CN116801883A

CN116801883A - Heteroaromatic ring compounds, preparation method and application thereof

Info

Publication number: CN116801883A
Application number: CN202280010512.9A
Authority: CN
Inventors: 刘金明; 唐建川; 任云; 何婷; 刘谦; 田强; 宋宏梅; 葛均友; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2021-03-18
Filing date: 2022-03-16
Publication date: 2023-09-22
Also published as: WO2022194192A1

Description

Heteroaromatic ring compounds, preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a heteroaromatic compound, a preparation method thereof, a pharmaceutical composition containing the heteroaromatic compound and application thereof.

Background

The RAS family is a class of guanine nucleotide binding proteins with gtpase activity. As a molecular switch, RAS can realize the conversion between the inactive state of GDP combination and the active state of GTP combination, transmit upstream signals received by cells to a plurality of downstream signal paths, regulate protein synthesis, gene transcription, cell growth, differentiation, apoptosis, migration and the like.

In the field of cancer research, the RAS gene is one of the most common proto-oncogenes in human cancers. RAS mutations result in sustained activation of downstream signaling pathways that promote tumor development. The RAS family includes HRAS, NRAS and KRAS, with about 85% of RAS mutations in all tumor types occurring in KRAS. In KRAS mutant tumors, the gtpase activity of KRAS itself is reduced and KRAS continues to maintain the active state. KRAS mutations are closely related to the occurrence of lung, pancreatic and colorectal cancers, and the frequency of glycine mutation at position 12 on KRAS to aspartic acid (KRAS G12D) is highest (about 34%).

Development of small molecule inhibitors against KRAS G12D has been one of the difficulties in the medical field. BI-2852 of Boringer John uses the principle of molecular gel to induce KRAS G12D to form dimer, blocking the interaction of KRAS and downstream proteins; the recolumation company induces the KRAS G12D protein to form a ternary complex using mTOR inhibitors, blocking KRAS interaction with downstream effector proteins; mirai corporation in WO2021041671A1 discloses a novel class of KRAS G12D inhibitors, the mechanism of action of which is not disclosed.

Although KRAS has become an excellent tumor therapeutic target, there is no clinically validated drug targeting KRAS G12D. Therefore, there is an urgent need in the art to develop KRAS G12D targeted inhibitors with novel structure, good bioactivity, and high patentability.

Summary of The Invention

On one hand, the invention provides a heteroaromatic compound which has a strong inhibition effect on a target KRAS G12D, so that the heteroaromatic compound has a better tumor treatment effect. The compounds of the present invention also have a variety of excellent properties, such as good physicochemical properties (e.g. solubility, physical and/or chemical stability) and good safety.

The compound is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound or metabolite thereof:

Wherein,

X ¹ selected from N and CR ⁵ ；

L is selected from the group consisting of covalent bonds, -O-, -S-, and-NR ⁶ -；

R ¹ Selected from hydrogen, C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substitution;

R ² selected from the group consisting of

Each X ² Each independently selected from N and CR ⁹ ；

R ³ Selected from C _1-6 Alkyl and C _1-6 A haloalkyl group; or alternatively

Two R's bound to the same carbon atom ³ And the carbon atoms together form a carbonyl group, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl;

R ⁴ selected from C _6-10 Aryl and 5-10 membered heteroaryl, each optionally substituted with one or more R ¹⁰ Substitution;

R ⁵ selected from hydrogen, halogen, cyano, C _1-6 Alkyl and C _1-6 A haloalkyl group;

R ⁶ selected from hydrogen and C _1-6 An alkyl group;

R ⁷ selected from hydrogen, halogen, cyano, -OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-O-C(O)-R ¹¹ 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-NR ¹¹ R ¹² 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-R ¹¹ 、-C(O)-OR ¹² 、-C(O)-NR ¹¹ R ¹² 、C _3-10 Cycloalkyl, C _6-10 Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1- ₆ alkylene-OR ¹³ 、-C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-6 A haloalkyl group;

R ⁸ selected from halogen, hydroxy, cyano, C _1-6 Alkyl, -C _1-6 alkyl-OH, -C _1-6 Alkyl-cyano and C _1-6 A haloalkyl group;

R ⁹ Selected from hydrogen, hydroxy and C _1-6 An alkyl group;

R ¹⁰ selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, -O-C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, each of said alkyl, cycloalkyl, heterocyclyl and heteroaryl optionally being substituted with one or more groups selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl and C _1-6 A substituent of a haloalkyl group;

R ¹¹ selected from hydrogen, C _1-6 Alkyl, C _1-6 Haloalkyl group,-C _1-6 alkyl-O-C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, each of said cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl, C _1-6 A substituent of a haloalkyl group;

R ¹² selected from hydrogen and C _1-6 An alkyl group;

R ¹³ selected from hydrogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, each of said cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl, C _1-6 A substituent of a haloalkyl group;

R ¹⁴ selected from hydrogen and C _1-6 An alkyl group;

m is 0, 1, 2, 3 or 4;

n is 0, 1 or 2; and is also provided with

o, p, q, r and s are each independently selected from 0, 1, 2 or 3, provided that o and r are not both 0 and p and q are not both 0.

In another aspect, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, or metabolite thereof, and one or more pharmaceutically acceptable carriers.

In another aspect, the invention provides a kit comprising a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, or a pharmaceutical composition of the invention, and optionally, packaging and/or instructions.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, or a pharmaceutical composition of the invention, for use in inhibiting KRAS G12D.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of KRAS G12D-mediated related diseases.

In another aspect, the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of KRAS G12D-mediated related diseases.

In another aspect, the invention provides a method of preventing or treating KRAS G12D-mediated diseases comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, or metabolite thereof, or a pharmaceutical composition of the invention.

In another aspect, the invention provides a process for preparing the compounds of the invention.

Detailed Description

Definition of the definition

Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

As used herein, the terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. For example, as used herein, the term "C _1-6 Alkyl "refers to a straight or branched alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl) optionally substituted with one or more (such as 1 to 3) suitable substituents, such as halogen.

As used herein, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C" as used herein _2-6 Alkenyl "refers to alkenyl having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon double bond (e.g., vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen.

As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C" as used herein _2-6 Alkynyl "refers to alkynyl having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds (e.g., ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutaneA radical, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spiro, fused or bridged systems, such as bicyclo [1.1.1 ]]Amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. For example, the term "C _3-6 Cycloalkyl "refers to a saturated or partially unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) having 3 to 6 ring-forming carbon atoms, optionally substituted with one or more (such as 1 to 3) suitable substituents, e.g., methyl-substituted cyclopropyl.

As used herein, the term "halo" or "halogen" group is defined to include fluorine, chlorine, bromine or iodine.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms. For example, the term "C _1-6 Haloalkyl "means haloalkyl having 1 to 6 carbon atoms, for example-CF ₃ 、-C ₂ F ₅ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ 、-CH ₂ Cl or-CH ₂ CH ₂ CF ₃ Etc.

As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic group, for example, having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., 1, 2, 3, or 4) independently selected from N, O or S (O) _t (wherein t is a heteroatom of 0, 1 or 2), such as 3-12 membered heterocyclyl, 3-7 membered heterocyclyl, 3-6 membered heterocyclyl, 5-6 membered heterocyclyl, etc., and the polycyclic group may be a fused, spiro or bridged ring, such as a 5-12 membered fused, 5-12 membered spiro or 5-12 membered bridged ring. Representative examples of heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, hexahydro-1H-pyrrolinyl, hexahydropyrrolizinyl, pyrrolidinonyl, Imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, and the like.

As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-polycyclic aromatic group having a conjugated pi-electron system. For example, the term "C _6-10 Aryl "or" C _6-10 An aromatic ring "refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring). Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO) ₂ 、C _1-6 Alkyl, etc.) substitution.

As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, for example having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular containing 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and additionally may be benzofused in each case. For example, the heteroaryl or heteroaryl ring may be selected from thienyl (ring), furyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), and the like, and benzo derivatives thereof; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), and the like, and benzo derivatives thereof.

The term "substitution" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted …," the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced or unsubstituted individually and/or together with an independently selected substituent. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with a independently selected substituent or not.

If substituents are described as "independently selected from" a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, under reasonable conditions.

As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g ² H、 ³ H. Deuterium D, tritium T); isotopes of carbon (e.g ¹¹ C、 ¹³ C, C is a metal alloy ¹⁴ C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g ³⁷ Cl); isotopes of fluorine (e.g ¹⁸ F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g ¹²³ I, I ¹²⁵ I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g ¹³ N is N ¹⁵ N); isotopes of oxygen (e.g ¹⁵ O、 ¹⁷ O and O ¹⁸ O); isotopes of phosphorus (e.g ³² P) is as follows; isotopes of sulfur (e.g ³⁵ S). Certain isotopically-labeled compounds of the present application (e.g., those into which a radioisotope is incorporated) are useful in pharmaceutical and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e ³ H) Carbon-14 (i.e ¹⁴ C) Are particularly useful for this purpose because of easy incorporation and easy detection. Using positron-emitting isotopes (e.g ¹¹ C、 ¹⁸ F、 ¹⁵ O and O ¹³ N) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present application can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by substituting an appropriate isotopically-labeled reagent for the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the application include those in which the crystallization solvent may be isotopically substituted, e.g., D ₂ O, acetone-d ₆ Or DMSO-d ₆ 。

The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the application may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.

It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates or metabolites thereof, which, upon administration to a patient in need thereof, are capable of providing the compounds of the invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

The compounds of the present invention may exist in the form of solvates (preferably hydrates) wherein the compounds of the present invention comprise a polar solvent as a structural element of the compound lattice. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires available lone pairs to oxidize to oxides; those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyl dioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L. Gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750; katritzky and a.j. Boulton, eds., academic Press; and G.W.H.Cheeseman and E.S.G.Werstiuk, advances in Heterocyclic Chemistry, vol.22, pp 390-392, A.R.Katritzky and A.J.Boulton, eds., academic Press.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, plenum Press,1973; and those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.

Compounds of formula (I)

An object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof:

wherein,

X ¹ selected from N and CR ⁵ ；

R ² selected from the group consisting of

Each X ² Each independently selected from N and CR ⁹ ；

R ³ Selected from C _1-6 Alkyl and C _1-6 A haloalkyl group; or alternatively

R ⁶ selected from hydrogen and C _1-6 An alkyl group;

R ⁹ selected from hydrogen, hydroxy and C _1-6 An alkyl group;

R ¹¹ selected from hydrogen, C _1-6 Alkyl, C _1-6 Haloalkyl, -C _1-6 alkyl-O-C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, each of said cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl, C _1-6 Haloalkyl groupA substituent group;

R ¹² selected from hydrogen and C _1-6 An alkyl group;

R ¹⁴ selected from hydrogen and C _1-6 An alkyl group;

m is 0, 1, 2, 3 or 4;

n is 0, 1 or 2;

According to some embodiments of the invention, R ⁷ Selected from hydrogen, halogen, cyano, -OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-O-C(O)-R ¹¹ 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-NR ¹¹ R ¹² 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-R ¹¹ 、-C(O)-OR ¹² 、-C(O)-NR ¹¹ R ¹² 、C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, said cycloalkyl and heterocyclyl optionally being substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, C _1-6 Alkyl and C _1-6 A haloalkyl group.

According to some embodiments of the invention, X ¹ Selected from N and CH. In a preferred embodiment, X ¹ Is N.

According to some embodiments of the invention, X ² Selected from CR ⁹ . In a preferred embodiment, X ² Selected from CH.

According to some embodiments of the invention, L is selected from the group consisting of covalent bonds, -O-, -S-, -NH-, and-N (C _1-3 Alkyl) -. In a preferred embodiment, L is selected from the group consisting of-O-, -NH-and-N (C _1-3 Alkyl) -. In a particularly preferred embodiment, L is-O-.

According to some embodiments of the invention, R ¹ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substituted, each R ⁷ Each independently selected from hydrogen, halogen, cyano, -OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-R ¹¹ 、-C(O)-NR ¹¹ R ¹² 、C _3-10 Cycloalkyl, C _6-10 Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1-6 alkylene-OR ¹³ 、-C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-6 A haloalkyl group. Preferably, R ¹ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substituted, each R ⁷ Each independently selected from hydrogen, halogen, cyano, -OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-R ¹¹ 、-C(O)-NR ¹¹ R ¹² 、C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some preferred embodiments, R ¹ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substituted, each R ⁷ Each independently selected from-OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-NR ¹¹ R ¹² 、C _3-6 Cycloalkyl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH, -C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ 、C _1-3 Haloalkyl and C _1-6 An alkyl group. Preferably, R ¹ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substituted, each R ⁷ Each independently selected from-OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-NR ¹¹ R ¹² And 3-12 membered heterocyclyl, optionally substituted with one or more independently selected heterocyclic groupsIs substituted with a substituent selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano and C _1-6 An alkyl group.

In some preferred embodiments, R ¹ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substituted, each R ⁷ Each independently selected from-OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-NR ¹¹ R ¹² A 5-10 membered heteroaryl and a 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH, -C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ 、C _1-3 Haloalkyl and C _1-6 An alkyl group. Preferably, R ¹ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substituted, each R ⁷ Each independently selected from-OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-NR ¹¹ R ¹² And a 3-12 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano and C _1-6 An alkyl group.

In some preferred embodiments, R ¹ To optionally be covered by one or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from C _3-6 Cycloalkyl, 5-6 membered heteroaryl and 5-8 membered heterocyclyl, said C _3-6 Cycloalkyl, 5-6 membered heteroaryl, and 5-8 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH, -C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-3 A haloalkyl group; wherein R is ¹³ Selected from C _1-6 Alkyl and 5-6 membered heterocyclyl; r is R ¹⁴ Selected from hydrogen and C _1-6 An alkyl group.

In some preferred embodiments, R ¹ To optionally be covered by one or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from the group consisting of a 5-6 membered heteroaryl and a 5-8 membered heterocyclyl, each of said 5-6 membered heteroaryl and 5-8 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH, -C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-3 A haloalkyl group; wherein R is ¹³ Selected from C _1-6 Alkyl and 5-6 membered heterocyclyl; r is R ¹⁴ Selected from hydrogen and C _1-6 An alkyl group.

In some preferred embodiments, R ¹ To optionally be covered by one or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from cyclopropyl, pyrrolidinyl, hexahydropyrrolizinyl, and imidazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH, -C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-3 A haloalkyl group; wherein R is ¹³ Selected from C _1-6 Alkyl and morpholinyl; r is R ¹⁴ Is C _1-6 An alkyl group.

In some preferred embodiments, R ¹ To optionally be covered by one or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from pyrrolidinyl, hexahydropyrrolinyl, and imidazolyl, each optionally substituted with one or more substituents independently selected from: halogen, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH, -C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-3 A haloalkyl group; wherein R is ¹³ Selected from C _1-6 Alkyl and morpholinyl; r is R ¹⁴ Is C _1-6 An alkyl group.

