procedure of step 3 of example 1, followed by 2- ((4- (7- ((1- ((2, 6-diazaspiro [3.3 ])]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E) -2-cyano-4, 4-dimethylpent-2-enoyl chloride as raw materials to obtain the target compound. MS m/z [ LC-MS]：834.45[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.38(s，1H)，7.79(s，1H)，7.54(s，1H)，6.95-7.01(m，2H)，6.72-6.75(m，1H)，4.62(s，1.7H)，4.20(s，1.7H)，3.94-4.06(m，4.6H)，3.87-3.89(m，2H)，3.67-3.81(m，3H)，3.45-3.52(m，1H)，3.10-3.17(m，2H)，2.24-2.80(m，6H)，1.58-1.96(m，11H)，1.52(d，J＝7.2Hz，3H)，1.46(d，J＝6.4Hz，3H)，1.28(s，9H)，1.12(d，J＝6.8Hz，3H)，1.09(d，J＝6.8Hz，3H)。
Example 25:(E) 2- ((4- (7- ((1- ((3- (4- (dimethylamino) but-2-enamido) azetidine) amino) 1-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro- & ltp & gt N, N-diisopropylbenzamide
Step 1: (1- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) azetidin-3-yl) carbamic acid tert-butyl ester
The objective compound was obtained by referring to the procedure of step 1 in example 1, starting from intermediate 3 and intermediate 15. MS m/z [ LC-MS ]:773.42[ M+1].
Step 2:2- ((4- (7- ((1- ((3-aminoazetidin-1-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:673.37[ M+1].
Step 3: (E) -2- ((4- (7- ((1- ((3- (4- (dimethylamino) but-2-enamido) azetidin-1-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the title compound was obtained starting from the product of step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride. MS m/z [ LC-MS]：784.43[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，6.95-7.00(m，2H)，6.80-6.87(m，1H)，6.74-6.78(m，1H)，6.16(d，J＝8.0Hz，1H)，5.94(d，J＝15.6Hz，1H)，4.73-4.82(m，1H)，4.04-4.08(m，2H)，3.84-4.00(m，3H)，3.66-3.80(m，4H)，3.44-3.50(m，1H)，3.14-3.16(m，2H)，3.04-3.06(m，2H)，2.67-2.74(m，2H)，2.22-2.34(m，8H)，2.10(d，J＝7.2Hz，2H)，1.84-2.06(m，3H)，1.71-1.80(m，6H)，1.52(d，J＝7.2Hz，3H)，1.47(d，J＝6.4Hz，3H)，1.15-1.22(m，2H)，1.12(d，J＝6.4Hz，3H)，1.08(d，J＝6.4Hz，3H)。
Example 26:2- ((4- (7- ((1- ((2-propenoyl-2, 6-diazaspiro [3.4 ]))]Octane-6-yl) sulfonyl group Piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropyl Benzamide compound
Step 1:6- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 18, to give the target compound. MS m/z [ LC-MS ]:813.45[ M+1].
Step 2:2- ((4- (7- ((1- ((2, 6-diazaspiro [3.4] oct-6-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:713.40[ M+1].
Step 3:2- ((4- (7- ((1- ((2-propenoyl-2, 6-diazaspiro [3.4] oct-6-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：767.41[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，6.95-7.00(m，2H)，6.73-6.77(m，1H)，6.33(dd，J＝16.8Hz，2.0Hz，1H)，6.15(dd，J＝16.8Hz，10.4Hz，1H)，6.57(dd，J＝10.4Hz，2.0Hz，1H)，4.16(d，J＝8.4Hz，1H)，4.07(d，J＝8.4Hz，1H)，3.89-4.02(m，4H)，3.84-3.86(m，2H)，3.73-3.80(m，1H)，3.63-3.70(m，2H)，3.43-3.50(m，2H)，3.33-3.39(m，3H)，2.68-2.76(m，2H)，2.18-2.43(m，4H)，2.06-2.17(m，4H)，1.68-1.95(m，7H)，1.52(d，J＝6.8Hz，3H)，1.46(d，J＝6.8Hz，3H)，1.12-1.21(m，2H)，1.11(d，J＝6.8Hz，3H)，1.07(d，J＝6.8Hz，3H)。
Example 27:2- ((4- (7- ((1- ((2-propenoyl))2, 6-diazaspiro [3.5]]Non-6-yl) sulfonyl) piperazine Pyridin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzene Formamide
Step 1:6- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 6-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 19, to give the target compound. MS m/z [ LC-MS ]:827.47[ M+1].
Step 2:2- ((4- (7- ((1- ((2, 6-diazaspiro [3.5] non-6-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:727.41[ M+1].
