Quinazoline compounds and pharmaceutical compositions thereof

Abstract

The present application discloses a quinazoline compound and a pharmaceutical composition thereof. The present application provides a quinazoline compound as shown in Formula I, a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, and a pharmaceutical composition comprising such a compound.

Description

Technical Field

[0001] The present application relates to the field of biomedicine, and specifically to a quinazoline compound and a pharmaceutical composition thereof. Background Art

[0002] HPK1 is the abbreviation of Hematopoietic Progenitor Kinase 1, which belongs to the serine / threonine kinase family and is also known as MAP4K1, which is Mitogen-activated protein kinase 1. HPK1 is mainly expressed in lymphoid organs, including bone marrow, fetal liver, lymph nodes, placenta, spleen and thymus (AdvImmunol, 2016, 129: 277-314), and is not distributed in major human tissues. Therefore, it is expected that kinase inhibitors that selectively act on this target are relatively safer. Summary of the invention

[0003] One objective of the present application is to provide a quinazoline compound and a pharmaceutical composition thereof. The compound of the present application can effectively inhibit the activity of HPK1 kinase and has extremely high drugability.

[0004] In one aspect, the present application provides a compound of formula I:

[0005]

[0006] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein R a , R b , R c , R d One of The rest are independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0007] R e Selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0008] X is selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0009] R 1 is a substituted cycloalkyl group, a substituted heterocyclic group or m is 0, 1, 2, 3, 4 or 5, R 14 C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0010] Ring A is a substituted benzene ring or a substituted 5-6-membered aromatic heterocycle, wherein the substituted 5-6-membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0011] R 2 Select from the following substituents:

[0012]

[0013] Where Y is C or N, R 7 H, C 1 -6 Alkyl, C 3 -8 Cycloalkyl, C 1 -6 Substituted alkyl or C 3 -8 Substituted cycloalkyl, R 8 H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It is a 4-6 membered heterocyclic group or a 4-6 substituted heterocyclic group.

[0014] In some embodiments, the R 1 for When m is 1 or 2.

[0015] In some embodiments, the R 14 C 1-6 alkyl.

[0016] In some embodiments, the R 1 is a substituted 5-8 membered cycloalkyl group or a substituted 5-8 membered heterocyclic group, wherein the substituted 5-8 membered heterocyclic group has 1 to 4 heteroatoms selected from O, S and N.

[0017] In some embodiments, the R 1 is a substituted 5-6 membered cycloalkyl group or a substituted 5-6 membered heterocyclic group, wherein the substituted 5-6 membered heterocyclic group has 1 to 4 heteroatoms selected from O, S and N.

[0018] In some embodiments, when R 1 When it is a substituted 5-8 membered cycloalkyl group, the R 1 for Where n is 1, 2, 3 or 4.

[0019] In some embodiments, the R 3 for—OR 4 or—NR 5 R 6 , where R 4 For H. Alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl, R 5 and R 6 Independently for H, Alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl, wherein R 5 and R 6 They are not cycloalkyl or substituted cycloalkyl at the same time.

[0020] In some embodiments, the R 4 H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0021] In some embodiments, the R 5 and R 6 Independently H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl, wherein R 5 and R 6 Not at the same time C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0022] In some embodiments, the R 13 H, C 1-6 Alkyl, C1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0023] In some embodiments, R 1 Select from the following substituents:

[0024]

[0025] In some embodiments, Ring A is selected from the following substituted aromatic rings:

[0026]

[0027] In some embodiments, the A ring is a substituted benzene ring, a substituted pyridine ring or a substituted pyrazole ring.

[0028] In some embodiments, when ring A is a substituted benzene ring or a substituted pyridine ring, R 2 The substitution position is at the para or meta position relative to X.

[0029] In some embodiments, R 2 Select from the following substituents:

[0030]

[0031] In some embodiments, R 12 Select from the following substituents:

[0032]

[0033] In some embodiments, the compound of formula I is as shown in formula I-1,

[0034]

[0035] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein R b , R c , R d , R e Each is independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl, C 1-6 Alkoxy;

[0036] X is selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0037] R 1is a substituted cycloalkyl group, a substituted heterocyclic group or m is 0, 1, 2, 3, 4 or 5, R 14 C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0038] Ring A is a substituted benzene ring or a substituted 5-6-membered aromatic heterocycle, wherein the substituted 5-6-membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0039] R 2 Select from the following substituents:

[0040]

[0041] Where Y is C or N, R 7 H, C 1 -6 Alkyl, C 3 -8 Cycloalkyl, C 1 -6 Substituted alkyl or C 3 - 8 Substituted cycloalkyl, R 8 H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It is a 4- to 6-membered substituted heterocyclic group or a 4- to 6-membered unsubstituted heterocyclic group.

[0042] In some embodiments, the compound of formula I is as shown in formula I-1-1 or I-1-2,

[0043]

[0044] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein Rb , R c , R d , R e Each is independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0045] X is selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0046] n is 1, 2, 3 or 4;

[0047] m is 0, 1, 2, 3, 4 or 5;

[0048] R 14 C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0049] Ring A is a substituted benzene ring or a substituted 5-6-membered aromatic heterocycle, wherein the substituted 5-6-membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0050] R 2 Select from the following substituents:

[0051]

[0052] Where Y is C or N, R 7 H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 8 H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It is a 4- to 6-membered substituted heterocyclic group or a 4- to 6-membered unsubstituted heterocyclic group.

[0053] In some embodiments, the compound of formula I is selected from the following compounds:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] In some embodiments, the compound of formula I is selected from the following compounds:

[0060] 8-(((1s,4s)-4-aminocyclohexyl)oxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-2-amine;

[0061] 4-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)quinazolin-8-yl)oxy)cyclohexan-1-ol;

[0062] 4-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinazolin-8-yl)oxy)cyclohexan-1-ol;

[0063] 4-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)oxy)cyclohexan-1-ol;

[0064] 8-(2-methoxyethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;

[0065] 3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)oxy)cyclopentan-1-ol;

[0066] 4-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)quinazolin-8-yl)oxy)cyclohexan-1-ol;

[0067] 4-((8-((4-hydroxycyclohexyl)oxy)quinazolin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamide;

[0068] 4-((8-((3-hydroxycyclopentyl)oxy)quinazolin-2-yl)amino)benzenesulfonamide; and

[0069] 3-((8-((4-Hydroxycyclohexyl)oxy)quinazolin-2-yl)amino)benzenesulfonamide.

[0070] On the other hand, the present application provides a pharmaceutical composition comprising the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof; and a pharmaceutically acceptable carrier.

[0071] Those skilled in the art can easily perceive other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of the present application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which the present application relates. Accordingly, the description in the drawings and specification of the present application is merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] The specific features of the invention involved in this application are shown in the attached claims. The features and advantages of the invention involved in this application can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows:

[0073] Figure 1 Shown is a schematic diagram of the synthetic route of the compound DD02001H described in this application;

[0074] Figure 2 Shown is a schematic diagram of the synthetic route of the compound DD02013H described in this application;

[0075] Figure 3 Shown is a schematic diagram of the synthetic route of the compound DD02014H described in this application;

[0076] Figure 4 Shown is a schematic diagram of the synthetic route of the compound DD02006H described in this application;

[0077] Figure 5 Shown is a schematic diagram of the synthetic route of the compound DD02008H described in this application;

[0078] Figure 6 Shown is a schematic diagram of the synthetic route of the compound DD02015H described in this application;

[0079] Figure 7 Shown is a schematic diagram of the synthetic route of the compound DD02021H described in this application;

[0080] Figure 8 Shown is a schematic diagram of the synthetic route of the compound DD02018H described in this application;

[0081] Fig. 9 Shown is a schematic diagram of the synthetic route of the compound DD02002H described in this application;

[0082] Fig.10 Shown is a schematic diagram of the synthetic route of compound DD02019H described in the present application. DETAILED DESCRIPTION

[0083] The following is an explanation of the implementation of the present application by means of specific embodiments. People familiar with this technology can easily understand other advantages and effects of the present application from the contents disclosed in this specification.