In some preferred embodiments, R ¹ To optionally be covered by one or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from cyclopropyl, pyrrolidinyl, hexahydropyrrolizinyl, and imidazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C _1-6 Alkyl, -C _1-6 Alkylene-morpholinyl, -C _1-3 alkylene-OH, -C _1-6 alkylene-N (C) _1-6 Alkyl group ₂ 、-C _1-6 alkylene-O-C (O) - (morpholinyl) and C _1-3 A haloalkyl group.

In some preferred embodiments, R ¹ Is optionally covered byOne or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from pyrrolidinyl, hexahydropyrrolinyl, and imidazolyl, each optionally substituted with one or more substituents independently selected from: halogen, C _1-6 Alkyl, -C _1-6 Alkylene-morpholinyl, -C _1-3 alkylene-OH, -C _1-6 alkylene-N (C) _1-6 Alkyl group ₂ 、-C _1-6 alkylene-O-C (O) - (morpholinyl) and C _1-3 A haloalkyl group.

In some preferred embodiments, R ¹ Selected from the group consisting of Wherein the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-6 Alkyl, C _1-6 alkylene-OH or C _1-6 Haloalkyl substituted 5-12 membered bicyclic heterocyclyl and 5-10 membered heteroaryl.

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-6 Alkyl, C _1-6 alkylene-OH or C _1-6 Haloalkyl-substituted 5-12 membered bicyclic heterocyclyl.

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1-3 alkylene-OH or C _1-3 Haloalkyl substituted 5-8 membered bicyclic heterocyclyl and 5-10 membered heteroaryl.

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1-3 alkylene-OH or C _1-3 Haloalkyl-substituted 5-8 membered bicyclic heterocyclyl.

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-3 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1-3 alkylene-OH or C _1-3 Haloalkyl substituted 5-8 membered nitrogen containing bicyclic heterocyclyl and 5-10 membered heteroaryl.

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-3 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1-3 alkylene-OH or C _1-3 Haloalkyl-substituted 5-8 membered nitrogen-containing bicyclic heterocyclyl.

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-3 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1-3 alkylene-OH or C _1-3 Haloalkyl substituted hexahydropyrrolizinyl and imidazoles.

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-3 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1-3 alkylene-OH or C _1-3 Haloalkyl-substituted hexahydropyrrolizinyl. In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-3 Alkyl, R ⁷ Selected from hexahydropyrrolizinyl and imidazolyl optionally substituted with one or more F, cl, methyl, chloromethyl, fluoromethyl or hydroxymethyl groups.

In some preferred embodiments, R ¹ Selected from the group consisting of

According to some embodiments of the inventionScheme, R ⁴ Selected from C _6-10 Aryl and 5-10 membered heteroaryl, each optionally substituted with one or more R ¹⁰ Substituted, each R ¹⁰ Each independently selected from hydrogen, halogen, hydroxy, cyano, C _1-3 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, -O-C _1-3 Alkyl, C _3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from hydrogen, halogen, hydroxy, cyano, C _1-3 Alkyl and C _1-3 The substituent of the haloalkyl group.

In some preferred embodiments, R ⁴ Selected from C _6-10 Aryl and 5-10 membered heteroaryl, said aryl and heteroaryl optionally being substituted with one or more R ¹⁰ Substituted, each R ¹⁰ Each independently selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, C _2-4 Alkynyl, -O-C _1-3 Alkyl and C _3-6 Cycloalkyl, said alkyl optionally substituted with one or more hydrogens and halogens.

In some preferred embodiments, R ⁴ Selected from phenyl, naphthyl and indazolyl, each of which is optionally substituted with one or more R ¹⁰ Substituted, each R ¹⁰ Each independently selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, C _1-3 Haloalkyl, C _2-4 Alkynyl, -O-C _1-3 Alkyl and C _3-6 Cycloalkyl groups.

In some preferred embodiments, R ⁴ Selected from the group consisting of

In some preferred embodiments, R ¹ To optionally be covered by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-6 Alkyl, C _1-6 alkylene-OH or C _1-6 Haloalkyl-substituted 3-6 membered heterocyclyl; and R is ⁴ Selected from C _6-10 Aryl, said aryl optionally being substituted with one R ¹⁰ Substituted, R ¹⁰ Selected from halogen, hydroxy, C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl, said alkyl optionally being substituted with one or more groups selected from halogen, hydroxy, cyano, C _1-6 Alkyl and C _1-6 The substituent of the haloalkyl group.

In some preferred embodiments, R ¹ Selected from optionally by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally substituted with one or more halogens, C _1-6 Alkyl, C _1-6 alkylene-OH or C _1-6 Haloalkyl substituted nitrogen containing 5-6 membered heterocyclyl; and R is ⁴ Is naphthyl, said naphthyl optionally being substituted with one R ¹⁰ Substituted, R ¹⁰ Selected from halogen, hydroxy, C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl, said alkyl optionally being substituted with one or more groups selected from halogen, hydroxy, cyano, C _1-6 Alkyl and C _1-6 The substituent of the haloalkyl group.

In some preferred embodiments, R ¹ Selected from optionally by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally covered by C _1-3 Alkyl-substituted tetrahydropyrrolyl; and R is ⁴ Is naphthyl, said naphthyl optionally being substituted with one R ¹⁰ Substituted, R ¹⁰ Selected from halogen, hydroxy, C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl groups, said alkyl groups optionally being substituted with one or more groups selected from halogen, hydroxyCyano, C _1-6 Alkyl and C _1-6 The substituent of the haloalkyl group.

According to some embodiments of the invention, each R ³ Each independently selected from C _1-6 Alkyl and C _1-6 Haloalkyl, or two R's attached to the same carbon atom ³ And the carbon atoms together form a carbonyl group or C _3-6 Cycloalkyl groups.

In some preferred embodiments, each R ³ Each independently selected from C _1-3 Alkyl, or two R's attached to the same carbon atom ³ And the carbon atoms together form a carbonyl group or C _3-6 Cycloalkyl groups.

In a particularly preferred embodiment, each R ³ Each independently selected from methyl, or two R's attached to the same carbon atom ³ And the carbon atoms together form a carbonyl group or a cyclopropyl group.

According to some embodiments of the invention, R ² Selected from the group consisting of

In some embodiments of the invention, R ² Selected from the group consisting of

The present invention encompasses compounds of formula (I) obtained by any combination of the above preferred groups.

According to some embodiments of the invention, the compounds of the invention have the structure of formula (II-A), formula (II-B) or formula (II-C):

wherein each group L, R ¹ 、R ³ 、R ⁴ 、R ⁸ M, n, o, p, q, r and s are as defined above.

According to some embodiments of the invention, the compounds of the invention have the structure of formula (II-A) or formula (II-C), wherein L is selected from the group consisting of covalent bonds, -O-, -S-, and-NH-; preferably, L is selected from the group consisting of-O-and-S-; more preferably, L is selected from-O-.

According to some embodiments of the invention, the compounds of the invention have the structure of formula (II-A) or formula (II-C), wherein o, p, q, r and s are each independently selected from 0, 1 or 2; preferably, o, p, q and r are each independently selected from 0 or 1, s is selected from 1 or 2; preferably, o and p are selected from 0 or 1, q and r are selected from 1, s is selected from 1 or 2; preferably, o and p are selected from 0, q and r are selected from 1, s is selected from 2.

According to some embodiments of the invention, the compounds of the invention have the structure of formula (II-A) or formula (II-C), wherein n is 0 or 1; preferably 0.

According to some embodiments of the invention, the compounds of the invention have the structure of formula (II-A) or formula (II-C), wherein m is 0, 1 or 2.

In some preferred embodiments, the compounds of the present invention have the structure of formula (II-A-1), (II-A-2), (II-C-1), (II-C-2) or (II-C-3):

wherein each group L, R ¹ 、R ³ 、R ⁴ And m is as defined above.

The groups of all embodiments in the above formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-A-1), (II-A-2), (II-C-1), (II-C-2) or (II-C-3) of the present invention may be appropriately selected to be arbitrarily combined, thereby obtaining different general formula ranges or specific schemes. These ranges and schemes are all within the scope of the invention.

The present invention encompasses compounds resulting from any combination of the various embodiments.

According to some embodiments of the invention, the compound of the invention is selected from:

preparation method

It is a further object of the present invention to provide a process for preparing the compounds of the present invention. For example, the present invention provides a process for preparing a compound of formula (II-a), comprising the steps of:

route 1

Therein, L, R ¹ 、R ³ 、R ⁴ 、R ⁸ M, n, o, p, q, r and s are as defined above;

LG ¹ 、LG ² and X represents a leaving group including, but not limited to, a halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, and the like;

PG ¹ 、PG ² and PG ³ Protecting groups for hydroxy or amino groups include, but are not limited to, benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), methyl, benzyl, and the like.

Step (1) of reacting the compound II-A-1 with the compound II-A-2 to obtain the compound II-A-3;

the reaction is preferably carried out in a suitable organic solvent which may be selected from the group consisting of methanol, toluene, tetrahydrofuran, 1, 4-dioxane and any combination thereof, preferably methanol.

The reaction is preferably carried out in the presence of a suitable organic or inorganic base which may be selected from diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.

The reaction is carried out at a suitable temperature, preferably 0-80 ℃.

The reaction is carried out for a suitable time, for example 2-24 hours.

Step (2) coupling the compound II-A-3 with the compound II-A-4 to obtain a compound II-A-5;

the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tris (dibenzylideneacetone) dipalladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride, tetrakis (triphenylphosphine) palladium, palladium acetate, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride. The ligand is a phosphorus ligand such as 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, 2-dicyclohexylphosphine-2 ',6' -diisopropyloxy-1, 1 '-biphenyl, 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl, preferably 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene. The base is an organic or inorganic base, such as diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.

The reaction is preferably carried out in a suitable solvent which may be selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1, 4-dioxane and any combination thereof, preferably 1, 4-dioxane.

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (3) subjecting the compound II-A-5 to a deprotection reaction to obtain a compound II-A-6;

the deprotection reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from ethyl acetate, methanol, 1, 4-dioxane, dichloromethane, and any combination thereof, preferably dichloromethane.

The deprotection reaction is preferably carried out in the presence of a suitable acid. The acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.

The deprotection reaction is carried out at a suitable temperature, preferably 0-40 ℃.

The reaction is carried out for a suitable time, for example 2-12 hours.

Step (4) coupling the compound II-A-6 with the compound II-A-7 to obtain a compound II-A-8;

the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tris (dibenzylideneacetone) dipalladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, tetrakis (triphenylphosphine) palladium, palladium acetate, preferably tris (dibenzylideneacetone) dipalladium. The ligand is a phosphorus ligand, such as 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl, preferably 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl. The base is an organic or inorganic base, such as sodium t-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (5) subjecting the compound II-A-8 to a deprotection reaction to obtain a compound II-A-9;

the deprotection reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of alcoholic protic solvents, tetrahydrofuran, N-dimethylformamide and any combination thereof, preferably N, N-dimethylformamide.

The deprotection reaction is preferably carried out in the presence of sodium ethanethiolate.

The deprotection reaction is carried out at a suitable temperature, preferably 50-100 ℃.

The reaction is carried out for a suitable time, for example 1 to 12 hours.

Step (6) subjecting the compound II-A-9 to a condensation reaction with the compound II-A-10 to obtain a compound II-A-11;

the condensation reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, N-dimethylformamide, dichloromethane, and any combination thereof, preferably N, N-dimethylformamide.

The condensation reaction is preferably carried out in the presence of a suitable organic base which may be selected from diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, preferably 1, 8-diazabicyclo [5.4.0] undec-7-ene.

The condensation reaction is carried out in the presence of a suitable condensing agent, which may be selected from the group consisting of a carboter condensing agent, 1-hydroxybenzotriazole, 2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate, preferably a carboter condensing agent.

The deprotection reaction is carried out at a suitable temperature, preferably 20-100 ℃.

The reaction is carried out for a suitable time, for example 2-24 hours.

Step (7) subjecting the compound II-A-11 to a deprotection reaction to obtain the compound II-A;

The reaction is carried out for a suitable time, for example 2-12 hours.

The present invention provides a second process for preparing a compound of formula (II-a), comprising the steps of:

route 2

PG ¹ and PG ³ Protecting groups representing amino groups, including but not limited to benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), benzyl, and the like;

step (1) reacting compound II-A-1 with compound II-A-10 to obtain compound IIa-A-2;

the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, toluene, tetrahydrofuran, 1, 4-dioxane, and any combination thereof, preferably N, N-dimethylformamide.

The reaction is preferably carried out in the presence of a suitable organic or inorganic base which may be selected from the group consisting of N, N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, preferably N, N-diisopropylethylamine.

The reaction is carried out at a suitable temperature, preferably 20-100 ℃.

The reaction is carried out for a suitable time, for example 1 to 12 hours.

Step (2) of subjecting the compound IIa-A-2 to a coupling reaction with the compound II-A-4 to obtain a compound IIa-A-3;

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (3) subjecting the compound IIa-A-3 to a deprotection reaction to obtain a compound IIa-A-4;

The reaction is carried out for a suitable time, for example 2-12 hours.

Step (4) of subjecting the compound IIa-A-4 to a coupling reaction with the compound II-A-7 to obtain a compound II-A-11;

the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tris (dibenzylideneacetone) dipalladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, tetrakis (triphenylphosphine) palladium, palladium acetate, preferably tris (dibenzylideneacetone) dipalladium. The ligand is a phosphorus ligand such as 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1 '-biphenyl, 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl, 1 '-bis (diphenylphosphine) ferrocene, preferably 1,1' -bis (diphenylphosphine) ferrocene. The base is an organic or inorganic base, such as sodium t-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.

The reaction is preferably carried out in a suitable solvent which may be selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1, 4-dioxane and any combination thereof, preferably 1, 4-dioxane and toluene.

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (5) subjecting the compound II-A-11 to a deprotection reaction to obtain the compound II-A;

the deprotection reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of alcoholic protic solvents, tetrahydrofuran, methylene chloride, N-dimethylformamide and any combination thereof, preferably methylene chloride.

The reaction is carried out in the presence of a suitable deprotecting reagent. The deprotection reagent may be selected from the group consisting of trimethyliodosilane, hydrobromic acid acetic acid solution, trifluoroacetic acid, preferably trimethyliodosilane or hydrobromic acid acetic acid solution.

The deprotection reaction is carried out at a suitable temperature, preferably 0-100 ℃.

The reaction is carried out for a suitable time, for example 0.5 to 12 hours.

The present invention provides a third process for preparing a compound of formula (II-a), comprising the steps of:

Route 3

LG ¹ and X represents a leaving group including, but not limited to, a halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, and the like;

step (1) subjecting a compound IIb-A-1 to a ring closure reaction to obtain a compound IIb-A-2;

the ring closure reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from methanol, ethanol, tetrahydrofuran, and any combination thereof, preferably methanol.

The reaction is preferably carried out in the presence of a suitable organic base which may be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.

The reaction is carried out at a suitable temperature, preferably 20-60 ℃.