Step 3:2- ((4- (7- ((1- ((2-propenoyl-2, 6-diazaspiro [3.5] non-6-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：781.42[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，6.95-7.00(m，2H)，6.73-6.77(m，1H)，6.32(dd，J＝16.8Hz，1.6Hz，1H)，6.16(dd，J＝16.8Hz，10.4Hz，1H)，5.66(dd，J＝10.4Hz，1.6Hz，1H)，3.89-4.04(m，3H)，3.69-3.86(m，6H)，3.61-3.68(m，2H)，3.44-3.50(m，1H)，3.36(d，J＝12.0Hz，1H)，3.21-3.27(m，1H)，3.14(d，J＝12.0Hz，1H)，3.00-3.06(m，1H)，2.71-2.78(m，2H)，2.18-2.44(m，4H)，2.10-2.12(m，2H)，1.56-1.90(m，11H)，1.52(d，J＝6.4Hz，3H)，1.46(d，J＝6.4Hz，3H)，1.25-1.31(m，2H)，1.11(d，J＝6.8Hz，3H)，1.07(d，J＝6.8Hz，3H)。
Example 28:5-fluoro-N, N-diisopropyl-2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -3- (pyridin-3-)) and) Group) acryl) -2, 5-diazabicyclo [2.2.1]Heptane-2-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diaza Spiro [3.5]]Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide
Reference is made to the procedure in example 11 as 2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [ 2.2.1) ]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E) -3- (pyridin-3-yl) acrylic acid as starting materials to give the target compound. MS m/z [ LC-MS]：830.42[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.71-8.74(m，1H)，8.52-8.57(m，1H)，8.32(s，1H)，7.77-7.82(m，1H)，7.65-7.72(m，2H)，7.26-7.30(m，1H)，6.93-6.97(m，2H)，6.71-6.78(m，1.3H)，6.60(d，J＝15.6Hz，0.7H)，5.00(s，0.7H)，4.72(s，0.3H)，4.44(s，0.7H)，4.41(s，0.3H)，3.80-4.04(m，4.7H)，3.58-3.78(m，4H)，3.37-3.53(m，3H)，3.26(d，J＝8.8Hz，0.3H)，2.64-2.72(m，2H)，2.14-2.38(m，4H)，1.90-2.09(m，4H)，1.64-1.87(m，7H)，1.50(d，J＝6.8Hz，3H)，1.44(d，J＝6.4Hz，3H)，1.12-1.20(m，2H)，1.09(d，J＝6.4Hz，3H)，1.09(d，J＝6.4Hz，3H)。
Example 29:5-fluoro-N, N-diisopropyl-2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -3- ((S) -1-A)) Pyrrolidin-2-yl) acryl) -2, 5-diazabicyclo [2.2.1]Heptane-2-yl) sulfonyl) piperidin-4-yl) methyl Radical) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide
Reference is made to the procedure in example 11 as 2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride and intermediate 20 were used as starting materials to give the target compound. MS m/z [ LC-MS]：836.47[M+1]。 1 H NMR(400MHz，CD 3 OD)：δ＝8.52(s，1H)，7.75-7.99(m，1H)，7.21-7.27(m，3H)，6.85(d，J＝15.2Hz，0.5H)，6.69-6.75(m，1H)，6.61(d，J＝15.2Hz，0.5H)，4.86-4.91(m，1H)，4.10-4.64(m，5H)，3.96-4.06(m，1H)，3.53-3.87(m，9H)，3.43-3.48(m，1H)，3.28-3.38(m，2H)，3.16-3.25(m，1H)，2.95-3.10(m，4H)，2.78-2.89(m，5H)，2.36-2.46(m，1H)，1.92-2.32(m，11H)，1.81-1.88(m，2H)，1.51(d，J＝6.4Hz，3H)，1.43(d，J＝6.4Hz，3H)，1.19(d，J＝6.8Hz，3H)，1.08(d，J＝6.8Hz，3H)。
Example 30:5-fluoro-N, N-diisopropyl-2- ((4- (7- ((1- (((1S, 4S) -5- ((E) -3- ((R) -1-A) Pyrrolidin-2-yl) acryl) -2, 5-diazabicyclo [2.2.1]Heptane-2-yl) sulfonyl) piperidin-4-yl) methyl Radical) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) benzamide
Reference is made to the procedure in example 11 as 2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride and intermediate 21 were used as starting materials to give the target compound. MS m/z [ LC-MS]：836.47[M+1]。 1 H NMR(400MHz，CD 3 OD)：δ＝8.52(s，1H)，7.75-7.99(m，1H)，7.21-7.27(m，3H)，6.85(d，J＝15.2Hz，0.5H)，6.69-6.75(m，1H)，6.61(d，J＝15.2Hz，0.5H)，4.86-4.91(m，1H)，4.10-4.64(m，5H)，3.96-4.06(m，1H)，3.53-3.87(m，9H)，3.43-3.48(m，1H)，3.28-3.38(m，2H)，3.16-3.25(m，1H)，2.95-3.10(m，4H)，2.78-2.89(m，5H)，2.36-2.46(m，1H)，1.92-2.32(m，11H)，1.81-1.88(m，2H)，1.51(d，J＝6.4Hz，3H)，1.43(d，J＝6.4Hz，3H)，1.19(d，J＝6.8Hz，3H)，1.08(d，J＝6.8Hz，3H)。
Example 31:2- ((4- (7- ((1- (((1S, 4S) -5-propenoyl-2, 5-diazabicyclo [ 2.2.1))]Heptane- 2-yl) sulfonyl) -4-methoxypiperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy Phenyl) -N-ethyl-5-fluoro-N-isopropylbenzamide
Step 1: (1S, 4S) -5- ((4- ((2- (5- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -4-methoxypiperidin-1-yl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 23, to give the target compound. MS m/z [ LC-MS ]:815.43[ M+1].
Step 2:2- ((4- (7- ((1- (((1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) sulfonyl) -4-methoxypiperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:715.38[ M+1].
Step 3:2- ((4- (7- ((1- (((1S, 4S) -5-propenoyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) sulfonyl) -4-methoxypiperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS ]:769.39[ M+1].
Example 32:2-((4-(7-(4- ((6-propenoyl-2, 6-diazaspiro [ 3.3)]Heptane-2-yl) sulfonyl group Benzyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1:4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) benzenesulfonyl fluoride
Intermediate 2 (442 mg), 4- (bromomethyl) benzenesulfonyl chloride (270 mg) and potassium carbonate (700 mg) were added to acetonitrile (10 mL), stirred at 60 ℃ for 2 hours, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane/methanol, 15:1) to give the objective compound (570 mg). MS m/z [ LC-MS ]:630.23[ M+1].
Step 2:6- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) phenyl) sulfonyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
The target compound was obtained by the method of step 1 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:792.39[ M+1].
Step 3:2- ((4- (7- (4- ((diazaspiro [3.3] heptane-2-yl) sulfonyl) benzyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The target compound was obtained by the method of step 2 in example 1 starting from the product of step 2. MS m/z [ LC-MS ]:692.34[ M+1].