[0084] Definition of terms

[0085] The term "substituent" or "substituent group" refers to an atom or group of atoms that replaces a hydrogen atom on a molecule. The term "substituted" means that the specified molecule bears one or more substituents.

[0086] The term "alkyl" refers to a branched and straight chain saturated aliphatic hydrocarbon group containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears after the symbol "C" in the form of a subscript, the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C 1-6 "Alkyl" refers to straight-chain and branched alkyl groups having one to six carbon atoms. 1-6 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl.

[0087] The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic hydrocarbon molecule by removing a hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears after the symbol "C" in subscript form, the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 "Cycloalkyl" means a cycloalkyl group having three to six carbon atoms. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0088] The term "heteroatom" refers to oxygen (O), sulfur (S) and nitrogen (N).

[0089] The terms "halo" and "halogen" refer to F, Cl, Br and I.

[0090] The term "cyano" refers to the group -CN.

[0091] The term "amino" refers to the group -NH2.

[0092] The term "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic 3-8 membered monocyclic, 7-12 membered bicyclic or 10-14 membered tricyclic ring system containing 1-4 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic) or 1-9 heteroatoms (if tricyclic) selected from O, S or N, wherein the non-aromatic ring system is fully saturated. The heterocycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the heterocycloalkyl group may be substituted with substituents.

[0093] The term "aromatic ring" or "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system of a hydrocarbon. The aryl group may optionally be substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of the aryl group may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

[0094] The term "aromatic heterocycle" or "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6-membered monocyclic radicals and 9 or 10-membered bicyclic radicals having at least one heteroatom (O, S or N) in at least one ring, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms independently selected from O, S and / or N. Each ring in the heteroatom-containing heteroaryl radical may contain 1 or 2 oxygen or sulfur atoms and / or 1-4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The heteroaryl radical may be attached to any available nitrogen or carbon atom of any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents.

[0095] The term "alkoxy" refers to an -O-alkyl group. Alkoxy groups may be optionally substituted with one or more substituents.

[0096] The term "isomers" or "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0097] The term "pharmaceutically acceptable" refers to compounds, substances, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without causing excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0098] The compound of formula I can form salts, which are also within the scope of the present application. Unless otherwise indicated, reference to the present application compound should be understood to include reference to one or more salts thereof. The term "salt" means an acidic and / or basic salt formed with an inorganic and / or organic acid and a base. In addition, the term "salt" may include zwitterions (inner salts), for example, when the compound of formula I contains a basic moiety (e.g., an amine or pyridine or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) salts are preferred, such as acceptable metal salts and amine salts, wherein the cation has no significant contribution to the toxicity or biological activity of the salt. However, other salts may also be used, for example, in separation or purification steps that may be used during preparation, and are thus covered within the scope of the present application. The salt of the compound of formula I may be formed by, for example, reacting the compound of formula I with an amount (e.g., one equivalent) of an acid or base in a medium such as a medium in which the salt is precipitated or in an aqueous medium, and then lyophilizing.

[0099] It should be further understood that solvates (e.g., hydrates) of compounds of Formula I are also within the scope of the present application. The term "solvate" refers to the physical association of a compound of Formula I with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, the solvate will be separable, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[0100] The term "metabolite" refers to a product produced by the metabolism of a particular compound or its salt in vivo. Metabolites of compounds can be identified using conventional techniques known in the art, and their activity can be determined using techniques such as those described in the present application. This product can be produced by, for example, oxidation, hydroxylation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Therefore, the present application includes metabolites of the present application compounds, including compounds produced by the following method, which includes contacting the present application compounds with a mammal for a period of time sufficient to produce its metabolites.

[0101] The term "prodrug" or "prodrug" generally refers to a compound that is a drug precursor, which, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt thereof. The content of prodrugs is well known in the art (see, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0102] Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetoxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halogen or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides and hydroxyamides. Prodrugs that are converted to active forms by other mechanisms in vivo are also included.

[0103] The compounds of formula I can form esters, which are also within the scope of the present application. The term "ester" refers to those esters that hydrolyze in vivo and include those that readily decompose in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids. Representative examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinate.

[0104] In addition, the compounds of Formula I can be isolated and purified after their preparation to obtain compositions containing an amount equal to or greater than 99% by weight of the compound of Formula I ("substantially pure"), which can then be used or formulated as described herein. Such "substantially pure" compounds of Formula I are also considered part of this application.

[0105] The compounds of the present application are intended to include all isotopes of atoms present in the compounds of the present application. Isotopes include atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0106] The term "derivative" refers to a compound formed by replacing atoms or atomic groups in the molecule of a parent compound with other atoms or atomic groups, which is called a derivative of the parent compound. For example, halogenated hydrocarbons, alcohols, aldehydes, and carboxylic acids can be regarded as derivatives of hydrocarbons because they are products of hydrocarbon hydrogen atoms being replaced by halogens, hydroxyls, oxygen, etc. For example, acyl halides, acid anhydrides, and esters are carboxylic acid derivatives because they are products of carboxylic acid hydroxyls being replaced by halogens and some organic groups. For example, taking methane (CH4) as the parent, methanol (CH3OH), formic acid (HCOOH), methyl chloride (CH3Cl), etc. are all derivatives of methane.

[0107] The term "carrier" includes pharmaceutically acceptable carriers, excipients or stabilizers that are non-toxic to cells or mammals at the dosages and concentrations used. The physiologically acceptable carrier is typically a pH buffered aqueous solution. Non-limiting examples of physiologically acceptable carriers include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinyl pyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates (including glucose, mannose or dextrins); chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN TM , polyethylene glycol (PEG) and PLURONICS TM In certain embodiments, the pharmaceutically acceptable carrier is a non-naturally occurring pharmaceutically acceptable carrier.

[0108] The term "inhibit" means that the activity of the target enzyme is reduced compared to the activity of the enzyme in the absence of the inhibitor. In some embodiments, the term "inhibit" means that the activity of HPK1 is reduced by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibition means that the activity of HPK1 is reduced by about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition means that the activity of HPK1 is reduced by about 95% to 100%, such as a 95%, 96%, 97%, 98%, 99%, or 100% reduction in activity. This reduction can be measured using a variety of techniques that are within the skill of the art, including in vitro kinase assays.

[0109] An "HPK1 antagonist" or "HPK1 inhibitor" is a molecule that reduces, inhibits or otherwise decreases one or more biological activities of HPK1 (e.g., serine / threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with a protein binding partner (e.g., SLP76)). Antagonism using the HPK1 antagonist does not necessarily indicate complete elimination of HPK1 activity. Rather, the activity may be reduced by a statistically significant amount, including, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% reduction in HPK1 activity compared to an appropriate control. DETAILED DESCRIPTION OF THE INVENTION

[0111] Quinazoline compounds

[0112] In one aspect, the present application provides a compound of formula I:

[0113]

[0114] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein R a , R b , R c , R d One of them can be The remaining can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0115] R e Can be selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0116] X may be selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0117] R 1 It may be a substituted cycloalkyl group, a substituted heterocyclic group or m can be 0, 1, 2, 3, 4 or 5, R 14 Can be C 1-6 Alkyl, C3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0118] Ring A may be a substituted benzene ring or a substituted 5-6 membered aromatic heterocycle, wherein the substituted 5-6 membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0119] R 2 The substituents may be selected from the following:

[0120]

[0121] Where Y can be C or N, R 7 Can be H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 8 Can be H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Can be independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 Can be H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It may be a 4- to 6-membered heterocyclic group or a 4- to 6-substituted heterocyclic group.

[0122] In this application, R a , R b , R c , R d One of them can be The remaining can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy represents a structure where R a , R b , R c , R dOne of them is When the other three can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy; for example, when R a for When R b , R c , R d can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy.