The reaction is carried out for a suitable time, for example 12-36 hours.

Step (2) subjecting the compound IIb-A-2 to substitution reaction to obtain a compound IIb-A-3;

the reaction is carried out in the presence of a suitable substitution reagent, which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxybromide, a catter condensing agent, preferably trifluoromethanesulfonic anhydride.

The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of dichloromethane, toluene, tetrahydrofuran, and any combination thereof, preferably dichloromethane.

The reaction is preferably carried out in the presence of a suitable organic or inorganic base, such as N, N-diisopropylethylamine, triethylamine, N-dimethylaniline, preferably N, N-diisopropylethylamine.

The reaction is carried out at a suitable temperature, preferably from 0 ℃ to 120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (3) reacting compound IIb-A-3 with compound II-A-10 to obtain compound IIb-A-4;

The reaction is carried out at a suitable temperature, preferably 20-100 ℃.

The reaction is carried out for a suitable time, for example 1 to 12 hours.

Step (4) subjecting the compound IIb-A-4 to a deprotection reaction to obtain a compound IIb-A-5;

The reaction is carried out for a suitable time, for example 2-12 hours.

Step (5) coupling the compound IIb-A-5 with the compound II-A-7 to obtain a compound IIb-A-6;

the coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tris (dibenzylideneacetone) dipalladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, tetrakis (triphenylphosphine) palladium, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6' -tri-isopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II), preferably methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6' -tri-isopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II). The base is an organic or inorganic base, such as sodium t-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.

The reaction is preferably carried out in a suitable solvent which may be selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1, 4-dioxane and any combination thereof, preferably toluene.

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (6) subjecting the compound IIb-A-6 to an oxidation reaction to obtain a compound IIb-A-7;

the oxidation reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from ethyl acetate, methanol, 1, 4-dioxane, dichloromethane, and any combination thereof, preferably dichloromethane.

The oxidation reaction is carried out in the presence of a suitable oxidizing agent. The oxidant can be selected from hydrogen peroxide, m-chloroperoxybenzoic acid and potassium hydrogen persulfate. Preferably m-chloroperoxybenzoic acid.

The reaction is carried out for a suitable time, for example 0.5 to 12 hours.

Step (7) substitution reaction of the compound IIb-A-7 with the compound II-A-4 to obtain a compound II-A-11;

the substitution reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from dichloromethane, toluene, tetrahydrofuran, and any combination thereof, preferably toluene.

The substitution reaction is preferably carried out in the presence of a suitable organic or inorganic base, for example sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium hydride, preferably potassium tert-butoxide.

The substitution reaction is carried out at a suitable temperature, preferably from 0 ℃ to 40 ℃.

The reaction is carried out for a suitable time, for example 0.5 to 16 hours.

Step (8) subjecting the compound II-A-11 to a deprotection reaction to obtain the compound II-A;

The reaction is carried out in the presence of a suitable deprotecting reagent. The deprotection reagent may be selected from the group consisting of trimethyliodosilane, hydrobromic acid acetic acid solution, trifluoroacetic acid. Preferably a solution of trimethyliodosilane or hydrobromic acid in acetic acid.

The reaction is carried out for a suitable time, for example 0.5 to 12 hours.

The present invention provides a process for preparing a compound of formula (II-C), comprising the steps of:

Route 4

LG ¹ represents a leaving group including, but not limited to, a halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, and the like;

PG ³ protecting groups representing amino groups, including but not limited to benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), benzyl, and the like;

(1) Reacting the compound II-A-9 to obtain a compound II-C-1;

the reaction is carried out in the presence of a suitable halogenated or pseudohalogenated reagent, which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxybromide, preferably trifluoromethanesulfonic anhydride.

The reaction is carried out at a suitable temperature, preferably from-70 ℃ to 100 ℃.

The reaction is carried out for a suitable time, for example 1 to 16 hours.

(2) Coupling the compound II-C-1 with the compound II-C-2 to obtain a compound II-C-3;

the coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tris (dibenzylideneacetone) dipalladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tetrakis (triphenylphosphine) palladium, palladium acetate, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex. The base is an organic or inorganic base, such as N, N-diisopropylethylamine, triethylamine, sodium t-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably sodium carbonate.

The reaction is preferably carried out in a suitable solvent which may be selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1, 4-dioxane and any combination thereof, preferably a combination of 1, 4-dioxane and water.

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

(3) Subjecting the compound II-C-3 to a reduction reaction to obtain a compound II-C-4;

the reduction reaction is preferably carried out in the presence of a metal catalyst. Preferably, the metal catalyst is a palladium metal catalyst or a platinum metal catalyst, such as palladium carbon, palladium hydroxide, platinum dioxide, preferably palladium carbon.

The reduction reaction is preferably carried out in the presence of hydrogen.

The reaction is preferably carried out in a suitable organic solvent which may be selected from methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and any combination thereof, preferably methanol.

The reaction is carried out at a suitable temperature, preferably 20-60 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

(4) Subjecting the compound II-C-4 to a deprotection reaction to obtain a compound II-C;

The reaction is carried out under suitable deprotection reagents. The deprotection reagent may be selected from the group consisting of trimethyliodosilane, hydrobromic acid acetic acid solution, trifluoroacetic acid. Hydrobromic acid acetic acid solution is preferred.

The reaction is carried out for a suitable time, for example 0.5 to 12 hours.

The present invention provides a second process for preparing a compound of formula (II-C), comprising the steps of:

Route 5

step (1) of subjecting the compound II-A-1 to a coupling reaction with the compound II-C-2 to obtain a compound IIa-C-3;

the coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tris (dibenzylideneacetone) dipalladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tetrakis (triphenylphosphine) palladium, palladium acetate, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex. The base is an organic or inorganic base such as N, N-diisopropylethylamine, triethylamine, sodium t-butoxide, potassium carbonate, cesium carbonate, potassium acetate, sodium carbonate, preferably potassium acetate.

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (2) of subjecting the compound IIa-C-3 to a coupling reaction with the compound II-A-4 to obtain a compound IIa-C-4;

the coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tris (dibenzylideneacetone) dipalladium, methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, tetrakis (triphenylphosphine) palladium, palladium acetate, preferably methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II). The base is an organic or inorganic base, such as diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (3) subjecting the compound IIa-C-4 to a deprotection reaction to obtain a compound IIa-C-5;

the reaction is preferably carried out in the presence of a metal catalyst. Preferably, the metal catalyst is a palladium metal catalyst or a platinum metal catalyst, such as palladium carbon, palladium hydroxide, platinum dioxide, preferably palladium carbon.

The reaction is preferably carried out in the presence of hydrogen.

The reaction is preferably carried out in a suitable organic solvent which may be selected from the group consisting of methanolic ammonia, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and any combination thereof, preferably methanolic ammonia.

The reaction is carried out at a suitable temperature, preferably 20-60 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (4) of subjecting the compound IIa-C-5 to a coupling reaction with the compound II-A-7 to obtain a compound II-C-4;

The reaction is carried out at a suitable temperature, preferably 50-120 ℃.

The reaction is carried out for a suitable time, for example 2-16 hours.

Step (5) subjecting the compound II-C-4 to a deprotection reaction to obtain a compound II-C;

The reaction is carried out in the presence of a suitable deprotecting reagent. The deprotection reagent may be selected from the group consisting of trimethyliodosilane, hydrobromic acid acetic acid solution, trifluoroacetic acid, preferably trifluoroacetic acid.

The deprotection reaction is carried out at a suitable temperature, preferably 0-80 ℃.

The reaction is carried out for a suitable time, for example 0.5 to 12 hours.

The specific conditions for each of the above reaction steps are well known in the art, and the present invention is not particularly limited thereto. Based on the teachings of the present invention, and in combination with the common general knowledge in the art, a person skilled in the art can choose and replace each substituent in the general formula to prepare different compounds, and these choices and substitutions are all within the scope of the present invention.

Pharmaceutical composition and kit

It is another object of the present invention to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, and one or more pharmaceutically acceptable carriers.

It is another object of the present invention to provide a kit comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound or metabolite thereof, or a pharmaceutical composition of the present invention, and optionally, packaging and/or instructions.

By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions or pharmaceutical formulations of the present invention include, but are not limited to, sterile liquids, such as water and oils.

The pharmaceutical composition may be in the form of, for example, a solid formulation, a semi-solid formulation, a liquid formulation, a gaseous formulation, or the like.

The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally or by oral administration.

The compounds of the present invention may be present in the pharmaceutical composition in an amount or amount of about 0.001mg to about 1000mg.

In some embodiments, the present invention provides a method of preparing a pharmaceutical composition of the present invention, the method comprising combining a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, or metabolite thereof, with one or more pharmaceutically acceptable carriers.

Therapeutic methods and uses

It is another object of the present invention to provide a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound or metabolite thereof, or a pharmaceutical composition of the present invention, for use in inhibiting KRAS G12D.

It is another object of the present invention to provide a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of KRAS G12D-mediated related diseases.

It is another object of the present invention to provide the use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention or treatment of KRAS G12D-mediated related diseases.

It is another object of the present invention to provide a method for preventing or treating KRAS G12D-mediated diseases comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound or metabolite thereof, or a pharmaceutical composition of the present invention.

According to some embodiments of the invention, the KRAS G12D-mediated related disease is a tumor, preferably the KRAS G12D-mediated related disease is a cancer.

The term "effective amount" as used herein refers to an amount sufficient to achieve a desired prophylactic or therapeutic effect, e.g., an amount that achieves alleviation of one or more symptoms associated with a disease to be treated.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.

The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg per kg body weight per day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, or preventing the progression of a disorder or condition to which such term applies or one or more symptoms of such disorder or condition.

As used herein, the term "preventing" includes inhibiting and delaying the onset of a disease, and includes not only preventing prior to the development of a disease, but also preventing recurrence of a disease after treatment.

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Examples

In order to make the objects and technical solutions of the present invention more apparent, embodiments of the present invention will be described in detail with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The specific conditions not specified in the examples were either conventional or manufacturer-recommended. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

The structure of the compound is that nuclear magnetic resonance is adopted ¹ H NMR) or Mass Spectrometry (MS). ¹ The H NMR measuring instrument is JEOL Eclipse 400 nuclear magnetic instrument, and the measuring solvent is deuterated methanol (CD) ₃ OD), deuterated chloroform (CDCl) ₃ ) Or hexadeuterated dimethyl sulfoxide (DMSO-d) ₆ ) The internal standard is Tetramethylsilane (TMS), and the chemical shift (δ) is given in parts per million (ppm).

The MS measurement instrument was an Agilent (ESI) mass spectrometer, manufacturer: agilent, model: agilent 6120B.

The preparation method for preparing the high performance liquid chromatograph comprises the following steps:

instrument model: agilent 1260, chromatographic column: waters SunFire Prep C18OBD (19 mm. Times.150 mm. Times.5.0 μm); chromatographic column temperature: 25 ℃; flow rate: 20.0mL/min; detection wavelength: 214nm; elution gradient: (0 min:10% A,90% B;16.0min:90% A,10% B); mobile phase a: acetonitrile; mobile phase B:0.05% formic acid in water.

Thin layer chromatography silica gel plate (TLC) an aluminum plate (20X 20 cm) produced by Merck was used, and the specification used for separation and purification by thin layer chromatography was GF 254 (1 mm) produced by tobacco stand.

Monitoring the reaction by Thin Layer Chromatography (TLC) or LC-MS; the developer system used included: the volume ratio of the solvent is adjusted according to the polarity of the compound or is adjusted by adding triethylamine and the like.

The microwave reaction uses Biotage Initiator + (400W, RT-300 ℃) microwave reactor.

Column chromatography generally uses 200-300 mesh silica gel as a carrier. The eluent system comprises: the volume ratio of the methylene dichloride to the methanol system to the petroleum ether to the ethyl acetate system is adjusted according to the polarity of the compound, and a small amount of triethylamine can be added for adjustment.

The reaction temperature is room temperature (20-35 ℃), without specific explanation in examples;

the reagents used in the present invention are available from Acros Organics, aldrich Chemical Company, tertbe chemistry, etc.

In the conventional synthesis methods, examples and examples of intermediate synthesis, the meanings of the abbreviations are shown below.

Abbreviations (abbreviations)	Meaning of
TLC	Thin layer chromatography
LC-MS	Liquid chromatography-mass spectrometry combination
DMF	N, N-dimethylformamide
Pd(dppf)Cl ₂	[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
CD ₃ OD	Deuterated methanol
CDCl ₃	Deuterated chloroform
DMSO-d ₆	Hexadeuterated dimethyl sulfoxide
TMS	Tetramethylsilane
NMR	Nuclear magnetic resonance
MS	Mass spectrometry
Boc	Boc-group
Cbz	Benzyloxycarbonyl group
s	Single peak (Single)
d	Double peak (doubelet)

t	Triplet (triplet)
q	Quartet (quatet)
dd	Double peaks (double)
m	Multiple peaks (multiple)
br	Broad peak (broad)
J	Coupling constant
Hz	Hertz device

Intermediate preparation example

Intermediate preparation example 1: preparation of (S) -7- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-ol

The first step: preparation of tert-butyl 2-chloro-4-methoxy-5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate

Sodium (175.6 mg,7.64 mmol) was dissolved in methanol (20 mL), after complete dissolution, the system was cooled to 0deg.C, a solution of tert-butyl 2, 4-dichloro-5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate (2.11 g,6.94 mmol) in methanol (20 mL) was added, stirred at 15deg.C for 4 hours, concentrated, diluted with ethyl acetate (50 mL), washed twice with water (30 mL), dried, and concentrated to give the title compound of this step (1.95 g, yield: 94%).

MS m/z(ESI):300.0[M+H] ⁺ 。

And a second step of: preparation of (S) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

2-chloro-4-methoxy-5, 6-dihydropyrido [3,4-d ]]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (1.95 g,6.52 mmol) and N-methyl-L-prolol (1.58 g,13.04 mmol) were dissolved in 1, 4-dioxane (30 mL), cesium carbonate (6.44 g,19.56 mmol) was added, nitrogen replaced three times, pd (dppf) Cl was added ₂ (486.71 mg,0.65 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (794.07 mg,1.30 mmol) were stirred at 100℃for 12 hours, cooled to room temperature, water (40 mL) was added, extraction was performed three times with ethyl acetate (30 mL), drying, concentration and purification by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) gave the title compound (2.3 g, yield: 93%) of the present step.

MS m/z(ESI):379.1[M+H] ⁺ 。

And a third step of: preparation of (S) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine trifluoroacetate salt

(S) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (2.3 g,6.60 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added dropwise, and stirred at room temperature for 2 hours, and concentrated to give the title compound of this step (3.9 g, yield: 94%).