Step 4:2- ((4- (7- (4- ((6-propenoyl-2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) benzyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 3 and acryloyl chloride. MS m/z [ LC-MS]：746.35[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74-7.77(m，3H)，7.52(d，J＝8.4Hz，2H)，6.95-7.00(m，2H)，6.74-6.77(m，1H)，6.28(dd，J＝17.2Hz，1.6Hz，1H)，6.06(dd，J＝17.2Hz，10.8Hz，1H)，5.65(dd，J＝10.8Hz，1.6Hz，1H)，4.19(s，2H)，3.84-4.04(m，10H)，3.74-3.81(m，1H)，3.53(s，2H)，3.44-3.51(m，1H)，2.24-2.46(m，4H)，1.74-1.84(m，4H)，1.53(d，J＝6.8Hz，3H)，1.47(d，J＝6.8Hz，3H)，1.12(d，J＝6.8Hz，3H)，1.07(d，J＝6.8Hz，3H)。
Example 33:2- ((4- (7- ((1- ((1-propenoylpiperidin-4-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1:4- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) piperidine-1-carboxylic acid tert-butyl ester
The procedure of step 1 of example 1 was followed using intermediate 3 and tert-butyl 4- (chlorosulfonyl) piperidine-1-carboxylate as starting materials to give the title compound. MS m/z [ LC-MS ]:786.44[ M+1].
Step 2: 5-fluoro-N, N-diisopropyl-2- ((4- (7- ((1- (piperidin-4-ylsulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) benzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:686.39[ M+1].
Step 3:2- ((4- (7- ((1- ((1-propenoylpiperidin-4-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：740.40[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，6.95-7.00(m，2H)，6.73-6.77(m，1H)，6.54(dd，J＝16.8Hz，10.4Hz，1H)，6.27(dd，J＝16.8Hz，1.6Hz，1H)，5.70(dd，J＝10.4Hz，2.4Hz，1H)，4.70-4.80(m，1H)，4.04-4.14(m，1H)，3.82-4.00(m，4H)，3.72-3.81(m，3H)，3.44-3.50(m，1H)，3.00-3.14(m，2H)，2.84(t，J＝12.0Hz，2H)，2.58-2.70(m，1H)，2.03-2.40(m，8H)，1.66-1.92(m，9H)，1.52(d，J＝6.8Hz，3H)，1.46(d，J＝6.8Hz，3H)，1.12-1.22(m，2H)，1.12(d，J＝6.8Hz，3H)，1.07(d，J＝6.8Hz，3H)。
Example 34:2- ((4- (7- ((1- (N- (1-propenoylazetidin-3-yl) sulfamido) piperidine-4-) Methyl) -2, 7-diazaspiro [3.5 ]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1:3- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidine) -1-sulfonylamino) azetidine-1-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 24, to give the target compound. MS m/z [ LC-MS ]:773.42[ M+1].
Step 2:2- ((4- (7- ((1- (N- (azetidin-3-yl) sulfamido) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:673.37[ M+1].
Step 3:2- ((4- (7- ((1- (N- (1-propenoylazetidin-3-yl) sulfamido) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Reference to the procedure of step 3 of example 1, starting from the product of step 2 and acrylic acid chlorideTo the target compound. MS m/z [ LC-MS]：727.38[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.36(s，1H)，7.75(s，1H)，6.95-7.00(m，2H)，6.74-6.78(m，1H)，6.33(dd，J＝16.8Hz，1.6Hz，1H)，6.13(dd，J＝16.8Hz，10.4Hz，1H)，5.69(d，J＝10.4Hz，1.6Hz，1H)，4.76-4.88(brs，1H)，4.44-4.52(m，1H)，4.32-4.40(m，1H)，4.18-4.26(m，1H)，3.62-4.14(m，9H)，3.44-3.51(m，1H)，2.68(t，J＝12.0Hz，2H)，2.20-2.42(m，4H)，2.08-2.18(m，2H)，1.66-1.88(m，7H)，1.53(d，J＝6.8Hz，3H)，1.47(d，J＝6.8Hz，3H)，1.12-1.22(m，2H)，1.12(d，J＝6.4Hz，3H)，1.08(d，J＝6.4Hz，3H)。
Example 35:2- ((4- (7- ((1- (N- ((1-propenoylazetidin-3-yl) methyl) -N-methylsulfonyl) Amino) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diiso Propyl benzamide
Step 1:3- (((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -N-methylpiperidine) -1-sulfonylamino) methyl) azetidine-1-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 25, to give the target compound. MS m/z [ LC-MS ]:801.45[ M+1].
Step 2:2- ((4- (7- ((1- (N- (azetidin-3-ylmethyl) -N-methylsulfonylmethyl) -piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:701.40[ M+1].
Step 3:2- ((4- (7- ((1- (N- ((1-propenoylazetidin-3-yl) methyl) -N-methylsulfonamido) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS ]：755.41[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，6.95-7.00(m，2H)，6.74-6.77(m，1H)，6.31(dd，J＝16.8Hz，2.0Hz，1H)，6.15(dd，J＝16.8Hz，10.4Hz，1H)，5.65(dd，J＝10.4Hz，2.0Hz，1H)，4.28(t，J＝8.0Hz，1H)，4.13-4.17(m，1H)，3.89-4.01(m，2H)，3.82-3.88(m，2H)，3.72-3.81(m，2H)，3.55-3.63(m，2H)，3.44-3.54(m，2H)，3.27(dd，J＝14.0Hz，6.8Hz，1H)，2.88-2.96(m，1H)，2.78(s，3H)，2.74(td，J＝12.0Hz，1.6Hz，2H)，2.17-2.41(m，4H)，2.06-2.16(m，2H)，1.66-1.90(m，8H)，1.52(d，J＝6.8Hz，3H)，1.47(d，J＝6.8Hz，3H)，1.13-1.22(m，2H)，1.12(d，J＝6.8Hz，3H)，1.08(d，J＝6.8Hz，3H)。
Example 36:2- ((4- (7- ((1- ((2-propenoyl-5-oxa-2, 8-diazaspiro [3.5 ])]Nonan-8-yl Sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-di Isopropyl benzamide
Step 1:8- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -5-oxa-2, 8-diazaspiro [3.5] nonan-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 26, to give the target compound. MS m/z [ LC-MS ]:829.44[ M+1].
Step 2:2- ((4- (7- ((1- ((5-oxa-2, 8-diazaspiro [3.5] nonan-8-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:729.39[ M+1].