[0123] In some embodiments, the R 1 Can be When m is 1 or 2.

[0124] In some embodiments, the R 14 Can be C 1-6 alkyl.

[0125] In some embodiments, the R 1 It may be a substituted 5- to 8-membered cycloalkyl group or a substituted 5- to 8-membered heterocyclic group, wherein the substituted 5- to 8-membered heterocyclic group has 1 to 4 heteroatoms selected from O, S and N.

[0126] In some embodiments, the R 1 It may be a substituted 5-6 membered cycloalkyl group or a substituted 5-6 membered heterocyclic group, wherein the substituted 5-6 membered heterocyclic group has 1 to 4 heteroatoms selected from O, S and N.

[0127] In some embodiments, when R 1 When it is a substituted 5-8 membered cycloalkyl group, the R 1 Can be Where n can be 1, 2, 3 or 4.

[0128] In some embodiments, the R 3 Can be—OR 4 or—NR 5 R 6 , where R 4 It can be H, Alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl, R 5 and R 6 Can be independently H, Alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl, wherein R 5 and R 6 They are not cycloalkyl or substituted cycloalkyl at the same time.

[0129] In some embodiments, the R 4 Can be H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0130] For example, when R 4 When H, R 3 is—OH, R 1 Can be Where n can be 1, 2, 3 or 4.

[0131] In some embodiments, the R 5 and R 6 Can be independently H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl, wherein R 5 and R 6 Not at the same time C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0132] For example, when R 5 and R 6 When both are H, R 3 is—NH2, R 1 Can be Where n is 1, 2, 3 or 4.

[0133] In some embodiments, the R 13 Can be H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0134] In some embodiments, when R 4 for When R 3 Can be

[0135] For example, when R 13 When it is methyl, R 3 for R 1 for Where n can be 1, 2, 3 or 4.

[0136] In some embodiments, when R 5 For H, R 6 for When R 3 Can be

[0137] For example, when R 13 When it is methyl, R 3 for R 1 for Where n can be 1, 2, 3 or 4.

[0138] In some embodiments, R 1 The substituents may be selected from the following:

[0139]

[0140] In some embodiments, Ring A can be selected from the following substituted aromatic rings:

[0141]

[0142] In some embodiments, the A ring may be a substituted benzene ring, a substituted pyridine ring or a substituted pyrazole ring.

[0143] In some embodiments, when ring A is a substituted benzene ring or a substituted pyridine ring, R 2 The substitution position may be at the para or meta position relative to X.

[0144] For example, the A ring can be selected from the following structures:

[0145]

[0146] In some embodiments, R 2 The substituents may be selected from the following:

[0147]

[0148] For example, the A ring can be selected from the following structures:

[0149]

[0150] In some embodiments, the A ring can be selected from the following structures:

[0151]

[0152] In some embodiments, R 12 The substituents may be selected from the following:

[0153]

[0154] For example, the A ring can be selected from the following structures:

[0155]

[0156] In some embodiments, the compound of formula I is as shown in formula I-1,

[0157]

[0158] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein R b , R c , R d , R e can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0159] X may be selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0160] R 1 It may be a substituted cycloalkyl group, a substituted heterocyclic group or m can be 0, 1, 2, 3, 4 or 5, R 14 Can C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0161] Ring A may be a substituted benzene ring or a substituted 5-6 membered aromatic heterocycle, wherein the substituted 5-6 membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0162] R 2 The substituents may be selected from the following:

[0163]

[0164] Where Y can be C or N, R 7 H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 8 Can be H, C1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Can be independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 Can be H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It may be a 4- to 6-membered substituted heterocyclic group or a 4- to 6-membered unsubstituted heterocyclic group.

[0165] In some embodiments, the compound of formula I can be as shown in formula I-1-1 or I-1-2,

[0166]

[0167] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein R b , R c , R d , R e can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0168] X may be selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0169] n can be 1, 2, 3 or 4;

[0170] m can be 0, 1, 2, 3, 4, or 5;

[0171] R 14 Can be C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0172] Ring A may be a substituted benzene ring or a substituted 5-6 membered aromatic heterocycle, wherein the substituted 5-6 membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0173] R 2 The substituents may be selected from the following:

[0174]

[0175] Where Y can be C or N, R 7 Can be H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 8 Can be H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Can be independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 Can be H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It may be a 4- to 6-membered substituted heterocyclic group or a 4- to 6-membered unsubstituted heterocyclic group.

[0176] In some embodiments, the R 3 Can be—OR 4 or—NR 5 R 6 , where R 4 It can be H, Alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl, R 5 and R 6 Can be independently H, Alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl, wherein R 5 and R 6 They are not cycloalkyl or substituted cycloalkyl at the same time.

[0177] In some embodiments, the R 4 Can be H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0178] For example, when R 4 When H, R 3 is—OH, R 1 Can be Wherein n is 1, 2, 3 or 4, the compound of formula I can be as shown in formula I-1-1a,

[0179]

[0180] In some embodiments, the R 5 and R 6 Can be independently H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl, wherein R 5 and R 6 Not at the same time C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0181] For example, when R 5 and R 6 When both are H, R 3 is—NH2, R 1 Can be Wherein n is 1, 2, 3 or 4, the compound of formula I can be as shown in formula I-1-1b,

[0182]

[0183] In some embodiments, when R 4 for When R 3 Can be The compound of formula I can be as shown in formula I-1-1c, wherein n can be 1, 2, 3 or 4,

[0184]

[0185] In some embodiments, the R 13 Can be H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0186] For example, when R 13 When it is methyl, R 3 for R1 for Where n can be 1, 2, 3 or 4.

[0187] In some embodiments, when R 5 For H, R 6 for When R 3 Can be The compound of formula I can be as shown in formula I-1-1d, wherein n can be 1, 2, 3 or 4,

[0188]

[0189] In some embodiments, the R 13 Can be H, C 1-6 Alkyl, C 1-6 Substituted alkyl, C 3-8 Cycloalkyl or C 3-8 Substituted cycloalkyl.

[0190] For example, when R 13 When it is methyl, R 3 for R 1 for Where n can be 1, 2, 3 or 4.

[0191] In some embodiments, R 1 The substituents may be selected from the following:

[0192]

[0193] In some embodiments, Ring A can be selected from the following substituted aromatic rings:

[0194]

[0195] In some embodiments, the A ring may be a substituted benzene ring, a substituted pyridine ring or a substituted pyrazole ring.

[0196] In some embodiments, when ring A is a substituted benzene ring or a substituted pyridine ring, R 2 The substitution position may be at the para or meta position relative to X.

[0197] For example, the A ring can be selected from the following structures:

[0198]

[0199] In some embodiments, R 2 The substituents may be selected from the following:

[0200]

[0201] For example, the A ring can be selected from the following structures:

[0202]

[0203] In some embodiments, the A ring can be selected from the following structures:

[0204]

[0205] In some embodiments, R 12 The substituents may be selected from the following:

[0206]

[0207] For example, the A ring can be selected from the following structures:

[0208]

[0209] In some embodiments, the compound of formula I can be selected from the following compounds:

[0210]

[0211]

[0212]

[0213]

[0214]

[0215] In some embodiments, the compound of formula I can be as shown in formula I-2,

[0216]

[0217] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein R b , R c , R d , R e can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0218] X may be selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0219] R1 It may be a substituted cycloalkyl group, a substituted heterocyclic group or m can be 0, 1, 2, 3, 4 or 5, R 14 Can be C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0220] Ring A is a substituted benzene ring or a substituted 5-6-membered aromatic heterocycle, wherein the substituted 5-6-membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0221] R 2 The substituents may be selected from the following:

[0222]

[0223] Where Y can be C or N, R 7 Can be H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 8 Can be H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Can be independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 Can be H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It may be a 4- to 6-membered substituted heterocyclic group or a 4- to 6-membered unsubstituted heterocyclic group.