MS m/z(ESI):279.1[M+H] ⁺ 。

Fourth step: preparation of (S) -7- (8-chloronaphthalen-1-yl) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

(S) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine trifluoroacetate (3.9 g, 7.7 mmol) and 1-bromo-8-chloronaphthalene (2.42 g,10.02 mmol) were dissolved in dry 1, 4-dioxane (80 mL), cesium carbonate (17.68 g,54.21 mmol) was added, and tris (dibenzylideneacetone) dipalladium (1.06 g,1.15 mmol) and 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (718 mg,1.54 mmol) were added under nitrogen protection, stirred at 95℃for 10 hours, water (50 mL) was added, extracted three times with ethyl acetate (40 mL), concentrated, and purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1 volume ratio) to give the title compound (1.70 g, 96.5%) in this step.

MS m/z(ESI):439.0[M+H] ⁺ 。

Fifth step: preparation of (S) -7- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-ol

(S) -7- (8-chloronaphthalen-1-yl) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (1.70 g,3.87 mmol) was dissolved in DMF (25 mL), sodium ethanethiolate (1.30 g,15.49 mmol) was added, stirred at 100deg.C for 1 hour, aqueous ammonium chloride (50 mL) was added, extracted three times with ethyl acetate (25 mL), then extracted twice with chloroform (30 mL), dried and concentrated to give the title compound of this step (1.5 g, yield: 91.1%).

MS m/z(ESI):425.1[M+H] ⁺ 。

Intermediate preparation example 2: preparation of benzyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

The first step: preparation of 8-benzyl-3-tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3, 8-dicarboxylate

Tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate (5.0 g,23.55 mmol) was dissolved in dichloromethane (50 mL). N, N-diisopropylethylamine (9.22 g,70.66 mmol) was added under nitrogen. The system was cooled to 0℃to which benzyl chloroformate (6.34 g,35.33 mmol) was added dropwise and stirred at 25℃for 4 hours, followed by water washing, drying and concentration to give the title compound (8.16 g, yield: 100%).

MS m/z(ESI):347.2[M+H] ⁺ 。

And a second step of: preparation of benzyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

8-benzyl-3-tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3, 8-dicarboxylate (8.16 g,23.52 mmol) was dissolved in trifluoroacetic acid (40 mL) and dichloromethane (80 mL). The system was stirred at 20 ℃ for 2 hours, concentrated, and aqueous phase pH >8 was added with sodium bicarbonate solution. The organic phase was extracted three times with ethyl acetate (50 mL), dried, concentrated and slurried (eluent: petroleum ether/ethyl acetate=10/1, volume ratio) for 12 hours, then filtered and dried to give the title compound (4.6 g, yield: 79%).

MS m/z(ESI):247.1[M+H] ⁺ 。

Intermediate preparation example 3: preparation of benzyl 3- (2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

The first step: preparation of 4- (8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

Tert-butyl 2, 4-dichloro-5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate (1.0 g,3.29 mmol) and N, N-diisopropylethylamine (1.29 g,9.87 mmol) were dissolved in DMF (10 mL) and benzyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.85 g,3.29 mmol) was added. The system was stirred at 80 ℃ for 2 hours, diluted with ethyl acetate (30 mL), then washed with water, dried, concentrated and purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=2/1, volume ratio) to give the title compound (1.2 g, yield: 67%).

MS m/z(ESI):514.2[M+H] ⁺ 。

And a second step of: preparation of tert-butyl 4-8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((hexahydro-1H-pyrrolizine-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate

4- (8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (1.3 g,2.53 mmol) and (hexahydro-1H-pyrrolizin-7 a-yl) methanol (0.714g, 5.06 mmol) were dissolved in 1.4-dioxane (20 mL) and cesium carbonate (2.5 g,7.59 mmol) was added. Three times with nitrogen, then [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (188.83 mg,0.25 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (308.08 mg,0.51 mmol) were added and stirred at 100℃for 12 hours. The system was cooled to room temperature, water (40 mL) was added, and extraction was performed three times with ethyl acetate (30 mL), and the organic layer was dried, concentrated, and purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (430 mg, yield: 53.5%).

MS m/z(ESI):619.4[M+H] ⁺ 。

And a third step of: preparation of benzyl 3- (2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

4- (8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (430 mg,0.70 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added dropwise and stirred at room temperature for 2 hours. The system was concentrated, and aqueous phase pH >8 was added with sodium bicarbonate solution, followed by extraction three times with ethyl acetate (30 mL), and the organic phase was dried and concentrated to give the title compound (220 mg, yield: 60.9%).

MS m/z(ESI):519.4[M+H] ⁺ 。

Intermediate preparation example 4: preparation of benzyl 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (methylsulfinyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

The first step: preparation of 4-hydroxy-2- (methylthio) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

Sodium methoxide (29.26 g,531 mmol) was dissolved in methanol (500 mL), ethyl 1-N-t-butoxycarbonyl-3-oxopiperidine-4-carboxylate (25.0 g,88.46 mmol) was added followed by S-methyl isothiourea sulfate (46.66 g,159.23 mmol). The system was stirred at room temperature for 16 hours, pH >5 was adjusted with 2 molar hydrochloric acid, concentrated, then vigorously stirred with water to form a solid, filtered, the solid was rinsed with ethyl acetate (100 mL), the filter cake was collected, and dried to give the title compound (22.67 g, yield: 77%).

MS m/z(ESI):298.1[M+H] ⁺ 。

And a second step of: preparation of tert-butyl 2- (methylthio) -4- ((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate

4-hydroxy-2- (methylthio) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (22.67 g,76.33 mmol) was dissolved in dichloromethane (300 mL), N-diisopropylethylamine (19.7 g,152.66 mmol) was added, the system was cooled to 0 ℃, trifluoromethanesulfonic anhydride (32.53 g,114.5 mmol) was added dropwise, after the dropwise addition was completed, the system was stirred at room temperature for 2 hours, concentrated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1, volume ratio) to give the title compound (20.4 g, yield: 62%).

MS m/z(ESI):430.1[M+H] ⁺ 。

And a third step of: preparation of 4- (8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (methylsulfanyl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

Tert-butyl 2- (methylthio) -4- ((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylate (1.0 g,2.33 mmol) and N, N-diisopropylethylamine (0.9 g,6.99 mmol) were dissolved in DMF (10 mL) and benzyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.57 g,2.33 mmol) was added. The system was stirred at 100℃for 2 hours, diluted with ethyl acetate (30 mL), then washed with water, dried, concentrated and purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=2/1, volume ratio) to give the title compound (1.0 g, yield: 82%).

MS m/z(ESI):526.2[M+H] ⁺ 。

Fourth step: preparation of benzyl 3- (2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

4- (8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (methylsulfanyl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (1.0 g,1.9 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added dropwise and stirred at room temperature for 2 hours. The system was concentrated, and sodium bicarbonate solution was added to bring the aqueous phase to pH >8, followed by extraction three times with ethyl acetate (30 mL), and the organic phase was dried and concentrated to give the title compound (810 mg, yield: 100%).

MS m/z(ESI):426.1[M+H] ⁺ 。

Fifth step: preparation of benzyl 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Benzyl 3- (2- (methylthio) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.81 g,1.9 mmol) and 3-benzyloxy-1-bromonaphthalene (0.89 g,2.86 mmol) were dissolved in toluene (10 mL) and cesium carbonate (1.86 g,5.7 mmol) was added. Three times with nitrogen, then methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (160.82 mg,0.19 mmol) was added and stirred at 100 ℃ for 12 hours. The system was cooled to room temperature, water (40 mL) was then added, and extraction was performed three times with ethyl acetate (30 mL), and the organic layer was dried, concentrated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1, volume ratio) to give the title compound (750 mg, yield: 60%).

MS m/z(ESI):658.2[M+H] ⁺ 。

Sixth step: preparation of benzyl 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (methylsulfinyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Benzyl 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (methylsulfanyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.75 g,1.14 mmol) was dissolved in dichloromethane (10 mL), the system was cooled to 0deg.C, m-chloroperoxybenzoic acid (0.23 g,1.14 mmol) was added and stirred at 0deg.C for 0.5 hours. Sodium thiosulfate solution was added and stirred for 0.5 hour, water (10 mL) was added, followed by extraction three times with ethyl acetate (30 mL), and the organic phase was dried, concentrated and purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (400 mg, yield: 52%).

MS m/z(ESI):674.2[M+H] ⁺ 。

Intermediate preparation example 5: preparation of ((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

The first step: preparation of (2R, 4S) -1- (tert-butyl) 2-methyl-4-fluoropyrrolidine-1, 2-dicarboxylic acid ester

(2R, 4R) -1- (tert-butyl) 2-methyl-4-hydroxypyrrolidine-1, 2-dicarboxylic acid ester (4.0 g,16.31 mmol) was dissolved in methylene chloride (50 mL), diethylaminosulfur trifluoride (5.0 g,30.99 mmol) was added at-78℃and the reaction mixture was stirred at-78℃for 2 hours, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction by TLC, an aqueous sodium hydrogencarbonate solution was added under an ice bath, and the organic phase was separated out by a separating funnel and dried and concentrated to give the title compound (4.0 g, yield: 99%).

LCMS:248.1[M+H] ⁺ 。

And a second step of: preparation of (2R, 4S) -1- (tert-butyl) 2-methyl 2- (3-chloropropyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester

(2R, 4S) -1- (tert-butyl) 2-methyl-4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (4 g,16.18 mmol) was dissolved in tetrahydrofuran (16 mL), hexamethylphosphoric triamide (3.77 g,21.03 mmol) was added thereto, cooled to-70℃and lithium bis trimethylsilylamide (21 mL,21.03 mmol) was slowly added dropwise. After stirring at-70℃for 1 hour, 1-bromo-3-chloropropane (12.74 g,80.9 mmol) is slowly added dropwise, the reaction is allowed to warm to room temperature and stirring is continued for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (50 mL), extracted three times with ethyl acetate (30 mL), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1, volume ratio) to give the title compound (1.90 g, yield: 36.3%).

LCMS:324.1[M+H] ⁺ 。

And a third step of: preparation of (2R, 4S) -2- (3-chloropropyl) -4-fluoropyrrolidine-2-carboxylic acid methyl ester hydrochloride

(2R, 4S) -1- (tert-butyl) 2-methyl-2- (3-chloropropyl) -4-fluoropyrrolidine-1, 2-dicarboxylic acid ester (2 g,6.18 mmol) was dissolved in ethyl acetate (30 mL), and an ethyl acetate hydrochloride solution (15 mL) was added to stir the reaction solution at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to give the title compound (1.608 g, crude product).

LCMS:224.1[M+H] ⁺ 。

Fourth step: preparation of (2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester

(2R, 4S) -2- (3-chloropropyl) -4-fluoropyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.608 g,16.18 mmol) was dissolved in acetonitrile (20 mL), sodium hydrogencarbonate (2.6 g,30.9 mmol) and potassium iodide (103 mg,0.618 mmol) were added and the reaction was stirred at 50℃for 12 hours. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1, volume ratio) to give the title compound (933 mg, yield: 80.4%).

LCMS:188.2[M+H] ⁺ 。

Fifth step: preparation of ((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol

(2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid methyl ester (933 mg,4.98 mmol) was dissolved in tetrahydrofuran (25 mL), lithium aluminum hydride (567 mg,14.94 mmol) was added at-40℃and the reaction solution was stirred at-40℃for 1 hour. The reaction was quenched with aqueous sodium sulfate at 0℃and diluted with tetrahydrofuran, and concentrated by filtration to give the title compound (716 mg, yield: 90.2%).

LCMS:160.1[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ5.32-5.16(m,1H),4.13-3.67(m,1H),3.49-3.32(m,3H),3.05-2.99(m,1H),2.91-2.78(m,1H),2.71-2.65(m,1H),2.26-2.17(m,2H),1.95-1.78(m,4H),1.65-1.59(m,1H)。

Intermediate preparation example 6: preparation of benzyl 3- (2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

The first step: preparation of tert-butyl 4- (8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate

Tert-butyl 4- (8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate (400 mg,0.74 mmol), ((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (123.89 mg,0.74 mmol), cesium carbonate (608.26 mg,1.85 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (43.21 mg,0.074 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (27.32 mg,0.037 mmol) were sequentially added to 1, 4-dioxane (10 mL), the reaction system was replaced three times with nitrogen, and stirred at 100℃for 12 hours. The system was cooled to room temperature, the solvent was then removed by rotary evaporation under reduced pressure, and the product was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (278 mg, yield: 56.10%).

MS m/z(ESI):637.4[M+H] ⁺ 。

And a second step of: preparation of benzyl 3- (2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

4- (8- ((benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (278 mg, 414.76. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled with an ice water bath, hydrochloric acid/1, 4-dioxane solution (3 mL) was added dropwise at 0℃after the dropwise addition, and the reaction system was stirred at room temperature for 4 hours. The reaction system was concentrated to remove the solvent, the residue was dissolved in ice water (10 mL), ph=7 was adjusted with sodium bicarbonate solution, a solid was precipitated, and the filtrate was suction-filtered and dried to give the title compound (184 mg, yield: 78.53%).

MS m/z(ESI):537.3[M+H] ⁺ 。

Intermediate preparation example 7: preparation of 3- (2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

The first step: preparation of 3- (7-benzyl-2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester

7-benzyl-2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [3,4-D ] pyrimidine (5.0 g,17.0 mmol), 8-t-butoxycarbonyl-8-azabicyclo [3.2.1] oct-2-ene-3-boronic acid pinacol ester (8.5 g,25.5 mmol), potassium acetate (5.0 g,51 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (1.24 g,1.7 mmol) were added to 1, 4-dioxane (50 mL) and water (10 mL), replaced with nitrogen three times, and the reaction system was stirred at 90℃for 12 hours. After the system was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and purification by thin layer chromatography (eluent: petroleum ether/ethyl acetate=2/1, volume ratio) gave the title compound (4.96 g, yield: 62.5%).

MS m/z(ESI):467.2[M+H] ⁺ 。

And a second step of: preparation of 3- (7-benzyl-2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester

3- (7-benzyl-2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester (4.96 g,10.6 mmol), ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (3.38 g,21.2 mmol), cesium carbonate (10.36 g,31.8 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (0.89 g,1.06 mmol) was sequentially added to toluene (80 mL), the reaction system was replaced three times with nitrogen gas, and stirred at 110℃for 4 hours. The system was cooled to room temperature, the solvent was then removed by rotary evaporation under reduced pressure, and the product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (3.2 g, yield: 51.0%).

MS m/z(ESI):590.3[M+H] ⁺ 。

And a third step of: preparation of 3- (2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

3- (7-benzyl-2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester (3.2 g,5.42 mmol) was dissolved in an methanolic ammonia solution (50 mL), 10% palladium on carbon (0.8 g) was added, replaced with hydrogen three times, and the reaction system was stirred in a hydrogen atmosphere at 45℃for 24 hours. The system was cooled to room temperature, filtered, and concentrated to give the title compound (2.58 g, yield: 94.8%).