Step 3:2- ((4- (7- ((1- ((2-propenoyl-5-oxa-2, 8-diazaspiro [3.5] nonan-8-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：783.40[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.75(s，1H)，6.95-7.00(m，2H)，6.74-6.77(m，1H)，6.35(dd，J＝17.2Hz，2.0Hz，1H)，6.17(dd，J＝16.8Hz，10.4Hz，1H)，5.70(dd，J＝10.4Hz，2.0Hz，1H)，4.09(s，2H)，3.82-4.01(m，6H)，3.64-3.80(m，5H)，3.44-3.51(m，1H)，3.33(t，J＝12.0Hz，1H)，3.10-3.25(m，3H)，2.79(td，J＝12.4Hz，2.0Hz，2H)，2.18-2.39(m，4H)，2.08-2.16(m，2H)，1.68-1.84(m，6H)，1.55-1.65(m，1H)，1.52(d，J＝6.8Hz，3H)，1.47(d，J＝6.8Hz，3H)，1.12-1.22(m，2H)，1.12(d，J＝6.4Hz，3H)，1.08(d，J＝6.4Hz，3H)。
Example 37:(E) -5-fluoro-N, N-diisopropyl-2- ((4- (7- ((1- ((6- (3- (pyridin-3-yl) propenoyl) Radical) -2, 6-diazaspiro [3.3]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonane- 2-yl) pyrimidin-5-yl) oxy) benzamide
Reference is made to the procedure of step 3 of example 1, followed by 2- ((4- (7- ((1- ((2, 6-diazaspiro [3.3 ])]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E) -3- (pyridin-3-yl) acryloyl chloride as starting materials to give the target compound. MS m/z [ LC-MS]：830.42[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.70-8.72(m，1H)，8.53-8.57(m，1H)，8.33(s，1H)，7.75-7.79(m，1H)，7.73(s，1H)，7.61(d，J＝16.0Hz，1H)，7.27-7.31(m，1H)，6.93-6.98(m，2H)，6.73-6.76(m，1H)，6.55(d，J＝16.0Hz，0.2H)，6.46(d，J＝16.0Hz，0.8H)，4.38(s，2H)，4.21(s，2H)，3.88-4.03(m，5H)，3.63-3.86(m，6H)，3.42-3.49(m，1H)，2.70(td，J＝12.0Hz，1.6Hz，2H)，2.16-2.40(m，4H)，2.04-2.14(m，2H)，1.65-1.81(m，6H)，1.52-1.59(m，1H)，1.51(d，J＝6.8Hz，3H)，1.45(d，J＝6.8Hz，3H)，1.12-1.21(m，2H)，1.10(d，J＝6.8Hz，3H)，1.06(d，J＝6.8Hz，3H)。
Example 38:2- ((4- (7- ((1- ((2-propenoyl-2, 8-diazaspiro [4.5 ]))]Decane-8-yl) sulphonyl) Piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropyl Benzamide compound
Step 1:8- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 8-diazaspiro [4.5] decane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 27, to give the target compound. MS m/z [ LC-MS ]:841.48[ M+1].
Step 2:2- ((4- (7- ((1- ((2, 8-diazaspiro [4.5] decan-8-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:741.43[ M+1].
Step 3:2- ((4- (7- ((1- ((2-propenoyl-2, 8-diazaspiro [4.5] decan-8-yl) sulfonyl) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：795.44[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.30(s，1H)，7.70(s，1H)，6.92-6.97(m，2H)，6.70-6.75(m，1H)，6.28-6.42(m，2H)，5.62-5.66(m，1H)，3.80-4.00(m，4H)，3.70-3.77(m，1H)，3.55-3.56(m，4H)，3.38-3.47(m，2H)，3.28-3.36(m，2H)，3.02-3.22(m，3H)，2.70(t，J＝12.0Hz，2H)，2.14-2.36(m，4H)，2.08(d，J＝7.2Hz，2H)，1.81(t，J＝7.2Hz，1H)，1.66-1.78(m，7H)，1.52-1.62(m，5H)，1.49(d，J＝7.2Hz，3H)，1.43(d，J＝6.4Hz，3H)，1.11-1.18(m，2H)，1.08(d，J＝6.4Hz，3H)，1.04(d，J＝6.4Hz，3H)。
Example 39:(S) -2- ((5- (3- ((7- ((2-propenoyl-2, 7-diazaspiro [3.5 ])]Nonan-7-yl) sulphones Acyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl-oxy) -5- fluoro-N, N-diisopropylbenzamide
Step 1: (S) -7- ((2- ((1- (6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-7-yl) sulfonyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 29 and intermediate 6, to give the target compound. MS m/z [ LC-MS ]:814.44[ M+1].
Step 2: (S) -2- ((5- (3- ((7- ((2, 7-diazaspiro [3.5] nonan-7-yl) sulfonyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:714.39[ M+1].
Step 3: (S) -2- ((5- (3- ((7- ((2-propenoyl-2, 7-diazaspiro [3.5] nonan-7-yl) sulfonyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：768.40[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.47(s，1H)，7.17-7.24(m，1H)，7.05-7.11(m，1H)，6.92-6.95(m，1H)，6.35(dd，J＝16.8Hz，2.0Hz，1H)，6.17(dd，J＝16.8Hz，10.4Hz，1H)，5.67(dd，J＝10.4Hz，2.0Hz，1H)，3.89(s，2H)，3.69-3.84(m，4H)，3.44-3.62(m，1H)，3.32-3.39(m，1H)，2.94-3.24(m，12H)，2.43-2.60(m，2H)，2.16-2.35(m，1H)，2.02-2.15(m，1H)，1.57-1.96(m，11H)，1.47(d，J＝6.4Hz，3H)，1.25-1.32(m，3H)，1.03-1.09(m，3H)，0.67-0.73(m，3H)。
Example 40:(S) -2- ((5- (3- ((7- ((6-propenoyl-2, 6-diazaspiro [ 3.3))]Heptane-2-yl) sulfonic acid Acyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl-oxy) -5- fluoro-N, N-diisopropylbenzamide
Step 1: (S) -6- ((2- ((1- (6- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-7-yl) sulfonyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 29 and intermediate 7, to give the target compound. MS m/z [ LC-MS ]:786.41[ M+1].