[0224] In some embodiments, the compound of formula I can be as shown in formula I-3,

[0225]

[0226] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein R b , R c , R d , Re can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0227] X may be selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0228] R 1 It may be a substituted cycloalkyl group, a substituted heterocyclic group or m can be 0, 1, 2, 3, 4 or 5, R 14 Can be C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0229] Ring A is a substituted benzene ring or a substituted 5-6-membered aromatic heterocycle, wherein the substituted 5-6-membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0230] R 2 The substituents may be selected from the following:

[0231]

[0232] Where Y can be C or N, R 7 Can be H, C 1 -6 Alkyl, C 3 -8 Cycloalkyl, C 1 -6 Substituted alkyl or C 3 -8 Substituted cycloalkyl, R 8 Can be H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Can be independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 Can be H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It may be a 4- to 6-membered substituted heterocyclic group or a 4- to 6-membered unsubstituted heterocyclic group.

[0233] In some embodiments, the compound of formula I can be as shown in formula I-4,

[0234]

[0235] or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof, wherein R b , R c , R d , R e can be independently selected from H, hydroxyl, halogen, cyano, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl, C 3-8 Substituted cycloalkyl and C 1-6 Alkoxy;

[0236] X may be selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl;

[0237] R 1 It may be a substituted cycloalkyl group, a substituted heterocyclic group or m can be 0, 1, 2, 3, 4 or 5, R 14 Can be C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 substituted cycloalkyl;

[0238] Ring A is a substituted benzene ring or a substituted 5-6-membered aromatic heterocycle, wherein the substituted 5-6-membered aromatic heterocycle has 1-4 heteroatoms selected from O, S and N;

[0239] R 2 The substituents may be selected from the following:

[0240]

[0241] Where Y can be C or N, R 7 Can be H, C 1 -6 Alkyl, C 3 -8 Cycloalkyl, C 1 -6 Substituted alkyl or C 3 -8Substituted cycloalkyl, R 8 Can be H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 9 and R 10 Can be independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 11 Can be H, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Substituted alkyl or C 3-8 Substituted cycloalkyl, R 12 It may be a 4- to 6-membered substituted heterocyclic group or a 4- to 6-membered unsubstituted heterocyclic group.

[0242] Pharmaceutical composition

[0243] On the other hand, the present application provides a pharmaceutical composition comprising at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or derivative thereof; and one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or excipients (collectively referred to as "carrier" materials in this application), and when desired, other active ingredients.

[0244] Without intending to be bound by any theory, the following examples are merely intended to illustrate the compounds, preparation methods and uses of the present application, and are not intended to limit the scope of the present application.

[0245] Example

[0246] Example 1: Synthesis of Compound DD02001H: 8-(((1s,4s)-4-aminocyclohexyl)oxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-2-amine

[0247] Figure 1 The synthetic route of compound DD02001H is shown.

[0248] 1.1 Synthesis of compound 2

[0249] Under N2 protection at 0°C, BH3 / THF (1.00M, 329mL, 2.20eq) was added dropwise to a solution of compound 1 (25.0g, 150mmol, 1.00eq) in THF (300mL). After the addition was complete, the mixture was stirred at 0°C for 30 minutes, and then the mixture was heated to 50°C and stirred for 12 hours. TLC (petroleum ether: ethyl acetate = 1:1, raw material R f =0.1, product R f =0.3) showed new spots formed, the starting material completely disappeared, and the reaction was complete. The mixture was then cooled to 0°C, MeOH (400 mL) was added dropwise until no bubbles were formed, then 40.0 mL of H2O was added and extracted with ethyl acetate (300 mL*2), the organic layer was washed with brine (100 mL*2), dried over anhydrous Na2SO4 and filtered, and then concentrated under reduced pressure to obtain compound 2 (45.0 g, 294 mmol, 98.2% yield), which was a light yellow oily substance with a structural formula 1 H NMR confirmed.

[0250]

[0251] 1 H NMR (400MHz, CDCl3) δ6.65-6.85(m,3H),4.63(s,2H),3.86(s,3H).

[0252] 1.2 Synthesis of compound 3

[0253]

[0254] MnO2 (128 g, 1.47 mol, 5.00 equiv) was added to a solution of compound 2 (45.0 g, 294 mmol, 1.00 equiv) in dichloromethane (DCM) (500 mL), and the resulting mixture was stirred at 25 °C for 12 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 1:1, material R f =0.45, product R f =0.8) showed that new spots were formed and the raw material spots disappeared. After the reaction was completed, the mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. Compound 3 (25.0 g, 166 mmol, 56.3% yield) was separated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 5 / 1). The structure was 1 H NMR confirmed.

[0255] 1H NMR (400MHz, DMSO-d6) δ9.85(s,1H),7.18(dd,J=8.0,1.2Hz,1H),7.02(dd,J=8.0,0.8Hz,1H),6.80(br s,2H),6.64(t,J=8.0Hz,1H),3.77-3.87(m,3H).

[0256] 1.3 Synthesis of compound 4

[0257]

[0258] A mixture of compound 3 (23.0 g, 152 mmol, 1.00 eq), urea (101 g, 1.67 mol, 89.7 mL, 11.0 eq) and NH4OAc (586 mg, 7.61 mmol, 0.05 eq) was stirred at 160°C for 0.5 h, and the mixture began to precipitate from the hot solution. After adding NMP (100 mL) to dissolve the solid precipitate, the reaction was stirred at 160°C for 1 hour. LC-MS showed that MS (RT = 0.247 minutes) target product 4 was detected, and the raw material disappeared. After the reaction was completed, the mixture was cooled to 25°C and poured into 100 mL of H2O, stirred at 25°C for 10 minutes, and filtered under reduced pressure. The crude product was dispersed with petroleum ether (60.0 mL) at 25°C with shaking for 5 min, and filtered under reduced pressure to obtain compound 4 (20.0 g, 114 mmol, 74.6% yield) as a gray solid. Structural 1 H NMR confirmed.

[0259] LCMS: product RT = 0.247 min, m / z = 177.2 (M+H) +

[0260] 1 H NMR (400MHz, DMSO) δ8.36 (s, 1H), 6.90 (br d, J = 4.0Hz, 1H), 6.87 (d, J = 8.0Hz, 1H), 6.79 (dd, J = 8.0, 4.0Hz, 1H), 5.98 (dd, J = 8.0, 4.0Hz, 1H), 3.79 (s, 3H).

[0261] 1.4 Synthesis of compound 5

[0262] Compound 4 (19.0 g, 108 mmol, 1.00 eq) was added to POCl3 (248 g, 1.61 mol, 150 mL, 15.0 eq) at 0°C, and the resulting mixture was stirred at 25°C for 0.5 hours, then heated to 140°C and stirred for 2 hours. LC-MS showed that the target product MS (RT = 0.655 minutes) was detected. After the reaction was completed, the mixture was slowly poured into 0-10°C ice water (200 mL) and stirred, then extracted with ethyl acetate (300 mL*4), the organic layer was washed with brine (100 mL*2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. It was dispersed with petroleum ether (60.0 mL) at 25°C with shaking for 5 minutes, and filtered to obtain a yellow solid compound 5 (7.60 g, 39.1 mmol, 36.2% yield). The structure was 1 H NMR confirmed.

[0263]

[0264] LCMS: product RT = 0.655 min, m / z = 195.0 (M+H) +

[0265] 1 H NMR (400 MHz, DMSO) δ9.56 (s, 1H), 7.69-7.79 (m, 2H), 7.54 (br d, J = 4.0 Hz, 1H), 3.99 (s, 3H).