MS m/z(ESI):502.3[M+H] ⁺ 。

Intermediate preparation example 8: preparation of 1, 8-dibromo-3- (methoxymethoxy) naphthalene

The first step: preparation of 2- (4, 5-dibromo-2-naphthyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan

1, 8-dibromonaphthalene (1 g,3.46 mmol), bis (1, 5-cyclooctadiene) bis-m-methoxydiidium (I) (114.49 mg, 173.10. Mu. Mol), 4 '-di-t-butyl-2, 2' -bipyridine (56.31 mg, 207.72. Mu. Mol) were dissolved in tetrahydrofuran (15.0 mL), replaced three times with nitrogen, 4, 5-tetramethyl-1, 3, 2-dioxaborolan (4.48 g,34.62 mmol) was added by injection under stirring, and the system was stirred at 70℃for 10 hours. After the reaction solution was cooled to room temperature, the reaction was quenched by dropping water (30 mL) into the reaction solution, extracted twice with ethyl acetate (30 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give the title compound (648 mg, yield: 22.72%).

MS m/z(ESI):413.0[M+H] ⁺ 。

And a second step of: preparation of 4, 5-dibromonaphthalen-2-ol

2- (4, 5-dibromo-2-naphthyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (254 mg,1.11 mmol) was dissolved in tetrahydrofuran (5.08 mL), water (17 mL) was further added, acetic acid (5.17 g,71.35 mmol) and 30% hydrogen peroxide (2.41 g,21.22 mmol) were added with stirring at 10℃and the reaction system was reacted at 10℃for 15 hours. Sodium bisulphite solution (20 mL) was added to the reaction solution, extracted twice with ethyl acetate (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4/1, volume ratio) to give the title compound (268 mg, yield: 75.87%).

MS m/z(ESI):303.1[M+H] ⁺ 。

And a third step of: preparation of 1, 8-dibromo-3- (methoxymethoxy) naphthalene

4, 5-Dibromonaphthalen-2-ol (162 mg, 509.67. Mu. Mol) was dissolved in methylene chloride (3.5 mL), and bromomethane (193.69 mg,1.53 mmol) and N, N-diisopropylethylamine (333.14 mg,2.55 mmol) were added with stirring at 0℃to react for 1 hour at a temperature of 0 ℃. To the reaction solution was added water (10 mL), extracted with methylene chloride (20 mL), the organic phases were washed twice with water (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=9/1, volume ratio) to give the title compound (160 mg, yield: 81.65%).

MS m/z(ESI):347.1[M+H] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ7.72(dd,J＝8.0Hz,J＝4.0Hz,1H),7.64(dd,J＝8.0Hz,J＝4.0Hz,2H),7.32(d,J＝4.0Hz,1H),7.16-7.11(m,1H),5.20(s,2H),3.44(s,3H)。

Preparation example

Example 1: preparation of 3- (7- (8-chloronaphthalen-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane (compound 1)

The first step: preparation of 3- (7- (8-chloronaphthalen-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester

(S) -7- (8-chloronaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-ol (200 mg,0.47 mmol) was dissolved in DMF (6 mL), 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane (280.56 mg,1.42 mmol), a catter condensing agent (415.74 mg,0.94 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (216.18 mg,1.42 mmol) were added under nitrogen protection, stirred at 90℃for 2 hours, cooled to room temperature, water (30 mL) was added, extracted three times with ethyl acetate (20 mL), dried, concentrated, and purified by silica gel column chromatography (eluent: dichloromethane/methanol=8/1, volume ratio) to give the title compound (120 mg, yield: 42.1%).

MS m/z(ESI):605.1[M+H] ⁺ 。

And a second step of: preparation of 3- (7- (8-chloronaphthalen-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane (compound 1)

3- (7- (8-chloronaphthalen-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (120 mg,0.29 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (2 mL), stirred at room temperature for 2 hours, the reaction was concentrated, diluted with ethyl acetate (20 mL), ph=8 adjusted with saturated sodium bicarbonate solution (10 mL), extracted twice with ethyl acetate (10 mL), the organic phases were combined, dried, concentrated, purified by preparative high performance liquid chromatograph to give the title compound (8 mg, yield: 8.0%).

MS m/z(ESI):505.2[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ ):δ7.93(dd,J＝7.2Hz,8.0Hz,1H),7.75(d,J＝7.6Hz,1H),7.60-7.53(m,2H),7.46(t,J＝8.0Hz,1H),7.35(d,J＝7.2Hz,1H),4.32(d,J＝8.8Hz,1H),4.28-4.24(m,1H),4.18-3.89(m,8H),3.75-3.71(m,1H),3.53-3.50(m,1H),3.38-3.30(m,2H),3.09-3.03(m,1H),2.99-2.94(m,2H),2.63-2.57(m,1H),2.35(s,3H),2.22-2.16(m,1H),1.95-1.89(m,1H),1.72-1.56(m,4H)。

Example 2: preparation of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 2)

The first step: preparation of tert-butyl (1R, 5S) -3- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8 carboxylate

Using the synthetic route of example 1, the reaction starting material 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane from the first step was replaced with tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate to give the title compound (108 mg, yield: 45.4%).

MS m/z(ESI):619.3[M+H] ⁺ 。

And a second step of: preparation of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 2)

Using the synthetic route of example 1, the second reaction starting material 3- (7- (8-chloronaphthalen-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester was replaced with (1R, 5S) -3- (7- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester to give the title compound (12 mg, yield: 13.5%).

MS m/z(ESI):519.2[M+H] ⁺

¹ H-NMR(400MHz,CD ₃ OD):δ8.50(br,1H),7.84-7.82(m,1H),7.70-7.68(m,1H),7.54-7.48(m,2H),7.40-7.32(m,2H),4.59-4.55(m,1H),4.49-4.44(m,1H),4.39-4.30(m,2H),4.05(s,2H),3.94-3.90(m,1H),3.74-3.69(m,1H),3.63-3.47(m,4H),3.25-3.12(m,3H),2.96-2.94(m,1H),2.86(s,3H),2.68-2.64(m,1H),2.29-2.23(m,2H),2.08-1.86(m,6H)。

Example 3: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H)) -yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) naphthalen-2-ol (compound 29)

The first step: preparation of benzyl 3- (7- (3-benzyloxy-1-naphthyl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H)) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

3- (7- (3-benzyloxy-1-naphthyl) -2- (methylsulfinyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester (50 mg, 70.49. Mu. Mol) and ((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (17.72 mg, 105.74. Mu. Mol) were dissolved in toluene (5 mL), cooled in an ice water bath, potassium t-butoxide (13.69 mg, 140.99. Mu. Mol) was added in portions at 0℃and the reaction system was stirred at 0℃for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (25 mg, yield: 43.82%).

MS m/z(ESI):769.4[M+H] ⁺

¹ H-NMR(400MHz,CD ₃ OD):δ8.11(d,J＝12Hz,1H),7.75(d,J＝8Hz,1H),7.50(d,J＝8Hz,2H),7.42-7.30(m,10H),7.08(s,1H),6.90(s,1H),5.19(s,4H),4.62(s,4H),4.41-4.36(m,2H),4.14-4.10(m,2H),3.48-3.46(m,1H),3.14-3.12(m,1H),2.99-2.92(m,3H),2.01-1.94(m,9H),1.37-1.22(m,7H)。

And a second step of: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2 s,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H)) -yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) naphthalen-2-ol

Benzyl 3- (7- (3-benzyloxy-1-naphthyl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H)) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (25 mg, 29.26. Mu. Mol) was dissolved in dichloromethane (4 mL), cooled with an ice water bath, and a hydrobromic acid/acetic acid solution (39.46 mg, 146.31. Mu. Mol) was dropped at 0℃after dropping, and the reaction system was stirred at 0℃for 0.5 hours. The reaction system was separated to remove the supernatant, and the solid was adjusted to ph=7 with sodium hydrogencarbonate solution and purified by high performance liquid chromatography to give the title compound (3.5 mg, yield: 19.24%).

MS m/z(ESI):545.3[M+H] ⁺

¹ H-NMR(400MHz,CD ₃ OD):δ8.40-8.38(m,1H),8.07(d,J＝8Hz,1H),7.64(d,J＝8Hz,1H),7.37(t,J＝8Hz,1H),7.26(t,J＝8Hz,1H),6.88(d,J＝4Hz,1H),6.79(d,J＝4Hz,1H),5.49-5.36(m,1H),4.50-4.36(m,2H),4.26-4.12(m,6H),3.76-3.68(m,1H),3.45-3.41(m,4H),3.16-2.98(m,4H),2.60-2.52(m,1H),2.25-1.98(m,10H)。

Example 4: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) naphthalen-2-ol (compound 28)

The first step: preparation of benzyl 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 3, the reaction starting material ((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol from the first step was replaced with (hexahydro-1H-pyrrolizine-7 a-yl) methanol to give the title compound (61 mg, yield: 45.9%) of the present step.

MS m/z(ESI):752.3[M+H] ⁺ 。

And a second step of: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) naphthalen-2-ol

Using the synthetic route of example 3, the second step of reaction starting 3- (7- (3-benzyloxy-1-naphthyl) -2- (((2 s,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H)) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate was replaced with benzyl 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (hexahydro-1H-pyrrolizine-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate to give the title compound (10 mg, yield: 30.1%).

MS m/z(ESI):527.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )δ8.30(s,1H),7.99(d,J＝8.4Hz,1H),7.66(d,J＝8.0Hz,1H),7.43-7.21(m,2H),6.81(dd,J＝8.0,2.0Hz,2H),4.07(d,J＝6.4Hz,4H),3.97(d,J＝12.0Hz,2H),3.87(s,2H),3.40-2.62(m,10H),2.03-1.54(m,12H)。

Example 5: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 32)

The first step: preparation of benzyl 3- (7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

3- (2- (2-fluoro- (hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester (100 mg,0.19 mmol) and 1, 8-dibromonaphthalene (108.68 mg,0.38 mmol) were dissolved in dry 1, 4-dioxane (5 mL), cesium carbonate (188 mg,0.57 mmol) was added, nitrogen protection, tris (dibenzylideneacetone) dipalladium (17 mg,0.019 mmol) and 1,1' -bis (diphenylphosphine) ferrocene (21 mg,0.038 mmol) were added, stirred at 95℃for 10 hours, extracted three times with ethyl acetate (10 mL), concentrated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound of this step (28.6 mg, yield: 40%).

MS m/z(ESI):725.2[M+H] ⁺ 。

And a second step of: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

3- (7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizine-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester (40 mg,0.055 mmol) was dissolved in dichloromethane (5 mL), trimethyliodosilane (110 mg,0.55 mmol) was added dropwise, stirred at room temperature for 1 hour, filtered, the filter cake was collected and suspended in ethyl acetate (10 mL), sodium sulfite (5 mL) was added and stirred for 5 minutes, water (10 mL) was added, the mixture was separated, then extracted twice with ethyl acetate (10 mL), the organic phases were combined, dried, concentrated, and purified by preparative high performance liquid chromatograph to give the title compound (15 mg, yield: 46.1%).

MS m/z(ESI):589.2[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ ):δ7.97(dd,J＝7.2Hz,8.0Hz,1H),7.83-7.81(m,1H),7.75(d,J＝8.0Hz,1H),7.55(t,J＝8.0Hz,1H),7.37-7.34(m,2H),4.10(d,J＝10Hz,1H),4.00(d,J＝12Hz,1H),3.86(t,J＝12Hz,1H),3.62-3.44(m,6H),3.35-3.19(m,7H),3.10(d,J＝4.0Hz,2H),2.95-2.89(m,2H),2.51-2.49(m,1H),1.86-1.67(m,8H),1.57-1.50(m,2H)。

Example 6: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-bromonaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 31)

The first step: preparation of benzyl 3- (7- (8-bromonaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

3- (2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a ((5H) -yl) methoxy)) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester (60 mg, 100.63. Mu. Mol), 1, 8-dibromonaphthalene (43.60 mg, 150.94. Mu. Mol), potassium t-butoxide (28.51 mg, 251.57. Mu. Mol), 1' -bis (diphenylphosphine) ferrocene (5.63 mg, 10.06. Mu. Mol) and tris (dibenzylideneacetone) dipalladium (4.65 mg, 5.03. Mu. Mol) were added to toluene (5 mL), replaced three times with nitrogen gas, and the reaction system was stirred at 90℃for 9 hours. The system was cooled to room temperature, the solvent was then removed by rotary evaporation under reduced pressure, and the product was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (43 mg, yield: 54.7%).

MS m/z(ESI):741.1[M+H] ⁺ 。

And a second step of: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-bromonaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

Benzyl 3- (7- (8-bromonaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (43 mg, 52.18. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled with an ice water bath, and a hydrobromic acid/acetic acid solution (68.70 mg, 254.73. Mu. Mol) was dropped at 0℃and the reaction system was stirred at 0℃for 0.5 hours. The reaction system was separated to remove the supernatant, and the solid was adjusted to ph=7 with sodium hydrogencarbonate solution and purified by high performance liquid chromatography to give the title compound (16.8 mg, yield: 46.8%).

MS m/z(ESI):607.2[M+H] ⁺

¹ H-NMR(400MHz,CD ₃ OD):δ7.88(dd,J＝8.0Hz,J＝4.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.28(t,J＝8.0Hz,1H),5.41-5.27(m,1H),4.37-4.18(m,4H),3.96-3.87(m,3H),3.66-3.51(m,4H),3.24-3.17(m,4H),3.11-2.83(m,2H),2.66-2.42(m,2H),2.27-1.83(m,9H)。

Example 7: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 30)

The first step: preparation of benzyl 3- (7- (8-chloronaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 6, the reaction starting material 1, 8-dibromonaphthalene in the first step was replaced with 1-bromo-8-chloronaphthalene to give the title compound (48 mg, yield: 65%).

MS m/z(ESI):697.3[M+H] ⁺ 。

And a second step of: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

The synthetic route of example 6 was used to replace the second step of reaction starting 3- (7- (8-bromonaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate with benzyl 3- (7- (8-chloronaphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate to give the title compound (11.0 mg, yield: 27.7%).

MS m/z(ESI):563.2[M+H] ⁺

¹ H-NMR(400MHz,CD ₃ OD):δ7.84(d,J＝8Hz,1H),7.69(d,J＝8Hz,1H),7.54-7.49(m,2H),7.39-7.31(m,2H),5.39-5.25(m,1H),4.36-4.09(m,4H),3.85-3.42(m,7H),3.22-3.07(m,4H),3.00-2.76(m,2H),2.64-2.41(m,2H),2.22-1.79(m,9H)。

Example 8: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 33)

The first step: preparation of benzyl 3- (7- (8-chloronaphthalen-1-yl) -2- (hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 5, the reaction starting material 1, 8-dibromonaphthalene in the first step was replaced with 1-bromo-8-chloronaphthalene to give the title compound in the present step (40 mg, yield: 33.9%).

MS m/z(ESI):679.2[M+H] ⁺ 。

And a second step of: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

The synthetic route of example 5 was followed to replace the second step starting material 3- (7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester with 3- (7- (8-chloronaphthalen-1-yl) -2- (hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester to give the title compound (18 mg, yield: 47.6%).