Step 2: (S) -2- ((5- (3- ((7- ((2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:686.36[ M+1].
Step 3: (S) -2- ((5- (3- ((7- ((6-propenoyl-2, 6-diazaspiro [3.3] heptan-2-yl) sulfonyl) -2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：740.37[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.47(s，1H)，7.17-7.25(m，1H)，7.06-7.11(m，1H)，6.93-6.96(m，1H)，6.33(dd，J＝16.8Hz，2.0Hz，1H)，6.12(dd，J＝16.8Hz，10.4Hz，1H)，5.69(dd，J＝10.4Hz，2.0Hz，1H)，4.27-4.41(m，2H)，4.07-4.10(m，2H)，3.91-4.02(m，4H)，3.48-3.84(m，5H)，3.33-3.40(m，1H)，3.11-3.18(m，4H)，3.01(s，4H)，2.46-2.55(m，2H)，1.96-2.32(m，3H)，1.74-1.82(m，4H)，1.48(d，J＝6.4Hz，3H)，1.26-1.34(m，3H)，1.04-1.10(m，3H)，0.68-0.74(m，3H)。
Example 41:(S) -5-fluoro-2- ((5- (3- ((9- ((3-fluoropyridin-2-yl) amino) -3-azaspiro [ 5.5)]Ten times Monoalan-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -N, N-diisopropylbenzamide
The procedure of example 5 was followed, starting from intermediate 10 and 2-bromo-3-fluoropyridine, to give the title compound. MS m/z [ LC-MS ]：663.39[M+1]。 1 H NMR(400MHz，DMSO-d 6 )：δ＝8.82-8.96(m，1H)，7.44-7.76(m，3H)，7.31-7.39(m，2H)，6.62-6.73(m，1H)，3.09-4.40(m，17H)，2.94-3.08(m，2H)，2.70-2.82(m，1H)，2.20-2.32(m，1H)，1.92-2.14(m，2H)，1.50-1.90(m，6H)，1.32-1.49(m，6H)，1.02-1.14(m，3H)，0.67-0.85(m，3H)。
Example 42:(S) -N-ethyl-5-fluoro-2- ((5- (3- ((9- ((3-fluoropyridin-2-yl) amino) -3-azaspiro) amino) [5.5]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) -N-isopropylbenzamide
The procedure of example 5 was followed, starting from intermediate 11 and 2-bromo-3-fluoropyridine, to give the title compound. MS m/z [ LC-MS]：649.38[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.49(s，1H)，7.85(d，J＝4.8Hz，1H)，7.14-7.24(m，1H)，7.06-7.16(m，3H)，6.98-7.04(m，1H)，6.44-6.48(m，1H)，4.45(d，J＝7.6Hz，1H)，3.82-3.97(m，2H)，3.26-3.61(m，4H)，3.04-3.16(m，1H)，2.26-2.66(m，6H)，2.08-2.23(m，1H)，1.56-1.96(m，14H)，1.23-1.38(m，6H)，1.05-1.10(m，3H)。
Example 43:(S) -5-fluoro-N, N-diisopropyll-2- ((5- (3- ((9- ((5-methylisoxazol-3-yl) ammonia) Radical) -3-azaspiro [5.5]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
The procedure of example 5 was followed, starting from intermediate 10 and 2-bromopyridine 3-bromo-5-methylisoxazole, to give the title compound. MS m/z [ LC-MS ]:649.40[ M+1].
Example 44:(S) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (3- ((9- (pyrimidin-2-ylamino) -3-aza) amino) Spiro [5.5 ]]Undec-3-yl) methyl) pyrrolidin-1-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
The procedure of example 5 was followed, starting from intermediate 11 and 2-bromopyrimidine, to give the title compound. MS m/z [ LC-MS]：632.38[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.51(s，1H)，8.24(d，J＝4.8Hz，2H)，7.10-7.26(m，2H)，6.95-7.00(m，1H)，6.50(t，J＝4.8Hz，1H)，5.90-6.06(brs，1H)，3.50-3.96(m，6H)，2.80-3.47(m，12H)，2.36-2.48(m，1H)，1.68-2.08(m，10H)，1.36-1.41(m，3H)，1.02-1.12(m，6H)。
Example 45:2- ((4- (7- (((R) -1- (((1S, 4S) -5- ((E) -4- (dimethylamino) but-2-enoyl) propanoic acid) room) 2, 5-diazabicyclo [2.2.1 ]Heptane-2-yl) sulfonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5]Nong (nong) Alk-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Step 1: (1S, 4S) -5- (((R) -3- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyrrolidin-1-yl) sulfonyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 17, to give the target compound. MS m/z [ LC-MS ]:785.42[ M+1].
Step 2:2- ((4- (7- (((R) -1- (((1S, S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) sulfonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-NN-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:685.37[ M+1].