[0266] 1.5 Synthesis of compound 6

[0267]

[0268] DIAD (26.3 g, 130 mmol, 25.3 mL, 1.50 eq) was added to a THF (300 mL) solution of compound 6-1 (10.0 g, 86.8 mmol, 10.1 mL, 1.00 eq), compound 6-1a (11.7 g, 104 mmol, 1.20 eq) and triphenylphosphine (34.2 g, 130 mmol, 1.50 eq) at 0°C, and the resulting mixture was stirred at 25°C under N2 protection for 12 hours. LCMS showed that the raw material was completely reacted and the product was formed. After the reaction was completed, the reaction mixture was adjusted to pH = 4 with 1 M HCl and extracted with ethyl acetate (300 mL), and the aqueous phase was adjusted to pH = 8 with NaHCO3 (saturated) and extracted again with ethyl acetate (100 mL*2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6-2 (8.00 g, 38.1 mmol, 43.8% yield), which was a yellow oily substance with a structural formula 1 HNMR confirmed.

[0269] LCMS product RT = 0.150 min, m / z = 211.1 (M+H) +

[0270] 1 H NMR (400 MHz, CDCl3) δ8.15(s,1H),8.04(s,1H),4.08-4.14(m,1H),2.95-2.98(m,2H),2.31(s,3H),2.09-2.15(m,6H).

[0271] Compound 6-2 (8.00 g, 38.1 mmol, 1.00 equivalent) and Pd / C (2.00 g, 10% purity) were stirred in methanol (50.0 mL), and the mixture was stirred at 25° C. under H2 (15 psi) for 12 hours. LCMS showed that compound 6-2 was completely consumed. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain yellow oily compound 6 (5.00 g, 27.7 mmol, 72.9% yield). The structure was 1 H NMR confirmed.

[0272] LCMS: product RT = 0.10 min, m / z = 181.1 (M+H) +

[0273] 1H NMR (400 MHz, CDCl3) δ7.09(s,1H),7.01(s,1H),3.92-3.98(m,1H),2.88-2.91(m,4H),2.26(s,3H),1.85-2.26(m,6H).

[0274] 1.6 Synthesis of compound 7

[0275]

[0276] TFA (23.4 mg, 205 umol, 15.2 uL, 0.10 eq) was added to a solution of compound 5 (400 mg, 2.06 mmol, 1.00 eq) and compound 6 (444 mg, 2.47 mmol, 1.20 eq) in IPA (10.0 mL), and the resulting mixture was stirred at 100 ° C for 2 hours. LCMS showed that the mass of the target product was detected (RT = 0.653 min). The mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 solution (50.0 mL), and then the organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a solid substance, and dispersed with petroleum ether (25.0 mL) to obtain compound 7 (570 mg, 1.68 mmol, 81.9% yield), which was a yellow solid, and the structure was determined by LCMS and 1 H NMR confirmed.

[0277] LCMS: product RT = 0.673 min, m / z = 339.3 (M+H) +

[0278] 1 H NMR(400MHz, CDCl3)δ9.05(s,1H),8.22(s,1H),7.60(s,1H),7.31-7.35(m,2H),7.21-7.25(m,1H),7 .10-7.12(m,1H),4.12-4.14(m,1H),4.05(s,3H),2.98-3.01(m,2H),2.34(s,3H),2.14-2.23(m,6H).

[0279] 1.7 Synthesis of compound 8

[0280]

[0281] To a solution of compound 7 (570 mg, 1.68 mmol, 1.00 eq) in DCM (15.0 mL) was added BBr3 (1.05 g, 4.21 mmol, 405.7 uL, 2.50 eq) dropwise. The mixture was stirred at 25 °C for 12 hours. LCMS (EW20001-101-P1A1) showed that the target product was detected (RT = 0.622 min). After the reaction was completed, the mixture was diluted with DCM (100 mL) and washed with saturated NaHCO3 solution (50.0 mL), the organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 8 (500 mg, crude) as a yellow solid, which was used directly in the next step.

[0282] LCMS: product RT = 0.847 min, m / z = 325.2 (M+H) +

[0283] 1.8 Synthesis of compound 10

[0284]

[0285] Cs2CO3 (502 mg, 1.54 mmol, 2.50 eq) was added to a DMF (3.00 mL) solution of compound 8 (200 mg, 616 umol, 1.00 eq) and compound 9 (273 mg, 740 umol, 1.20 eq), and the resulting mixture was stirred at 80 ° C for 1 hour. LCMS showed that the target product was detected (RT = 0.799 min). After the reaction was completed, water (50.0 mL) was added to quench the mixture and extracted with ethyl acetate (50.0 mL * 2), and the organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 10 (320 mg, 613 umol, 99.5% yield), a yellow oily substance, which was used directly in the next step without further purification.

[0286] LCMS product RT = 0.799 min, m / z = 522.3 (M+H) + .

[0287] 1.9 Synthesis of compound DD02001H

[0288]

[0289] A mixture of compound 10 (320 mg, 613 umol, 1.00 eq) and HCl / dioxane (4 M, 10.0 mL, 65.2 eq) was stirred at 25 °C for 1 hour. LCMS showed that the target product was detected (RT = 0.651 min). The mixture was concentrated to obtain a residue, which was purified by preparative HPLC. The mixture was adjusted to pH = 8 with saturated NaHCO3 solution, extracted with DCM (50.0 mL*2), and the organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound DD02001H. The compound structure was confirmed by LCMS, HPLC (EW20001-106-P1A2) and 1 H-NMR confirmed that it was a yellow solid (27.2 mg, 91.7 umol, 14.9% yield, 96.7% purity).

[0290] LCMS product RT = 0.644 min, m / z = 422.3 (M+H) +

[0291] 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),8.14(s,1H),7.68(s,1H),7.23-7.25(m,1H),7.12-7.13(m,2H),7.06(s,1H),4.67-4 .68(m,1H),4.05-4.09(m,1H),2.89-2.92(m,2H),2.78-2.80(m,1H),2.26(s,3H),2.05-2.15(m,8H),1.62-1.74(m,8H).

[0292] Example 2: Synthesis of Compound DD02013H: 4-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)quinazolin-8-yl)oxy)cyclohexane-1-ol

[0293] Figure 2 The synthetic route of compound DD02013H is shown.

[0294] 2.1 Synthesis of compound 11

[0295]

[0296] At 0°C, a solution of BBr3 (1.42 g, 5.65 mmol, 545 uL, 2.20 eq) in DCM (5.00 mL) was added dropwise to a solution of compound 5 (500 mg, 2.57 mmol, 1.00 eq) in DCM (10.0 mL). After the addition was complete, the mixture was stirred at 25°C for 12 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.585 min). After the reaction was completed, the mixture was quenched with water (50.0 mL) and extracted with DCM (50.0 mL). The organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1, TLC (petroleum ether: ethyl acetate = 3:1, R f =0.3) to obtain yellow solid compound 11 (400 mg, 2.21 mmol, 86.2% yield). The structure was confirmed by LCMS and 1 H NMR confirmed.

[0297] LCMS: product RT = 0.575 min, m / z = 181.0 (M+H) +

[0298] 1 H NMR (400MHz, CDCl3) δ9.30 (s, 1H), 7.59-7.64 (m, 1H), 7.49-7.52 (m, 1H), 7.42-7.45 (m, 2H).

[0299] 2.2 Synthesis of compound 12

[0300]

[0301] Cs2CO3 (721.6 mg, 2.21 mmol, 2.00 eq) was added to a DMF (5.00 mL) solution of compound 11 (200 mg, 1.11 mmol, 1.00 eq) and compound 11a (639 mg, 1.66 mmol, 1.50 eq), and the resulting mixture was stirred at 80 ° C for 2 hours. LCMS detected the molecular weight of the target product (RT = 1.229 minutes). After the reaction was completed, water (50.0 mL) was added to quench the reaction, and ethyl acetate (50.0 mL*2) was used for extraction, and the organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1, TLC (petroleum ether / ethyl acetate = 5:1, R f =0.4)) to obtain yellow solid compound 12 (100 mg, 254 umol, 22.9% yield). 1H NMR confirmed.