MS m/z(ESI):545.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ ):δ7.92(dd,J＝8.0Hz,2.0Hz,1H),7.79-7.76(m,1H),7.74(d,J＝8.0Hz,1H),7.53(t,J＝7.6Hz,1H),7.40-7.36(m,2H),4.12(d,J＝12Hz,1H),3.91(d,J＝10Hz,1H),3.77(t,J＝10Hz,1H),3.55-3.41(m,6H),3.30-3.16(m,7H),3.08(d,J＝5.6Hz,2H),2.98-2.87(m,2H),2.62-2.56(m,1H),1.90-1.67(m,8H),1.57-1.52(m,2H)。

Example 9: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (2- (2-methyl-1H-imidazol-1-yl) ethoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) naphthalen-2-ol (compound 34)

The first step: preparation of benzyl 3- [7- (3-benzyloxy-1-naphthyl) -2- [2- (2-methylimidazol-1-yl) ethoxy ] -5,6,7, 8-tetrahydro-5H-pyrido [3,4-d ] pyrimidin-4-yl ] -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 3, the reaction starting material ((2S, 7 aR) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol from the first step was replaced with 2- (2-methylimidazol-1-yl) ethanol to give the title compound (90 mg, yield: 36.2%) of the present step.

MS m/z(ESI):737.3[M+H] ⁺ 。

And a second step of: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (2- (2-methyl-1H-imidazol-1-yl) ethoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) naphthalen-2-ol

Using the synthetic route of example 3, the second step of reaction starting 3- (7- (3-benzyloxy-1-naphthyl) -2- (((2 s,7 ar) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H)) -yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate was replaced with benzyl 3- [7- (3-benzyloxy-1-naphthyl) -2- [2- (2-methylimidazol-1-yl) ethoxy ] -5,6,7, 8-tetrahydro-5H-pyrido [3,4-d ] pyrimidin-4-yl ] -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate to give the title compound (23 mg, yield: 44.5%).

MS m/z(ESI):512.3[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ7.99(d,J＝8.4Hz,1H),7.66(d,J＝8.0Hz,1H),7.40-7.36(m,1H),7.28-7.24(m,1H),7.09(d,J＝4.0Hz,1H),6.85(d,J＝2.4Hz,1H),6.74-6.72(m,2H),4.48(t,J＝6.4Hz,2H),4.26(t,J＝5.6Hz,2H),4.15-3.65(m,8H),3.25-3.22(m,4H),2.84(s,1H),2.31(s,3H),1.87-1.84(m,4H)。

Example 10: preparation of 4- (4- ((1R, 3S, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) naphthalen-2-ol (Compound 35A or 35B)

Preparation of 4- (4- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) naphthalen-2-ol (Compound 35A or 35B)

The first step: preparation of 7-benzyl-2-chloro-4-methoxy-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

7-benzyl-2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (2.0 g,6.73 mmol) was dissolved in anhydrous methanol (30 mL), cooled by ice-salt bath, sodium methoxide (385.65 mg,7.07 mmol) was added in portions at 0℃and the reaction system was stirred at 0℃for 3 hours. The reaction was quenched by dropwise addition of ice water (50 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, backwashed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (1.91 g, yield: 93%).

MS m/z(ESI):290.1[M+H] ⁺ 。

And a second step of: preparation of (S) -7-benzyl-4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

7-benzyl-2-chloro-4-methoxy-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (1.9 g,6.23 mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (942.10 mg,8.10 mmol), cesium carbonate (5.13 g,15.57 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (364.08 mg, 622.93. Mu. Mol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (230.20 mg, 311.47. Mu. Mol) were added to 1, 4-dioxane (30 mL), and the reaction system was replaced three times with nitrogen gas and stirred at 100℃for 1 hour. After the system was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (2.1 g, yield: 86.9%).

MS m/z(ESI):369.3[M+H] ⁺ 。

And a third step of: preparation of (S) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

10% Palladium on carbon (0.5 g), (S) -7-benzyl-4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (2.0 g,5.16 mmol) was added to anhydrous methanol (30 mL), replaced with hydrogen three times, and the reaction was stirred at room temperature for 5 hours. The filter cake was washed with methanol (50 mL) and the solvent was removed by rotary evaporation under reduced pressure to give the title compound (1.15 g, yield: 76.12%).

MS m/z(ESI):279.3[M+H] ⁺ 。

Fourth step: preparation of (S) -7- (3- (benzyloxy) naphthalen-1-yl) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

(S) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (1.1 g,3.75 mmol), 3- (benzyloxy) -1-bromonaphthalene (1.78 g,5.63 mmol), cesium carbonate (3.09 g,9.39 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (177 mg,0.375 mmol) and tris (dibenzylideneacetone) dipalladium (173 mg,0.187 mmol) were added to 1, 4-dioxane (15 mL) and the reaction system was replaced three times with nitrogen gas and stirred at 100℃for 8 hours. After the system was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (910 mg, yield: 45.1%).

MS m/z(ESI):511.3[M+H] ⁺ 。

Fifth step: preparation of (S) -7- (3- (benzyloxy) naphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-ol

(S) -7- (3- (benzyloxy) naphthalen-1-yl) -4-methoxy-2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (900 mg,1.67 mmol) and sodium ethanethiolate (569.10 mg,6.70 mmol) were added to N, N-dimethylformamide (5 mL), replaced with nitrogen three times, and the reaction was stirred at 100℃for 2 hours. After the system was cooled to room temperature and purified by high performance liquid chromatography, the title compound was obtained (370 mg, yield: 42.27%).

MS m/z(ESI):497.2[M+H] ⁺

¹ H-NMR(400MHz,CD ₃ OD):δ8.05(t,J＝8.0Hz,1H),7.80-7.74(m,1H),7.51-7.44(m,3H),7.41-7.31(m,4H),7.18-7.11(m,1H),7.02-6.91(m,1H),5.20(s,2H),4.61-4.56(m,1H),4.21(m,1H),3.95-3.70(m,3H),3.50-3.48(m,1H),3.27-3.21(m,1H),3.07(s,3H),3.02-2.95(m,1H),2.78-2.60(m,2H),2.44-2.36(m,1H),2.25-1.95(m,4H)。

Sixth step: preparation of (S) -7- (3- (benzyloxy) naphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl triflate

(S) -7- (3- (benzyloxy) naphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-ol (150 mg, 267.83. Mu. Mol) and N, N-diisopropylethylamine (0.1 g, 803.49. Mu. Mol) were dissolved in dichloromethane (5 mL), cooled to-40℃and trifluoromethanesulfonic anhydride (114.49 mg, 401.75. Mu. Mol) was added dropwise thereto at-40℃and the reaction system was stirred for 1 hour. 1 drop of ammonium chloride solution was added dropwise at-40℃to quench, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was purified by thin layer chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (103 mg, yield: 58.1%).

MS m/z(ESI):629.2[M+H] ⁺ 。

Seventh step: preparation of tert-butyl 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate

(S) -7- (3- (benzyloxy) naphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl trifluoromethanesulfonate (113 mg, 170.76. Mu. Mol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester (115.65 mg, 341.52. Mu. Mol), sodium carbonate (45.70 mg, 426.90. Mu. Mol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (10.10 mg, 13.66. Mu. Mol) were added to 1, 4-dioxa (5 mL) and water (0.5 mL), and the reaction system was stirred at 100℃for 12 hours by three substitutions of nitrogen. After the system was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and purified by thin layer chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (108 mg, yield: 87.3%).

MS m/z(ESI):688.3[M+H] ⁺ 。

Eighth step: preparation of 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

10% Palladium on carbon (15 mg, 89.77. Mu. Mol) and 3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester (65 mg, 89.77. Mu. Mol) were added to anhydrous methanol (4 mL), replaced three times with hydrogen, the reaction system was stirred at room temperature for 2 hours, suction filtered, the filter cake was washed with methanol (10 mL), and the solvent was distilled off under reduced pressure to give the title compound (58 mg, yield: 89.0%).

MS m/z(ESI):690.4[M+H] ⁺ 。

Ninth step: preparation of 4- (4- (8-azabicyclo [3.2.1] oct-3-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) naphthalen-2-ol (compound 35)

3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (58 mg, 79.87. Mu. Mol) was dissolved in dichloromethane (3 mL), cooled by ice water bath, hydrobromic acid/acetic acid (107.71 mg, 399.34. Mu. Mol) was dropped at 0℃and the reaction system was stirred at 0℃for 0.5 hours. The reaction system was separated to remove the supernatant, the solid was adjusted to ph=7 with sodium bicarbonate solution, extracted three times with ethyl acetate (10 mL), the organic phases were combined, backwashed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give the title compound (30 mg, crude).

MS m/z(ESI):500.3[M+H] ⁺ 。

Tenth step: preparation of 4- (4- ((1R, 3S, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) naphthalen-2-ol (Compound 35A or 35B)

The crude product of the ninth step was purified by high performance liquid chromatography to give the title compound 35A (2.10 mg, yield: 4.58%) and compound 35B (2.56 mg, yield: 5.58%).

Compound 35A: retention time was 7.0 minutes;

MS m/z(ESI):500.3[M+H] ⁺ ；

¹ H-NMR(400MHz,CD ₃ OD):δ8.54(br,1H),8.03(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.37(dt,J＝8.0Hz,J＝4.0Hz,1H),7.25(dt,J＝8.0Hz,J＝4.0Hz,1H),6.87(d,J＝4.0Hz,1H),6.79(d,J＝4.0Hz,1H),4.42(d,J＝8.0Hz,1H),4.22(s,2H),4.04(s,2H),3.53-3.44(m,3H),3.14-3.09(m,2H),2.99-2.97(m,2H),2.83-2.81(m,1H),2.54-2.43(m,5H),2.43-2.29(m,5H),2.15-2.10(m,1H),2.06-2.00(m,2H),1.86-1.82(m,2H),1.77-1.69(m,1H)。

compound 35B: retention time was 7.8 minutes;

MS m/z(ESI):500.3[M+H] ⁺ ；

¹ H-NMR(400MHz,CD ₃ OD):δ8.52(br,1H),8.03(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.37(dt,J＝8.0Hz,J＝4.0Hz,1H),7.25(dt,J＝8.0Hz,J＝4.0Hz,1H),6.87(d,J＝4.0Hz,1H),6.79(d,J＝4.0Hz,1H),4.51-4.42(m,2H),4.22(s,2H),4.16(s,2H),3.58-3.50(m,3H)3.15-3.03(m,4H),2.65-2.60(m,4H),2.34-2.15(m,7H),1.97-1.89(m,4H),1.83-1.74(m,1H)。

example 11: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-fluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 37)

The first step: preparation of benzyl 3- (7- (8-fluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 5, the reaction starting material 1, 8-dibromonaphthalene in the first step was replaced with 1-bromo-8-fluoronaphthalene to give the title compound in the present step (80 mg, yield: 59.5%).

MS m/z(ESI):663.4[M+H] ⁺ 。

And a second step of: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-fluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

Using the synthetic route of example 5, the second reaction starting material 3- (7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester was replaced with 3- (7- (8-fluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester to give the title compound (23 mg, yield: 37.9%).

MS m/z(ESI):529.3[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.76(d,J＝7.6Hz,1H),7.66(d,J＝8.0Hz,1H),7.55-7.45(m,2H),7.32-7.16(m,2H),4.11-4.01(m,4H),4.01(s,2H),3.81(s,2H),3.65-3.38(m,4H),3.08-3.03(m,2H),2.72-2.66(m,4H),1.95-1.73(m,10H),1.68-1.61(m,2H)。

Example 12: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 36)

The first step: preparation of benzyl 3- (7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 5, the reaction starting material 1, 8-dibromonaphthalene in the first step was replaced with (8-chloro-7-fluoro-1-naphthalene) trifluoromethanesulfonate to give the title compound in the present step (40 mg, yield: 26.78%).

MS m/z(ESI):697.3[M+H] ⁺ 。

And a second step of: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

Using the synthetic route of example 5, the second reaction starting material 3- (7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester was replaced with 3- (7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester to give the title compound (15 mg, yield: 42.9%).

MS m/z(ESI):563.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.04-8.00(m,1H),7.78(d,J＝7.6Hz,1H),7.62-7.51(m,2H),7.40(d,J＝7.6Hz,1H),4.14-4.02(m,4H),3.89(s,2H),3.75-3.71(m,2H),3.60(s,2H),3.09-2.92(m,4H),2.60-2.54(m,2H),2.50-2.48(m,2H),1.89-1.67(m,10H),1.59-1.52(m,2H)。

Example 13: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 38)

The first step: preparation of benzyl 3- (7, 8-difluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 5, the reaction starting material 1, 8-dibromonaphthalene in the first step was replaced with (7, 8-difluoro-1-naphthyl) trifluoromethylsulfonate to give the title compound in the present step (60 mg, yield: 40.1%).

MS m/z(ESI):681.3[M+H] ⁺ 。

And a second step of: preparation of 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine

Using the synthetic route of example 5, the second reaction starting material 3- (7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester was replaced with 3- (7, 8-difluoronaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester to give the title compound (22 mg, yield: 42.1%).

MS m/z(ESI):547.3[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.85-7.82(m,1H),7.70-7.61(m,2H),7.50-7.46(m,1H),7.29(d,J＝7.6Hz,1H),4.09-3.93(m,4H),3.93(s,2H),3.63(s,2H),3.40-3.08(m,4H),2.99-2.85(m,4H),2.62-2.56(m,2H),1.91-1.69(m,10H),1.61-1.54(m,2H)。

Example 14: preparation of 4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 86A or 86B)

Preparation of 4- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 86A or 86B)

The first step: preparation of 3- (7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

3- (2- ((2R, 7 aS) -2-Fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (100 mg,0.19 mmol), 1-bromo-8-chloronaphthalene (96.29 mg,0.38 mmol), cesium carbonate (194.85 mg,0.57 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (22.10 mg, 38.77. Mu. Mol) and tris (dibenzylideneacetone) dipalladium (26.54 mg, 28.41. Mu. Mol) were added to 1, 4-dioxane (3 mL), and the reaction system was stirred at 95℃for 8 hours with nitrogen substitution three times. After the system was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, volume ratio) to give the title compound (97 mg, yield: 69.61%).

MS m/z(ESI):662.4[M+H] ⁺ 。

And a second step of: preparation of 4- (-8-azabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 86)

3- (7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (97.0 mg, 131.83. Mu. Mol) was dissolved in methylene chloride (3 mL), trifluoroacetic acid (1 mL) was added dropwise at 25℃and the reaction system was stirred at 25℃for 1.5 hours. The reaction solution was concentrated, and the residue was diluted with ethyl acetate (3 mL), washed three times with sodium hydrogencarbonate solution (10 mL), and the organic phases were combined, backwashed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give the title compound (40.0 mg, crude product).