Step 3:2- ((4- (7- (((R) -1- (((1S, S) -5- ((E) -4- (dimethylamino) but-2-enoyl) -2, 5-diazabicyclo [2.2.1] heptane-2-yl) sulfonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the title compound was obtained starting from the product of step 2 and (E) -4- (dimethylamino) but-2-enoyl chloride. MS m/z [ LC-MS]：796.43[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，6.89-6.99(m，3H)，6.74-6.77(m，1H)，6.29(d，J＝15.2Hz，0.3H)，6.11(d，J＝15.2Hz，0.7H)，4.97(s，0.7H)，4.63(s，0.3H)，4.43(s，0.7H)，4.41(s，0.3H)，3.74-4.01(m，5H)，3.64(d，J＝11.6Hz，0.3H)，3.21-3.52(m，7.7H)，3.05-3.10(m，2H)，2.96-3.02(m，1H)，2.14-2.46(m，11H)，1.78-2.04(m，4H)，1.68-1.76(m，4H)，1.55-1.66(m，2H)，1.52(d，J＝6.8Hz，3H)，1.46(d，J＝6.8Hz，3H)，1.11(d，J＝6.8Hz，3H)，1.07(d，J＝6.8Hz，3H)。
Example 46:(E) -4- ((1S, 4S) -5- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) Yl) pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonan-7-yl) methyl) piperidin-1-yl) sulfonyl) -2, 5-diaza-bis Ring [2.2.1]Heptan-2-yl) -4-oxobut-2-enoic acid isopropyl ester
Reference is made to the procedure of step 3 of example 1 as 2- ((4- (7- ((1- (((1S, S) -2, 5-diazabicyclo [ 2.2.1))]Heptane-2-yl) sulfonyl) piperidin-4-yl methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidine-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride and (E) -4-chloro-4-oxo-but-2-enoate isopropyl ester are used as raw materials to obtain a target compound. MS m/z [ LC-MS]：839.43[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.35(s，1H)，7.74(s，1H)，7.19(d，J＝15.2Hz，0.3H)，7.03(d，J＝15.2Hz，0.7H)，6.95-7.00(m，2H)，6.85(d，J＝15.2Hz，1H)，6.74-6.77(m，1H)，5.06-5.14(m，1H)，4.97(s，0.7H)，4.68(s，0.3H)，4.41-4.46(m，1H)，3.82-3.99(m，4H)，3.74-3.80(m，1H)，3.64-3.72(m，2H)，3.57(dd，J＝9.6Hz，2.0Hz，1H)，3.44-3.51(m，2H)，3.31-3.37(m，1.7H)，3.22(d，J＝9.2Hz，0.3H)，2.69(t，J＝11.6Hz，2H)，2.18-2.37(m，4H)，2.07-2.14(m，2H)，1.88-2.06(m，2H)，1.68-1.85(m，7H)，1.52(d，J＝6.8Hz，3H)，1.47(d，J＝6.4Hz，3H)，1.27-1.30(m，6H)，1.13-1.22(m，2H)，1.12(d，J＝6.4Hz，3H)，1.08(d，J＝6.4Hz，3H)。
Example 47:2- ((4- ((S) -3- ((9- (((1S, 4S) -5-propenoyl-2, 5-diazabicyclo [ 2.2.1)] Heptane-2-sulfonylamino) -3-azaspiro [5.5]Undecan-3-yl) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) -5- fluoro-N, N-diisopropylbenzamide
Step 1: (1S, 4S) -5- (N- (3- (((S) -1- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) pyrrolidin-3-yl) methyl) -3-azaspiro [5.5] undec-9-yl) sulfamoyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 13, to give the target compound. MS m/z [ LC-MS ]:827.47[ M+1].
Step 2:2- ((4- ((S) -3- ((9- ((1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-sulfonylamino) -3-azaspiro [5.5] undec-3-yl) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:727.41[ M+1].
Step 3:2- ((4- ((S) -3- ((9- (((1S, S) -5-propenoyl-2, 5-diazabicyclo [2.2.1] heptane-2-sulfonylamino) -3-azaspiro [5.5] undec-3-yl) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：781.42[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.39(s，1H)，7.79(s，1H)，6.90-6.97(m，2H)，6.58-6.67(m，1H)，6.36-6.47(m，1.3H)，6.26(dd，J＝16.8Hz，10.0Hz，0.7H)，5.69-5.74(m，1H)，4.98(s，0.7H)，4.61(s，0.3H)，4.44(s，0.7H)，4.42(s，0.3H)，4.26-4.30(m，1H)，3.60-3.90(m，4H)，3.43-3.52(m，3H)，3.30-3.39(m，2H)，3.12-3.25(m，2H)，2.20-2.46(m，7H)，1.96-2.06(m，3H)，1.73-1.90(m，6H)，1.54-1.69(m，4H)，1.52(d，J＝6.4Hz，3H)，1.46(d，J＝6.4Hz，3H)，1.30-1.39(m，3H)，1.11-1.16(m，6H)。
Example 48:2- ((4- (7- (((R) -1- (((R) -3-acrylamidopiperidin-1-yl) sulfonyl) pyrrolidine) 3-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzoyl Amines
Step 1: ((R) -1- (((R) -3- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyrrolidin-1-yl) sulfonyl) piperidin-3-yl) carbamic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 17 and intermediate 30, to give the target compound. MS m/z [ LC-MS ]:787.43[ M+1].
Step 2:2- ((4- (7- (((R) -1- (((R) -3-aminopiperidin-1-yl) sulfonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:687.38[ M+1].
Step 3:2- ((4- (7- (((R) -1- (((R) -3-acrylamidopiperidin-1-yl) sulfonyl) pyrrolidin-3-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：741.39[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.33(s，1H)，7.73(s，1H)，6.92-6.99(m，2H)，6.72-6.78(m，1H)，6.19-6.33(m，2H)，6.03-6.12(m，1H)，5.61(d，J＝10.4Hz，1H)，4.08-4.17(m，1H)，3.80-4.01(m，4H)，3.72-3.79(m，1H)，3.18-3.50(m，7H)，2.96-3.11(m，2H)，2.16-2.48(m，7H)，1.92-2.13(m，3H)，1.55-1.80(m，7H)，1.51(d，J＝6.4Hz，3H)，1.45(d，J＝6.4Hz，3H)，1.10(d，J＝6.4Hz，3H)，1.06(d，J＝6.4Hz，3H)。
Example 49:2- ((4- (7- ((1- (N- (1-propenoylazetidin-3-yl) -N-methylsulfonamidyl) yl) Piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropyl Benzamide compound
Step 1:3- ((4- ((2- (5- (2- (diisopropylcarbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) -N-methylpiperidine) -1-sulfonylamino) azetidine-1-carboxylic acid tert-butyl ester
The procedure of step 1 in example 1 was followed, starting from intermediate 3 and intermediate 31, to give the target compound. MS m/z [ LC-MS ]:787.43[ M+1].
Step 2:2- ((4- (7- ((1- (N- (azetidin-3-yl) -N-methylsulfonylamino) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide hydrochloride
The objective compound was obtained by the method of step 2 in example 1 starting from the product of step 1. MS m/z [ LC-MS ]:687.38[ M+1].