[0302] LCMS: product RT = 1.229 mins, m / z = 393.2 (M+H) +

[0303] 1 H NMR(400MHz, CDCl3)δ9.25(s,1H),7.55-7.60(m,1H),7.49-7.51(m,1H),7.34-7.37(m,1H),4.53-4.57(m, 1H),3.90-3.92(m,1H),2.15-2.20(m,2H),1.86-1.89(m,4H),1.60-1.64(m,2H),0.93(s,9H),0.08(s,6H).

[0304] 2.3 Synthesis of compound 12a

[0305]

[0306] K2CO3 (3.92 g, 28.4 mmol, 2.00 eq) was added to a solution of compound 12-1 (2.00 g, 14.2 mmol, 1.50 mL, 1.00 eq) and compound 12-1a (1.59 g, 15.6 mmol, 2.03 mL, 1.10 eq) in dimethyl sulfoxide (10.0 mL), and the resulting mixture was stirred at 40°C for 2 hours. TLC (petroleum ether: ethyl acetate = 5:1) showed that compound 12-1 (R f =0.6) was retained, and the formation of new products was detected. After the reaction was completed, the reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL*2), the combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 12-2 (3.20 g, crude oil), the structure of which was 1 After confirmation by H NMR, it was used in the next step without further purification.

[0307] 1 H NMR (400MHz, CDCl3) δ 8.09-8.12 (m, 2H), 6.59-6.62 (m, 2H), 3.55 (t, J = 7.2Hz, 2H), 3.10 (s, 1H), 2.50 (t, J = 7.2Hz, 2H), 2.30 (s, 6H).

[0308] Pd / C (1.00 g, 10% purity, 1.00 equiv) was added to a solution of compound 12-2 (3.20 g, 14.3 mmol, 1.00 equiv) in MeOH (30.0 mL). The suspension was degassed under vacuum and purged with hydrogen several times, after which the resulting solution was stirred for 2 hours under a H2 (15 psi) atmosphere at 25°C. TLC (dichloromethane: methanol = 10: 1) showed that the raw material point of compound 12-2 (Rf = 0.5) disappeared, and the formation of a new compound was detected. After the reaction was completed, the mixture was filtered and concentrated to obtain compound 12a (2.30 g, 11.9 mmol, 83.0% yield), the product was a reddish brown oil, the structure was 1 H NMR confirmed without further purification.

[0309] 1 H NMR (400MHz, DMSO) δ 6.47-6.54 (m, 4H), 4.34 (br.s, 2H), 3.19 (t, J = 7.2Hz, 2H), 2.72 (s, 1H), 2.30 (t, J = 7.2Hz, 2H), 2.14 (s, 6H).

[0310] 2.4 Synthesis of compound 13

[0311]

[0312] To a solution of compound 12 (100 mg, 254 umol, 1.00 eq) and compound 12a (59.0 mg, 305 umol, 1.20 eq) in IPA (3.00 mL) was added TFA (29.0 mg, 255 umol, 18.8 uL, 1.00 eq). The resulting mixture was stirred at 100 ° C for 1 hour. LCMS showed that the molecular weight of the target product was detected (RT = 0.913 min). After the reaction was completed, it was extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated NaHCO3 solution (50.0 mL) and brine (50.0 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 13 (130 mg, crude product), a yellow solid, which was not purified and used directly in the next step.

[0313] 2.5 Synthesis of compound DD02013H

[0314]

[0315] TFA (0.50 mL) was added to a DCM (5.00 mL) solution of compound 13 (130 mg, 236 umol, 1.00 equivalent), and the resulting mixture was stirred at 25 ° C for 1 hour. LCMS showed that the molecular weight of the target product was detected (RT = 0.701 min). After the reaction was completed, the mixture was concentrated to obtain a residual solid, which was purified by preparative high-performance liquid chromatography. The resulting solid was adjusted to pH = 8 with a saturated NaHCO3 solution, extracted with DCM (50.0 mL*2), washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid, the target compound DD02013H (47.6 mg, 130.7 umol, 55.3% yield, 94.9% purity), and the structure was confirmed by LCMS, HPLC and 1 H-NMR confirmed.

[0316] LCMS product RT = 0.997 min, m / z = 436.3 (M+H) +

[0317] HPLC product RT = 2.951 mins, purity: 95.6%

[0318] 1 H NMR(400MHz, CDCl3)δ9.00(s,1H),7.83-7.85(m,2H),7.29-7.31(m,1H),7 .17-7.19(m,3H),6.85-6.87(m,2H),4.78-4.79(m,1H),3.76-3.81(m,1H) ,3.49(t,J=7.2Hz,2H),2.95(s,3H),2.54(t,J=7.2Hz,2H),2.33(s,6H),2 .16-2.21(m,2H),2.03-2.06(m,2H),1.80-1.83(m,2H),1.69-1.73(m,2H).

[0319] Example 3: Synthesis of Compound DD02014H: 4-((2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinazolin-8-yl)oxy)cyclohexane-1-ol

[0320] Figure 3 The synthetic route of compound DD02014H is shown.

[0321] Cs2CO3 (1.00 g, 3.08 mmol, 2.50 eq) was added to a DMF (10.0 mL) solution of compound 8 (400 mg, 1.23 mmol, 1.00 eq) and compound 11a (569.1 mg, 1.48 mmol, 1.20 eq), and the resulting mixture was stirred at 80 ° C for 1 hour. LCMS showed that the molecular weight of the target product was detected (RT = 0.958 min). After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated NaHCO3 solution (50.0 mL) and brine (50.0 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was dispersed by shaking with petroleum ether: ethyl acetate (3:1, 20.0 mL), filtered and dried to obtain a yellow solid, compound 14 (300 mg, 559 umol, 45.3% yield), and the structure was characterized by LCMS.

[0322] LCMS product RT = 0.912 min, m / z = 537.3 (M+H) + .

[0323] A mixture of compound 14 (300 mg, 559 umol, 1.00 eq) and HCl / MeOH (4 M, 10.0 mL, 71.6 eq) was stirred at 25°C for 1 hour. LCMS (EW20001-117-P1A1) showed that the product disappeared and the molecular weight of the target product appeared (RT = 0.729 min). After the reaction was completed, the mixture was concentrated, and the obtained solid was purified by preparative HPLC. The mixture was then adjusted to pH = 8 with a saturated NaHCO3 solution, extracted with DCM (50.0 mL*2), and the organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid, compound DD02014H (35.5 mg, 138 umol, 24.6% yield, 96.9% purity). The structure was confirmed by LCMS, HPLC and 1 H NMR confirmed.

[0324] LCMS product RT = 0.730 min, m / z = 423.2 (M+H) +

[0325] HPLC product RT = 1.192 mins, purity: 98.0%

[0326] 1H NMR(400MHz, CDCl3)δ9.01(s,1H),8.61(s,1H),7.49(s,1H),7.28-7.30(m,1H),7.17-7.22(m,3H),4.66-4.68(m,1H),4.23-4.30(m, 1H),3.85-3.89(m,1H),2.99-3.03(m,2H),2.33(s,3H),2.25-2.29(m,4H),2.15-2.17(m,4H),1.95-2.06(m,2H),1.84-1.88(m,4H).

[0327] Example 4: Compound DD02006H: Synthesis of 4-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)oxy)cyclohexane-1-ol

[0328] Figure 4 The synthetic route of compound DD02006H is shown.

[0329] 4.1 Synthesis of compound 16

[0330] To a solution of compound 5 (1.00 g, 5.14 mmol, 1.00 eq) and compound 16a (1.08 g, 5.65 mmol, 1.10 eq) in IPA (20.0 mL) was added TFA (586 mg, 5.14 mmol, 380 uL, 1.00 eq) at 25°C. After mixing well, the reaction mixture was heated to 100°C and stirred for 3 hours.

[0331]

[0332] LCMS showed that the molecular weight of the target product was detected (RT = 0.691 minutes). After the reaction was completed, the mixture was poured into 30.0 mL of H2O, then extracted with ethyl acetate (60.0 mL*4), the organic layer was washed with brine (60.0 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 16 (1.50 g, crude product) as a yellow solid. The product was used directly in the next step without purification.