MS m/z(ESI):563.3[M+H] ⁺ 。

And a third step of: preparation of 4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 86A or 86B)

The crude product of the second step was purified by high performance liquid chromatography to give the title compound 86A (18.0 mg, yield: 21.82%) and compound 86B (10.0 mg, yield: 11.85%).

Compound 86A: retention time was 5.72 minutes;

MS m/z(ESI):563.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )：δ7.93(d,J＝8.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.60-7.51(m,2H),7.45(t,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),5.27(d,J＝4.0Hz,2H),4.19-3.95(m,5H),3.89(s,1H),3.56(d,J＝10Hz,1H),3.42(s,1H),3.17-2.98(m,5H),2.82(dd,J＝12Hz,J＝8.4Hz,1H),2.68(d,J＝14.4Hz,1H),2.12-1.71(m,13H)。

compound 86B: the retention time was 6.11 minutes;

MS m/z(ESI):563.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )：δ7.93(dd,J＝8.0Hz,J＝1.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.56(dd,J＝16.4Hz,J＝8.0Hz,2H),7.45(t,J＝7.6Hz,1H),7.37(d,J＝7.6Hz,1H),5.27(d,J＝12.0Hz,2H),4.21-3.88(m,7H),3.57(d,J＝7.2Hz,1H),3.43-3.29(m,2H),3.19-3.11(m,2H),3.01(d,J＝5.0Hz,1H),2.91-2.78(m,2H),2.22-1.90(m,9H),1.86-1.73(m,4H)。

example 15: preparation of 4- (4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5-fluoronaphthalen-2-ol (compound 89A or 89B)

Preparation of 4- (4- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5-fluoronaphthalen-2-ol (compound 89A or 89B)

The first step: preparation of 3- (7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Using the synthetic route of example 14, the first reaction starting material 1-bromo-8-chloronaphthalene was replaced with 8-fluoro-3- (methoxymethoxy) naphthalen-1-yl trifluoromethanesulfonate to give the title compound (60 mg, yield: 44.41%).

MS m/z(ESI):706.4[M+H] ⁺ 。

And a second step of: preparation of 4- (4- (-8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5-fluoronaphthalen-2-ol (compound 89)

Using the synthetic route of example 14, the second reaction starting material 3- (7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was replaced with 3- (7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester to give the title compound (42.1 mg, crude product).

MS m/z(ESI):562.3[M+H] ⁺ 。

And a third step of: preparation of 4- (4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5-fluoronaphthalen-2-ol (compound 89A or 89B)

The crude product of the second step was purified by high performance liquid chromatography to give the title compound 89A (5.0 mg, yield: 9.6%) and compound 89B (6.1 mg, yield: 11.5%).

Compound 89A: the retention time was 4.65 minutes;

MS m/z(ESI):562.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )：δ7.49(d,J＝8.0Hz,1H),7.36-7.31(m,1H),6.99-6.94(m,1H),6.88(s,1H),6.76(d,J＝4.0Hz,1H),5.35(s,1H),5.21(s,1H),4.13-3.98(m,5H),3.62-3.41(m,3H),3.08-2.67(m,9H),2.33-1.94(m,8H),1.87-1.74(m,5H)。

compound 89B: the retention time was 5.31 minutes;

MS m/z(ESI):562.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )：δ7.49(d,J＝8.0Hz,1H),7.36-7.31(m,1H),6.99-6.94(m,1H),6.88(s,1H),6.76(d,J＝4.0Hz,1H),5.35(s,1H),5.21(s,1H),4.12-3.93(m,7H),3.08-2.82(m,8H),2.13-1.98(m,10H),1.88-1.76(m,5H)。

example 16: preparation of 4- (4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5, 6-difluoronaphthalen-2-ol (compound 90A or 90B)

Preparation of 4- (4- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5, 6-difluoronaphthalen-2-ol (compound 90A or 90B)

The first step: preparation of tert-butyl 3- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 14, the reaction starting material 1-bromo-8-chloronaphthalene in the first step was replaced with 7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl trifluoromethane sulfonate to give the title compound (55 mg, yield: 38.3%).

MS m/z(ESI):724.4[M+H] ⁺ 。

And a second step of: preparation of 4- (4- (8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5, 6-difluoronaphthalen-2-ol (compound 90)

Using the synthetic route of example 14, the second reaction starting material 3- (7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was replaced with 3- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester to give the title compound (37 mg, crude product).

MS m/z(ESI):580.3[M+H] ⁺

And a third step of: preparation of 4- (4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5, 6-difluoronaphthalen-2-ol (compound 90A or 90B)

The crude product of the second step was purified by high performance liquid chromatography to give the title compound 90A (3.0 mg, yield: 4.1%) and compound 90B (1.6 mg, yield: 2.3%).

Compound 90A: the retention time was 5.15 minutes;

MS m/z(ESI):580.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )：δ7.58-7.45(m,2H),6.91(s,1H),6.85(s,1H),5.38(s,1H),5.21(s,1H),4.14-4.04(m,4H),3.63-3.44(m,3H),3.13-2.67(m,8H),2.33-2.08(m,10H),1.90-1.80(m,5H)。

compound 90B: the retention time was 5.53 minutes;

MS m/z(ESI):580.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )：δ7.58-7.45(m,2H),6.91(s,1H),6.85(s,1H),5.38(s,1H),5.21(s,1H),4.13-3.83(m,7H),3.03-2.74(m,8H),2.11-1.95(m,10H),1.89-1.78(m,5H)。

example 17: preparation of 4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -7- (8-bromonaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7A-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 87A or 87B)

Preparation of 4- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -7- (8-bromonaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7A-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 87A or 87B)

The first step: preparation of 3- (7- (8-bromonaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Using the synthetic route of example 14, the first reaction starting material 1-bromo-8-chloronaphthalene was replaced with 1, 8-dibromonaphthalene to give the title compound (272 mg, yield: 58.1%).

MS m/z(ESI):706.3[M+H] ⁺ 。

And a second step of: preparation of 4- (8-azabicyclo [3.2.1] oct-3-yl) -7- (8-bromonaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 87)

Using the synthetic route of example 14, the second reaction starting material 3- (7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was replaced with 3- (7- (8-bromonaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester to give the title compound (37 mg, crude product).

MS m/z(ESI):580.3[M+H] ⁺ 。

And a third step of: preparation of 4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -7- (8-bromonaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7A-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine (Compound 87A or 87B)

The crude product of the second step was purified by high performance liquid chromatography to give the title compound 87A (8.2 mg, yield: 17.5%) and compound 87B (7.0 mg, yield: 15.3%).

Compound 87A: the retention time was 6.05 minutes;

MS m/z(ESI):580.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )：δ7.97(d,J＝8.0Hz,1H),7.82(d,J＝4.0Hz,1H),7.77(d,J＝8.0 Hz,1H),7.58-7.54(m,1H),7.41-7.38(m,2H),5.33(s,1H),5.20(s,1H),4.14-3.81(m,7H),3.56(d,J＝10Hz,1H),3.20-3.00(m,6H),2.82(dd,J＝12.4Hz,J＝8.4Hz,1H),2.68(d,J＝14.4Hz,1H),2.38-2.25(m,3H),2.10-1.75(m,9H)。

compound 87B: the retention time was 6.81 minutes;

MS m/z(ESI):580.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d ₆ )：δ7.97(d,J＝8.0Hz,1H),7.81(d,J＝4.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.60-7.52(m,1H),7.41-7.36(m,2H),5.33(s,1H),5.21(s,1H),4.14-3.96(m,4H),3.84-3.79(m,3H),3.56(d,J＝10Hz,1H),3.23-3.00(m,6H),2.82(dd,J＝12.4Hz,J＝8.4Hz,1H),2.68(d,J＝14.4Hz,1H),2.11-1.75(m,12H)。

example 18: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyridin [3,4-d ] pyrimidin-7 (8H) -yl) -5-fluoronaphthalen-2-ol (compound 40)

The first step: preparation of benzyl 3- (7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Using the synthetic route of example 5, the reaction starting material 1, 8-dibromonaphthalene in the first step was replaced with 1-bromo-8-fluoro-3- (methoxymethoxy) naphthalene to give the title compound (17 mg, yield: 8.6%).

MS m/z(ESI):723.3[M+H] ⁺ 。

And a second step of: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((hexahydro-1H-pyrrolizine-7 a-yl) methoxy) -5, 6-dihydropyridin [3,4-d ] pyrimidin-7 (8H) -yl) -5-fluoronaphthalen-2-ol

The synthetic route of example 5 was followed to replace the second step starting material, benzyl 3- (7- (8-bromonaphthalen-1-yl) -2- ((hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate with benzyl 3- (7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate to give the title compound (2.3 mg, yield: 21.22%).

MS m/z(ESI):545.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO)：δ7.49(d,J＝8.0Hz,1H),7.36-7.30(m,1H),6.96(dd,J＝16.0Hz,J＝8.0Hz,1H),6.87(s,1H),6.74(d,J＝4.0Hz,1H),4.00(d,J＝6.0Hz,6H),3.62(s,3H),3.01-2.92(m,3H),2.83(s,2H),2.70-2.55(m,3H),1.93-1.53(m,14H)。

Example 19: preparation of 4- (4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5-bromonaphthalen-2-ol (compound 88A or 88B)

Preparation of 4- (4- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5-bromonaphthalen-2-ol (compound 88A or 88B)

The first step: preparation of 3- (7- (8-bromo-3- (methoxymethoxy) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Using the synthetic route of example 14, the reaction starting material 1-bromo-8-chloronaphthalene in the first step was replaced with 1, 8-dibromo-3- (methoxymethoxy) naphthalene to give the title compound (36 mg, yield: 22.31%).

MS m/z(ESI):766.3[M+H] ⁺ 。

And a second step of: preparation of 4- (4- (8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5-bromonaphthalen-2-ol (compound 88)

Using the synthetic route of example 14, the second reaction starting material 3- (7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester was replaced with 3- (7- (8-bromo-3- (methoxymethoxy) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester to give the title compound (10.0 mg, crude product).

MS m/z(ESI):625.3[M+H] ⁺ 。

And a third step of: preparation of 4- (4- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5, 6-dihydropyrido [3,4-d ] pyrimidin-7 (8H) -yl) -5-bromonaphthalen-2-ol (compound 88A or 88B)

The crude product of the second step was purified by high performance liquid chromatography to give the title compound 88A (3.0 mg, yield: 10.09%) and compound 88B (2.5 mg, yield: 8.41%).

Compound 88A: the retention time was 6 minutes;

MS m/z(ESI):625.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO)：δ7.70(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),7.42-7.38(m,1H),7.22-7.17(m,1H),6.98-6.91(m,1H),5.33(s,1H),5.20(s,1H),4.14-3.72(m,10H),3.03(d,J＝32.0Hz,4H),2.84(d,J＝12.0Hz,2H),2.12-1.73(m,13H)。

compound 88B: the retention time was 7.4 minutes;

MS m/z(ESI):625.3[M+H] ⁺

¹ H-NMR(400MHz,DMSO)：δ7.69(s,1H),7.53(d,J＝8.0Hz,1H),7.22-7.17(m,1H),6.95(d,J＝16.0Hz,2H),5.33(s,1H),5.20(s,1H),4.13-3.77(m,10H),3.07(s,2H),3.00(s,2H),2.83(s,2H),2.11-1.69(m,13H)。

the compounds of table 1 below were prepared in a manner similar to that described above for examples 1-19:

TABLE 1 characterization data for Compounds

Biological testing

Experimental example 1: KRAS-G12D (guanine-5' -triphosphate (GTP) hydrolase G12D mutant)/SOS 1 in vitro enzymatic binding inhibition Activity assay

Experiment system:

KRAS-G12D/SOS1 binding assay kit (manufacturer: cisbio)

Protein: tag1-SOS1 and Tag2-KRAS G12D

And (3) tag: anti tag1 tb ³⁺ And Anti tag2 XL665

Buffer solution: diluent Buffer and Detection Buffer

Activating nucleotides: GTP (manufacturer Sigma)

Experimental parameters:

KRAS-G12D/SOS1 binding assay kit component: tag1-SOS1, tag2-KRAS G12D, anti-Tag 1 tb ³⁺ And Anti tag2 XL665 are 1 each

GTP：10000nM

Compound and KRAS-G12D/SOS1 protein preincubation binding time: room temperature 15 min

Protein and tag reaction time: incubate in sealed condition at 4deg.C for 3 hours or extend to overnight

Parameters of the enzyme-labeled instrument: BMG PHERAstar Fluorescence, homogeneous time-resolved fluorescence (HTRF) method, excitation wavelength of 337nm, emission wavelength of 620nm and 665nm

The experimental steps are as follows:

the test compounds were incubated with mixtures of Tag1-SOS1 and Tag2-KRAS G12D with GTP in a Diluent Buffer system for 15 minutes at room temperature for protein binding. The Detection Buffer diluted label was added to the reaction plate, incubated at 4℃for 3 hours or extended overnight, the reaction plate was placed in a microplate reader and the signal values from each well in the plate were read using the HTRF method.

And (3) data processing:

in vehicle group (containing 1 xTag 1-SOS1, 1 xTag 2-KRAS G12D, anti-Tag 1 tb) ³⁺ And Anti-Tag 2 XL665,1% DMSO) as negative controls, and a reaction buffer group (containing 1 xTag 1-SOS1, anti-Tag 1 tb) ³⁺ And Anti tag2 XL665,1% dmso) as a blank, the relative inhibition activity was calculated for each concentration group with inhibition = 100% - (test group-blank)/(vehicle group-blank) ×100%. The half maximal Inhibitory Concentration (IC) of the compound was calculated by fitting a curve according to a four parameter model ₅₀ )。

Experimental results:

The inhibitory activity of the compounds on the in vitro enzymatic binding of KRAS-G12D/SOS1 was determined as described above and the results are shown in Table 2.

TABLE 2 results of KRAS-G12D/SOS1 in vitro enzymatic binding inhibition Activity experiments

Compounds of formula (I)	IC ₅₀ (nM)
1	340
28	26
29	50
31	115
32	7
33	31
34	35
35A	26
35B	6
40	7
86A	20
86B	627
87A	20
88B	180
89A	10
89B	164
90A	17

Conclusion:

in KRAS-G12D/SOS1 in vitro enzymatic binding inhibition activity experiments, the compound provided by the invention shows stronger inhibition activity.

Experimental example 2: surface Plasmon Resonance (SPR) binding experiments of Compounds with His-KRAS (G12D & Q61H) proteins

Experiment system:

protein: his-KRAS (G12D & Q61H)

Experimental parameters:

His-KRAS (G12D & Q61H) concentration: 0.04mg/mL

Buffer system:

1)Protein immobilization buffer:10mM HEPES,150mM NaCl,0.05％Tween-20and 10μM GDP

2)Running buffer A:10mM HEPES,150mM NaCl,0.05％Tween-20and 10μM GDP

3)Running buffer B:10mM HEPES,150mM NaCl,0.05％Tween-20and 10μM GDP,1％DMSO

concentration of compound: 50 mu M-0.781 mu M, and the final concentration of DMSO is 1%

Binding dissociation time: 120s on/200s off

Flow rate: 50 mu L/min

Instrument parameters: biacore T200 (GE Healthcare)

And (3) a chip: s series NTA sensor chip

The experimental steps are as follows:

(1) Protein immobilization

1) And (3) setting the temperature: the instrument temperature was set to 25 ℃.