Step 3:2- ((4- (7- ((1- (N- (1-propenoylazetidin-3-yl) -N-methylsulfonamido) piperidin-4-yl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxy) -5-fluoro-N, N-diisopropylbenzamide
Referring to the procedure of step 3 in example 1, the objective compound was obtained starting from the product of step 2 and acryloyl chloride. MS m/z [ LC-MS]：741.39[M+1]。 1 H NMR(400MHz，CDCl 3 )：δ＝8.33(s，1H)，7.73(s，1H)，6.93-6.99(m，2H)，6.72-6.76(m，1H)，6.32(dd，J＝16.8Hz，1.6Hz，1H)，6.15(dd，J＝16.8Hz，10.4Hz，1H)，5.67(dd，J＝10.4Hz，1.6Hz，1H)，4.58(m，1H)，4.34(t，J＝8.4Hz，1H)，4.20-4.27(m，2H)，4.07-4.12(m，1H)，3.81-4.00(m，4H)，3.72-3.79(m，1H)，3.56-3.62(m，2H)，3.42-3.50(m，1H)，2.82(s，3H)，2.71(td，J＝12.0Hz，1.6Hz，2H)，2.18-2.38(m，4H)，2.10(d，J＝6.8Hz，2H)，1.94-2.06(m，1H)，1.68-1.82(m，6H)，1.51(d，J＝6.8Hz，3H)，1.45(d，J＝6.8Hz，3H)，1.12-1.21(m，2H)，1.10(d，J＝6.8Hz，3H)，1.06(d，J＝6.8Hz，3H)。
Biological testing
Biochemical detection of inhibition of binding of Menin to MLL by Compounds
Wild-type memin can bind with high affinity to the N-terminal conserved sequence of MLL, and compounds bind to the memin by competing with the MLLN terminal. FITC-MLL (4-43) (synthesized by Kirschner Inc.) contains conserved sequences that bind MLL to Menin. We constructed methods for detecting binding activity of Menin to MLL and used for detecting binding activity of compounds by fluorescence polarization binding experiments (Fluorescence Polarization Binding Assay, FP Assay). The specific method comprises the following steps:
Compounds were diluted 5-fold in a gradient (total of 8 concentrations) starting at 1mM with 100% dmso. Mu.l of each concentration was added to 48. Mu.l of reaction buffer (50mM NaCl,50mM Tris (pH 7.5), 0.05% Tween-20,1mM DTT) and mixed well as 4X compound (final concentration 10000, 2000, 400, 80, 16,3.2,0.64,0 nM) for use. 2 XMenin was formulated with reaction buffer at a final concentration of 5nM,4 XFITC-MLL (4-43) at a final concentration of 2nM. Mu.l of 4 x compound was added to 384 well plates (OptiPlate-384, purchased from Perkinelmer), 10. Mu.l of 2 x Menin was added, centrifuged, 5. Mu.l of FITC-MLL (4-43) was added, and the reaction was started by centrifugation and protected from light at 23℃for 1 hour. After the reaction, the signal values (excitation wavelength 480 nm/emission wavelength 535 nm) were read on an EnVison2104 Multilabel Reader (purchased from Perkinelmer). IC for processing data and obtaining compounds by data analysis software GraphPad Prism 50 Value of
Cell proliferation activity assay of the compounds:
MV-4-11 cells are human acute myelogenous leukemia cells, which contain MLL-AF4 fusion proteins. This experiment was performed using Promega company after incubation of MV-4-11 cells with different concentrations of the compoundThe detection reagent establishes a screening method for inhibiting MV-4-11 cell proliferation.
MV-4-11 cells were cultured in 1640 (Biological Industries, cat# 01-100-1 ACS) medium containing 10% fetal bovine serum (Biological Industries, cat# 04-001-1 ACS) at 37℃under 5% CO 2 . Subculture was performed 2-3 times a week. Cells were seeded at 5000 cells/well in 96-well cell culture plates195. Mu.L/well at 37℃in 5% CO 2 Is cultured. After 24 hours, the compounds were mixed by 3-fold gradient dilution with 100% DMSO starting at 10mM (total 10 concentrations), and then 4. Mu.L of each concentration was added to 96. Mu.L of RPMI-1640 medium for dilution and mixing. mu.L of the diluted compound was added to the plated cell suspension at each concentration, and the compound was incubated with the cells in a cell incubator for 72 hours (3 days). Then 35. Mu.L CellTiter-Blue (Promega, cat. G8082) reagent, 37℃and 5% CO were added 2 The reaction was carried out for 4 hours under the conditions. Reading chemiluminescence values on BMG Clariostar Microplate Reader, processing the data with GraphPad Prism software, and calculating to obtain IC for inhibiting cell proliferation 50 Values.
Note that: * Refers to multiplication, representing a multiple.
TABLE 1 inhibitory Activity of example Compounds against Menin-MLL protein binding and MV-4-11 cell proliferation (IC 50 )
TABLE 1The inhibitory activity IC of the compounds of the present invention on the binding of the Menin-MLL protein and the proliferation of MV-4-11 cells is shown 50 Values. The data show that the compounds provided by the invention have good binding inhibition activity of the Menin-MLL protein and also have good inhibition activity on proliferation of MLL-AF4 positive expression MV-4-11 cells
Assay of compounds for CYP450 subtype 3A4 inhibition
Detecting the relative activity of the test substance and the positive control on the main subtype CYP3A4 metabolite of the mixed human liver microsome CYP450 enzyme by a liquid chromatography-tandem mass spectrometer (LC-MS/MS) analysis method, calculating the IC50 value of the inhibition effect of the positive control substance and the test substance on the mixed human liver microsome cytochrome P450 enzyme, and evaluating the in vitro inhibition effect of the test substance on the main subtype CYP3A4 of the CYP450 enzyme.