[0333] LCMS: product RT = 0.691 min, m / z = 350.2 (M+H) +

[0334] 4.2 Synthesis of compound 17

[0335]

[0336] At 0°C, BBr3 (2.80 g, 11.2 mmol, 1.08 mL, 3.00 eq) dissolved in DCM (10.0 mL) was added dropwise to a solution of compound 16 (1.30 g, 3.72 mmol, 1.00 eq) in DCM (20.0 mL). After the addition was complete, the mixture was stirred at 0°C for 30 min, and then the mixture was heated to 25°C and stirred for 12 h. LCMS showed that the molecular weight of the target product was detected (RT = 0.677 min). After the reaction was completed, the mixture was poured into ice water (30.0 mL), extracted with ethyl acetate (60.0 mL*3), and the organic layer (30.0 mL*2) was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 17 (1.20 g, crude product) as a gray solid. The product was used directly in the next step without purification.

[0337] LCMS: product RT = 0.677 min, m / z = 336.2 (M+H) +

[0338] 4.3 Synthesis of compound 18

[0339]

[0340] Compound 17 (150 mg, 447 umol, 1.00 eq), compound 11a (276 mg, 894 umol, 2.00 eq) and Cs2CO3 (364 mg, 1.12 mmol, 2.50 eq) were dissolved in DMF (10.0 mL), and the mixture was then heated to 80°C for 12 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.934 minutes). After the reaction was completed, the mixture was poured into 30.0 mL of H2O, and then extracted with ethyl acetate (30.0 mL*4), and the organic layer was washed with brine (30.0 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 18 (200 mg, crude product) as a yellow solid. The product was used directly in the next step without purification.

[0341] LCMS product: RT = 0.934 min, m / z = 548.4 (M+H) +

[0342] 4.4 Synthesis of compound DD02006H

[0343]

[0344] HCl / 1,4-dioxane (4M, 2.00 mL, 21.9 eq) was added dropwise to a solution of compound 18 (200 mg, 365 umol, 1.00 eq) in DCM (6.00 mL) at 25°C, and the resulting mixture was stirred for 2 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.746 min). Thin layer chromatography (DCM: MeOH = 8: 1, material R f =0.5, product R f =0.2) showed new spots formed, and no residual material. The mixture was poured into 30.0 mL H2O, and the pH value was adjusted to about 8 with saturated NaHCO3, then extracted with ethyl acetate (30.0 mL*4), and the organic layer was washed with brine (30.0 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was subjected to pre-HPLC and concentrated under reduced pressure to obtain the target product as a yellow solid (68.6 mg, 157 umol, 43.1% yield, 99.4% purity). The structure was 1 H NMR, LCMS and HPLC confirmed.

[0345] LCMS product: RT = 0.734 min, m / z = 434.3 (M+H) + ;

[0346] HPLC product RT = 1.373 mins, 99.4% purity;

[0347] 1 H NMR(400MHz,DMSO)δ9.57-9.71(m,1H),9.12-9.27(m,1H),7.90-8.06(m,2H),7.4 0-7.47(m,1H),7.28-7.34(m,1H),7.18-7.26(m,1H),6.86-6.99(m,2H),4.75(br s,1H),4.52-4.64(m,1H),3.63(br s,1H),3.07(br d,J=4.0Hz,4H),2.24(s,3H),1.91-2.05(m,2H),1.74-1.87(m,2H),1.56-1.72(m,4H).

[0348] Example 5: Synthesis of Compound DD02008H: 8-(2-methoxyethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine

[0349] Figure 5 The synthetic route of compound DD02008H is shown.

[0350] Compound 17 (150 mg, 447 umol, 1.00 eq), compound 17a (68.4 mg, 492 umol, 46.2 uL, 1.10 eq) and Cs2CO3 (437 mg, 1.34 mmol, 3.00 eq) were dissolved in DMF (10.0 mL), and the mixture was heated to 80 ° C and stirred for 12 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.703 minutes). Thin layer chromatography (DCM: MeOH = 10: 1, material Rf = 0.1, product Rf = 0.3) showed that new spots were formed and there was no starting material. After the reaction was completed, the mixture was poured into 30.0 mL H2O, and then extracted with ethyl acetate (30.0 mL*4), and the organic layer was washed with brine (30.0 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, DCM / MeOH=20 / 1 to 5 / 1) gave the target compound DD02008H (71.94 mg, 183 umol, 40.9% yield, 98.6% purity) as a yellow solid. 1 HNMR, LCMS and HPLC confirmed.

[0351] LCMS product: RT = 0.710 min, m / z = 416.2 (M + H + Na) +

[0352] HPLC product: RT = 1.267 min, 98.7% purity

[0353] 1 H NMR (400MHz, CDCl3) δ9.04 (s, 1H), 7.72 (br d,J=8.0Hz,2H),7.33(dd,J=8.0,4.0Hz,1H),7.15-7.24(m,2H),6.97(d,J=8.0Hz,2H),4.33-4 .41(m,2H),3.91-3.99(m,2H),3.56(s,3H),3.13-3.25(m,4H),2.58-2.65(m,4H),2.38(s,3H).

[0354] Example 6: Compound DD02015H: Synthesis of 3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)oxy)cyclopentane-1-ol

[0355] Figure 6 The synthetic route of compound DD02015H is shown.

[0356] Compound 17 (150 mg, 447 umol, 1.00 eq), compound 18a (331 mg, 894 umol, 2.00 eq) and Cs2CO3 (364 mg, 1.12 mmol, 2.50 eq) were dissolved in DMF (10.0 mL), and the mixture was heated to 80°C and stirred for 12 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.893 min), and TLC (DCM: MeOH = 10: 1, material Rf = 0.1, product Rf = 0.25) showed that a new spot was formed and there was no starting material. After the reaction, the mixture was poured into 30 mL of water, then extracted with ethyl acetate (30.0 mL*4), washed with brine (30.0 mL*2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residual solid was purified by column chromatography (SiO2, DCM / MeOH=20 / 1 to 5 / 1) to obtain a yellow solid compound 19 (200 mg, 375 umol, 83.8% yield). LCMS product: RT=0.893 min, m / z=534.4 (M+H) +

[0357] Compound 19 (200 mg, 375 umol, 1.00 eq) was dissolved in DCM (6.00 mL), and HCl / 1,4-dioxane (4 M, 4.00 mL, 42.7 eq) was added dropwise at 25°C. After the addition was complete, the mixture was stirred for 2 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.721 min), and HPLC showed that the reaction of the starting material was complete. After the reaction was completed, the mixture was poured into 30.0 mL H2O, adjusted to a pH value of about 8 with saturated NaHCO3, and then extracted with ethyl acetate (30.0 mL*4), the organic layer was washed with brine (30.0 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain the yellow solid target compound DD02015H (110 mg, 262 umol, 70.0% yield, 100% purity). The structure was 1 HNMR, LCMS and HPLC confirmed.

[0358] LCMS product: RT = 0.716 min, m / z = 420.3 (M+H) +

[0359] HPLC product: RT = 1.286 min, 100% purity.

[0360] 1H NMR (400MHz, CDCl3) δ9.04 (s, 1H), 7.60 (br d, J = 8.0Hz, 2H), 7.32-7.38 (m, 1H), 7.21-7.24 (m, 2H), 6.93-7.01 (m, 2H), 5.15 (t, J = 4.0Hz, 1H), 4.41 (br t,J=4.0Hz,1H),3.17-3.26(m,4H),2.62(m,4H),2.38(s,3H),1.94-2.20(m,6H).

[0361] Example 7: Compound DD02021H: Synthesis of 4-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)quinazolin-8-yl)oxy)cyclohexane-1-ol

[0362] Figure 7 The synthetic route of compound DD02021H is shown.