2) Insert S-series NTA sensor chip and then execute the "Prime" command.

3) The manual procedure was started and the flow rate was set at 10uL/min.

4) Flow cell 2 was selected and then a mixture of 350mM EDTA (pH 8.0) and 50mM NaOH (1 v:1 v) was autoinjected to flush the chip surface at a rate of 60. Mu.L/min for 60s and repeated twice.

5) Chip surface activation: flow cell 2 was selected, 10mM NiCl2 was autoinjected at a flow rate of 4. Mu.L/min for 500s.

6) His-KRAS (G12D & Q61H) was diluted to 40. Mu.g/mL with Protein immobilization buffer. 120uL His-KRAS (G12D & Q61H) was autofed, his-KRAS (G12D & Q61H) protein was immobilized on the surface of flow cell 2 at a feeding rate of 4. Mu.L/min for 1150s.

7) The flow rate was adjusted back to 10uL/min and the equilibrium chip surface to baseline was substantially stable (baseline drop rate <2 RU/min).

(2) Sample detection

The program was written in Biacore T200 Control Software using the method mode. The temperature was set at 25℃and the flow rate was set at 50uL/min. The procedure starts with 8 Running buffer B samples, then the compound is automatically sampled from small to large concentration, and the compound flows through the surface of the protein fixed on the chip and is combined with the chip. Flow cell 1 was set as the reference channel and 0 concentration was set as the built-in blank. The needle was washed with 50% dmso for each cycle. The signal value effect of DMSO was corrected with a 1% DMSO standard curve.

And (3) data processing:

the binding and dissociation signals of the compounds to the proteins were recorded in real time and the signal values of the reference channel and the built-in blank (double subtraction) were subtracted during data processing (Biacore T200 evaluation software). The signal values of the reference channel and the built-in blank were double subtracted sensorgrams fitted with kinetic or steady-state Affinity (1:1) patterns. By K _D Value (K) _d /K _a ) Characterizing the affinity of a compound to a protein, wherein K _d K is the dissociation constant _a Is the binding constant.

Experimental results:

the affinity of the compounds for His-KRAS (G12D & Q61H) protein was determined as described above and the results are shown in table 3:

TABLE 3 affinity test results of Compounds with His-KRAS (G12D & Q61H)

Compounds of formula (I)	K _D (nM)
2	556

Conclusion:

in the binding assay of the compounds to His-KRAS (G12D & Q61H), the compounds of the present application show a strong affinity.

The above embodiments do not limit the solution of the application in any way. Various modifications of the application, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims

A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof:

wherein,

X ¹ selected from N and CR ⁵ ；

L is selected from the group consisting of covalent bonds,-O-, -S-and-NR ⁶ -；

R ¹ Selected from hydrogen, C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substitution;

R ² selected from the group consisting of

Each X ² Each independently selected from N and CR ⁹ ；

R ³ Selected from C _1-6 Alkyl and C _1-6 A haloalkyl group; or alternatively

Two R's bound to the same carbon atom ³ And the carbon atoms together form a carbonyl group, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl;

R ⁴ selected from C _6-10 Aryl and 5-10 membered heteroaryl, each optionally substituted with one or more R ¹⁰ Substitution;

R ⁵ selected from hydrogen, halogen, cyano, C _1-6 Alkyl and C _1-6 A haloalkyl group;

R ⁶ selected from hydrogen and C _1-6 An alkyl group;

R ⁷ selected from hydrogen, halogen, cyano, -OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-O-C(O)-R ¹¹ 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-NR ¹¹ R ¹² 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-R ¹¹ 、-C(O)-OR ¹² 、-C(O)-NR ¹¹ R ¹² 、C _3-10 Cycloalkyl, C _6-10 Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1- ₆ alkylene-OR ¹³ 、-C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-6 A haloalkyl group;

R ⁸ selected from halogen, hydroxy, cyano, C _1-6 Alkyl, -C _1-6 alkyl-OH, -C _1-6 Alkyl-cyano and C _1-6 A haloalkyl group;

R ⁹ selected from hydrogen, hydroxy and C _1-6 An alkyl group;

R ¹⁰ selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, -O-C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, each of said alkyl, cycloalkyl, heterocyclyl or heteroaryl being optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl and C _1-6 A substituent of a haloalkyl group;

R ¹¹ selected from hydrogen, C _1-6 Alkyl, C _1-6 Haloalkyl, -C _1-6 alkyl-O-C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl, C _1-6 A substituent of a haloalkyl group;

R ¹² selected from hydrogen and C _1-6 An alkyl group;

R ¹³ selected from hydrogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl, C _1-6 A substituent of a haloalkyl group;

R ¹⁴ selected from hydrogen and C _1-6 An alkyl group;

m is 0, 1, 2, 3 or 4;

n is 0, 1 or 2; and is also provided with

o, p, q, r and s are each independently selected from 0, 1, 2 or 3, provided that o and r are not both 0 and p and q are not both 0.
The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, or metabolite thereof, wherein:

R ⁷ Selected from hydrogen, halogen, cyano, -OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-O-C(O)-R ¹¹ 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、- NR ¹² -C(O)-NR ¹¹ R ¹² 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-R ¹¹ 、-C(O)-OR ¹² 、-C(O)-NR ¹¹ R ¹² 、C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, C _1-6 Alkyl and C _1-6 A haloalkyl group.
The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, or metabolite thereof, wherein:

X ¹ selected from N and CH;

preferably X ¹ Is N.
The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite thereof, wherein:

l is selected from the group consisting of covalent bonds, -O-, -S-, -NH-, and-N (C) _1-3 Alkyl) -;

preferably, L is selected from the group consisting of-O-, -NH-and-N (C _1-3 Alkyl) -;

more preferably, L is-O-.
The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite thereof, wherein:

R ¹ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substituted, each R ⁷ Each independently selected from hydrogen, halogen, cyano, -OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-R ¹¹ 、-C(O)-NR ¹¹ R ¹² 、C _3-10 Cycloalkyl, C _6-10 Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1-6 alkylene-OR ¹³ 、-C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-6 A haloalkyl group;

preferably, R ¹ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being substituted with one or more R ⁷ Substituted, each R ⁷ Each independently selected from-OR ¹¹ 、-O-C(O)-NR ¹¹ R ¹² 、-NR ¹¹ R ¹² 、-NR ¹² -C(O)-R ¹¹ 、-NR ¹² -C(O)-OR ¹¹ 、-C(O)-NR ¹¹ R ¹² 、C _3-6 Cycloalkyl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH, -C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ 、C _1-3 Haloalkyl and C _1-6 An alkyl group;

more preferably, R ¹ To optionally be covered by one or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from C _3-6 Cycloalkyl, 5-6 membered heteroaryl and 5-8 membered heterocyclyl, said C _3-6 Cycloalkyl, 5-6 membered heteroaryl, and 5-8 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH,-C _1-6 alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-3 A haloalkyl group; wherein R is ¹³ Selected from C _1-6 Alkyl and 5-6 membered heterocyclyl; r is R ¹⁴ Selected from hydrogen and C _1-6 An alkyl group;

more preferably, R ¹ To optionally be covered by one or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from cyclopropyl, pyrrolidinyl, hexahydropyrrolizinyl, and imidazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C _1-6 Alkyl, -C _1-6 Alkylene group-R ¹³ 、-C _1-3 alkylene-OH, -C _1- ₆ alkylene-NR ¹³ R ¹⁴ 、-C _1-6 alkylene-O-C (O) -R ¹³ And C _1-3 A haloalkyl group; wherein R is ¹³ Selected from C _1-6 Alkyl and morpholinyl; r is R ¹⁴ Is C _1-6 An alkyl group;

more preferably, R ¹ To optionally be covered by one or more R ⁷ Substituted C _1-6 Alkyl, each R ⁷ Each independently selected from cyclopropyl, pyrrolidinyl, hexahydropyrrolizinyl, and imidazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C _1-6 Alkyl, -C _1-6 Alkylene-morpholinyl, -C _1-3 alkylene-OH, -C _1-6 alkylene-N (C) _1-6 Alkyl group ₂ 、-C _1-6 alkylene-O-C (O) - (morpholinyl) and C _1-3 A haloalkyl group;

more preferably, R ¹ Selected from: wherein the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite thereof, wherein:

R ¹ to optionally be covered by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-6 Alkyl, C _1-6 alkylene-OH or C _1-6 Haloalkyl-substituted 5-12 membered bicyclic heterocyclyl;

preferably, R ¹ To optionally be covered by one R ⁷ Substituted C _1-6 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1- ₃ alkylene-OH or C _1-3 Haloalkyl-substituted 5-8 membered bicyclic heterocyclyl;

more preferably, R ¹ To optionally be covered by one R ⁷ Substituted C _1-3 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1-3 Alkylene groupradical-OH or C _1-3 Haloalkyl-substituted 5-8 membered nitrogen-containing bicyclic heterocyclyl;

more preferably, R ¹ To optionally be covered by one R ⁷ Substituted C _1-3 Alkyl, R ⁷ Selected from optionally substituted by one or more halogens, C _1-3 Alkyl, C _1-3 alkylene-OH or C _1-3 Haloalkyl-substituted hexahydropyrrolizinyl;

more preferably, R ¹ To optionally be covered by one R ⁷ Substituted C _1-3 Alkyl, R ⁷ Selected from hexahydropyrrolizinyl optionally substituted with one or more F, cl, methyl, chloromethyl, fluoromethyl or hydroxymethyl groups;

more preferably, R ¹ Selected from the group consisting of
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite thereof, wherein:

R ⁴ selected from C _6-10 Aryl and 5-10 membered heteroaryl, each optionally substituted with one or more R ¹⁰ Substituted, each R ¹⁰ Each independently selected from hydrogen, halogen, hydroxy, cyano, C _1-3 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, -O-C _1-3 Alkyl, C _3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl being optionally substituted with one or more groups selected from hydrogen, halogen, hydroxy, cyano, C _1-3 Alkyl and C _1-3 A substituent of a haloalkyl group;

preferably, R ⁴ Selected from C _6-10 Aryl and 5-10 membered heteroaryl, each optionally substituted with one or more R ¹⁰ Substituted, each R ¹⁰ Each independently selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, C _2-4 Alkynyl, -O-C _1-3 Alkyl and C _3-6 Cycloalkyl, said alkyl optionally substituted with one or more hydrogens and halogens;

more preferably, R ⁴ Selected from phenyl, naphthyl and indazolyl, each of which is optionally substituted with one or more R ¹⁰ Substituted, each R ¹⁰ Each independently selected from hydrogen, halogen, hydroxy, C _1-3 Alkyl, C _1-3 Haloalkyl, C _2-4 Alkynyl, -O-C _1-3 Alkyl and C _3-6 Cycloalkyl groups.
The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite thereof, wherein:

each R ³ Each independently selected from C _1-6 Alkyl and C _1-6 Haloalkyl, or two R's attached to the same carbon atom ³ And the carbon atoms together form a carbonyl group or C _3-6 Cycloalkyl;

preferably, each R ³ Each independently selected from C _1-3 Alkyl, or two R's attached to the same carbon atom ³ And the carbon atoms together form a carbonyl group or C _3-6 Cycloalkyl;

more preferably, each R ³ Each independently selected from methyl, or two R's attached to the same carbon atom ³ And the carbon atoms together form a carbonyl group or a cyclopropyl group.
The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite thereof, wherein the compound has the structure of formula (II-a) or formula (II-B) or formula (II-C):

Wherein each group L, R ¹ 、R ³ 、R ⁴ 、R ⁸ M, n, o, p, q, r and s are defined in any one of claims 1 to 8;

preferably, the compound has the structure of formula (II-A-1), (II-A-2), (II-C-1), (II-C-2) or (II-C-3):
a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, or metabolite thereof, said compound having the structure:
a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound or metabolite thereof, and one or more pharmaceutically acceptable carriers.
A kit comprising a compound according to any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, or a pharmaceutical composition according to claim 11.
Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound or metabolite thereof, or a pharmaceutical composition of claim 11, in the manufacture of a medicament for the prevention or treatment of a KRAS G12D-mediated related disease, wherein the medicament is preferably administered by the oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or transdermal route, wherein the KRAS G12D-mediated related disease is preferably a tumor.
A process for preparing a compound of formula (II-a) or (II-C) according to claim 9, comprising the following process:

a process for preparing a compound of formula (II-a), comprising the steps of:

route 1

Wherein,

L、R ¹ 、R ³ 、R ⁴ 、R ⁸ m, n, o, p, q, r and s are as defined in any one of claims 1 to 8;

LG ¹ 、LG ² and X represents a leaving group, preferably selected from a halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl;

PG ¹ 、PG ² and PG ³ A protecting group representing a hydroxyl group or an amino group, said protecting group preferably being selected from the group consisting of benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), methyl and benzyl; or alternatively

A second process for preparing a compound of formula (II-a), comprising the steps of:

route 2

Therein, L, R ¹ 、R ³ 、R ⁴ 、R ⁸ M, n, o, p, q, r and s are as defined in any one of claims 1 to 8;

LG ¹ 、LG ² and X represents a leaving group, preferably selected from a halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl;

PG ¹ and PG ³ A protecting group representing an amino group, said protecting group preferably being selected from the group consisting of benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc) and benzyl; or alternatively

A process for preparing a compound of formula (II-a), comprising the steps of:

Route 3

Therein, L, R ¹ 、R ³ 、R ⁴ 、R ⁸ 、m、n、o、p、q、r and s are as defined in any one of claims 1 to 8;

LG ¹ and X represents a leaving group, preferably selected from a halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl;

PG ¹ and PG ³ A protecting group representing an amino group, said protecting group preferably being selected from the group consisting of benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc) and benzyl;

a process for preparing a compound of formula (II-C), comprising the steps of:

route 4

Therein, L, R ¹ 、R ³ 、R ⁴ 、R ⁸ M, n, o, p, q, r and s are as defined in any one of claims 1 to 8;

LG ¹ represents a leaving group, preferably selected from a halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl;

PG ³ a protecting group representing an amino group, said protecting group preferably being selected from the group consisting of benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc) and benzyl; or alternatively

A second process for preparing a compound of formula (II-C), comprising the steps of:

route 5

Therein, L, R ¹ 、R ³ 、R ⁴ 、R ⁸ M, n, o, p, q, r and s are as defined in any one of claims 1 to 8;

LG ¹ 、LG ² and X represents a leaving group, preferably selected from a halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl;

PG ¹ And PG ³ Represents a protecting group for an amino group, said protecting group preferably being selected from the group consisting of benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc) and benzyl.