The experiments were divided into positive control and test groups. Positive controls or test substances were incubated with human liver microsomes and probe substrates for CYP3A4 enzyme, including human liver microsomes (0.05 mg/mL), NADPH (1.5 mM), PBS buffer (100 mM, ph=7.4), probe substrates (midazolam 4 μm or testosterone 40 μm) and inhibitors (final test substance concentrations of 0, 1, 2.5, 5.0, 10.0, 25.0 μm; final positive control ketoconazole concentrations of 0, 0.0025, 0.005, 0.01, 0.025, 0.05, 0.1, 0.25 μm.) in a total incubation volume of 100 μl. The specific operation steps are as follows:
2.1 preparation of liver microsome dilution
A stock solution of 20mg/mL human liver microsomes was thawed on ice, and diluted 40-fold with PBS buffer (100 mM, pH=7.4) to prepare a dilution of 0.5mg/mL liver microsomes.
2.2 preparation of Mixed incubation liquid
A mixed incubation with a dilution of liver microsomes and a substrate solution (midazolam or testosterone) was prepared using PBS buffer (100 mm, ph=7.4).
2.3 the mixed incubation was pre-incubated for 5min at 37℃in a thermostated shaker at 100 rpm.
2.4 preincubating, respectively adding test substance working solutions or positive control ketoconazole working solutions with different concentrations (the final concentration of the test substance is 0, 1, 2.5, 5.0, 10.0 and 25.0 mu M; the final concentration of the positive control ketoconazole is 0, 0.0025, 0.005, 0.01, 0.025, 0.05, 0.1 and 0.25 mu M.), stirring uniformly, adding NADPH (final concentration of 1.5 mM), starting reaction, continuously placing in a constant-temperature oscillator at 37 ℃ and 100rpm, incubating for 100 mu L of total volume, incubating for a certain time (the solution of a probe substrate is midazolam and the solution of a probe substrate is testosterone is incubated for 15 min), adding 150 mu L of an ice internal standard solution, centrifuging at 12000rpm for 10min, taking 200 mu L of supernatant, calculating the area ratio of each metabolic product peak to the internal standard naphthalene peak by using a MassLynx V4.1 SCN software, and calculating the area ratio of the metabolic product per area of the metabolic product by using an Excel software. The inhibition IC50 values for the positive control and test subjects were calculated from Excel directly at the two concentration points or by Graphpad Prism (version 6.01) software.
TABLE 2 inhibition of CYP450 enzyme major subtype 3A4 by example compounds
Examples IC 50 (μM)
16 ＞25
22 ＞25
23 25
25 ＞25
26 ＞25
29 ＞25
30 ＞25
39 ＞25
40 20.5
44 18.6
46 ＞25
Table 2 shows the inhibition IC of CYP450 enzyme major subtype 3A4 by the compounds of the invention 50 Value (midazolam as substrate). The data show that the compound provided by the invention has very weak inhibition effect on CYP450 enzyme main subtype 3A4, is beneficial to avoiding potential drug interaction risks and improves the safety of clinical medication.

Claims (10)

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
wherein,
x isWherein the position is as follows with SO 2 Is connected with the mother nucleus or is connected with the mother nucleus,
v is N or CH, and the R is H,
the ring A is a 7-12 membered nitrogen-containing spiro ring,
the C ring is a 3-12 membered nitrogen-containing heterocycle,
the D ring is a 3-12 membered nitrogen-containing heterocycle,
R 1 is hydrogen, halogen or C 1-6 Alkyl, or C 1-6 A haloalkyl group, a halogen atom,
R 2 each independently is hydrogen, halogen, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CF 3 、-NR 13 R 14 OR-OR 13 ，
R 3 Is a halogen, and is preferably a halogen,
R 20 and R is 21 Each independently is hydrogen or C 1-6 An alkyl group, a hydroxyl group,
R 4 and R is 5 Each independently is hydrogen, halogen, CN, C 1-6 Alkyl, or C 1-6 A haloalkyl group, a halogen atom,
R 11 and R is 12 Each independently selected from H, halogen and C 1-6 Alkyl, or R 11 And R is 12 Are linked together to form a 3-5 membered carbocyclic ring,
R 41 h, C of a shape of H, C 1-6 Alkyl, - (CO) -R 15 、-(CO)-OR 13 And- (CO) -NR 13 R 14 The alkyl group may optionally be substituted with halogen, -CN, -NR 13 R 14 、-OR 13 Or 3-8 membered heterocycloalkyl,
R 42 and R is 43 Each independently selected from H, halogen, -CN and C 1-6 An alkyl group, a hydroxyl group,
R 13 and R is 14 Each independently selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen,
R 15 each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 2-6 Alkenyl and C 2-6 Alkynyl, said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl and alkynyl being optionally substituted with halogen, -CN, or C 1-6 An alkyl group is substituted and a substituent is substituted,
n is each independently 0, 1, 2, or 3,
provided that the following compounds are not included:
2. the compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein V is N, R 3 Is fluorine, R 11 And R is 12 Is hydrogen.
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein R 1 Is hydrogen or C 1-6 Alkyl and D ring is 7-12 membered nitrogen-containing spiro ring.
4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein R 41 Is C 1-6 Alkyl, - (CO) -R 15 、-(CO)-OR 13 And- (CO) -NR 13 R 14 The alkyl group may optionally be substituted with halogen, -CN, -NR 13 R 14 、-OR 13 Or 3-8 membered heterocycloalkyl, R 13 And R is 14 As defined in claim 1.
5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein R 2 Each independently of the otherEarth being hydrogen, halogen, CN, NO 2 、-OH、-NH 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CF 3 、-NH-C 1-6 Alkyl, or-O-C 1-6 An alkyl group.
6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein R 13 And R is 14 Each independently selected from hydrogen and C 1-6 Alkyl, R 15 Selected from C 1-6 Alkyl and C 3-8 Cycloalkyl groups.
7. The following compounds, or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites or prodrugs thereof:
8. a pharmaceutical composition comprising a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, and optionally a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 8, in the manufacture of a medicament for the treatment of a disease associated with MLL activity.
10. The use according to claim 9, wherein the disease associated with MLL activity is a cancer, preferably an acute leukemia (including MLL acute leukemia, MLL partial tandem repeat acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia and CALM acute leukemia), chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gall bladder and bile duct cancer, liver cancer, hepatocellular cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorioallantoic carcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, soft-wire sarcoma, chondrosarcoma, skin sarcoma or skin sarcoma.
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