[0363] 7.1 Synthesis of Compound 20

[0364] Compound 5 (500 mg, 2.57 mmol, 1.00 eq), compound 19a (988 mg, 5.14 mmol, 2.00 eq), Pd2(dba)3 (353 mg, 386 umol, 0.15 eq) and BINAP (184 mg, 295 umol, 1.15e-1 eq) were dissolved in 1,4-dioxane (30.0 mL) at 25°C, Cs2CO3 (1.67 g, 5.14 mmol, 2.00 eq) was added to the resulting mixture, and then the reaction mixture was heated to 100°C.

[0365]

[0366] The reaction was stirred for 10 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.643 min). After the reaction was completed, the mixture was poured into 30.0 mL H2O, then extracted with DCM (50.0 mL*3), the organic layer was washed with brine (30.0 mL*3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 20 (600 mg, crude product) as a yellow solid. The product was used directly in the next step without purification.

[0367] 7.2 Synthesis of compound 21

[0368]

[0369] Compound 20 (600 mg, 1.71 mmol, 1.00 eq) was dissolved in DCM (10.0 mL), and the resulting solution was added dropwise with BBr3 (429 mg, 1.71 mmol, 165 uL, 1.00 eq) dissolved in DCM (5.00 mL). After the addition was complete, the system was stirred at 25°C for 12 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.321 min). After the reaction was completed, the mixture was poured into ice water (40.0 mL), the pH was adjusted to about 8 with saturated NaHCO3, and then extracted with DCM (50.0 mL * 3), the organic layer was washed with brine (30.0 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 21 (600 mg, crude product) as a yellow solid. The product was used directly in the next step without purification. LCMS product RT = 0.324 min, m / z = 337.2 (M + H) +

[0370] 7.3 Synthesis of compound 22

[0371]

[0372] Compound 21 (600 mg, 1.78 mmol, 1.00 eq), compound 11a (1.37 g, 3.57 mmol, 2.00 eq) and Cs2CO3 (1.45 g, 4.46 mmol, 2.50 eq) were dissolved in DMF (10.0 mL), and the resulting mixture was heated to 80°C for 12 hours. LCMS showed that the molecular weight of the target product was detected (RT = 0.830 min), and thin layer chromatography (DCM: MeOH = 10: 1, material R f =0.1, product R f =0.3) showed new spots formed, and no starting material. After the reaction was completed, the mixture was poured into 30.0 mL of H2O, then extracted with ethyl acetate (60.0 mL*3), the organic layer was washed with brine (40.0 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the obtained material was purified by column chromatography (SiO2, DCM / MeOH=40 / 1 to 5 / 1) to obtain compound 22 (700 mg, 1.08 mmol, 60.5% yield, 84.6% purity) as a yellow solid.

[0373] LCMS product RT = 0.830 min, m / z = 549.4 (M+H) +

[0374] HPLC product RT = 2.563 mins, 84.6% purity.

[0375] 7.4 Synthesis of Compound DD02021H

[0376]

[0377] Compound 22 (600 mg, 925 umol, 1.00 equivalent) and HCl / 1,4-dioxane (4 M, 6.00 mL, 25.9 equivalent) were dissolved in DCM (10.0 mL), and the resulting mixture was stirred at 25°C for 1 hour. LCMS showed that the molecular weight of the target product was detected (RT = 0.680 min), and thin layer chromatography (DCM: MeOH = 10: 1, material R f =0.3, product R f =0.15) showed new spots formed, and there was no starting material. After the reaction was completed, the mixture was slowly poured into 40.0mL H2O with stirring, and then extracted with ethyl acetate (80.0mL*3), the organic layer was washed with brine (50.0mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained solid was purified by preparative high performance liquid chromatography, the obtained substance was adjusted to pH 8 with saturated NaHCO3, then extracted with DCM (40.0mL*4), the organic layer was washed with brine (40.0mL*3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the target product DD02021H, (148mg, 329umol, 35.6% yield, 96.7% purity), as a yellow solid, the structure was 1 H NMR, LCMS and HPLC confirmed.

[0378] LCMS product RT = 0.717 min, m / z = 435.3 (M+H) +

[0379] HPLC product RT = 1.232 min, 96.7% purity

[0380] 1 H NMR (400MHz, DMSO) δ9.74(s,1H),9.26(s,1H),8.86(d,J=8.0Hz,1H),8.02(d,J=4.0Hz,1H),7.43-7.57(m,2H),7.24-7.40(m,2H),4.78(br s,1H),4.62-4.73(m,1H),3.54-3.69(m,1H),3.08-3.16(m,4H),2.47(m,3 H),2.23(s,3H),1.93-2.04(m,2H),1.74-1.88(m,2H),1.58-1.72(m,4H).

[0381] Example 8: Synthesis of Compound DD02018H: 4-((8-((4-hydroxycyclohexyl)oxy)quinazolin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamide

[0382] Figure 8 The synthetic route of compound DD02018H is shown.

[0383] At 25°C, compound 11 (400 mg, 2.21 mmol, 1.00 eq), compound 11a (1.28 g, 3.32 mmol, 1.50 eq) and Cs2CO3 (1.44 g, 4.43 mmol, 2.00 eq) were dissolved in DMF (10.0 mL), and the resulting mixture was heated to 80°C and stirred for 2 hours. LCMS showed that the molecular weight of the target product was detected (RT = 1.218 min). After the reaction was completed, the mixture was slowly poured into 40.0 mL of H2O, then extracted with DCM (80.0 mL*3), the organic layer was washed with brine (50.0 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound 15 (310 mg, crude product) as a gray solid. The product was used directly in the next step without purification.

[0384] Compound 15 (260 mg, 661 umol, 1.00 eq), compound 15a (231.53 mg, 992.38 umol, 1.50 eq) and TFA (75.4 mg, 661 umol, 49.0 uL, 1.00 eq) were dissolved in IPA (10.0 mL), and the resulting mixture was heated to 80° C. and stirred for 2 hours, and then the mixture was heated to 100° C. and stirred for 2 hours. LCMS showed that the molecular weight of the target product was detected (RT=0.762 min), and HPLC showed that the purity was 59.7% (RT=1.535 min). After the reaction, the mixture was slowly poured into 40.0 mL of H2O under stirring, the pH was adjusted to about 8 with saturated NaHCO3, and then extracted with DCM (80.0 mL*3), the organic layer was washed with brine (50.0 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography. The obtained substance was adjusted to pH about 8 with saturated NaHCO3, extracted with DCM (40.0 mL*4), the organic layer was washed with brine (40.0 mL*3), dried over anhydrous Na2SO4, filtered and concentrated to obtain the target product DD02018H (17.1 mg, 35.13 umol, 5.31% yield, 97.7% purity) as a light yellow solid, the structure of which is 1 H NMR, LCMS and HPLC confirmed.

[0385] LCMS product RT = 0.771 min, m / z = 476.2 (M+H) +

[0386] HPLC product RT = 1.535 mins, 97.3% purity

[0387] 1 H NMR (400MHz, DMSO-d6) δ10.15(br s,1H),9.30(br s,1H),8.23(br d,J=8.0Hz,2H),8.13(br s,1H),7.83(br d,J=8.0Hz,2H),7.49(br s,1H),7.27-7.42(m,2H),4.73(br s,1H),4.60(br s,1H),3.87(br s,1H),3.07(br s,2H),2.62-2.67(m,2H),2.33(br s,3H),1.84-2.08(m,3H),1.73(m,9H).

[0388] Example 9: Synthesis of Compound DD02002H: 4-((8-((3-hydroxycyclopentyl)oxy)quinazolin-2-yl)amino)benzenesulfonamide

[0389] Fig. 9 The synthetic route of compound DD02002H is shown.

[0390] 9.1 Synthesis of Compound 23

[0391] Under nitrogen protection, compound 11 (200 mg, 1.11 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), triphenylphosphine (581 mg, 2.22 mmol), DIAD (449 mg, 2.22 mmol) were added in sequence, stirred for 15 min, and finally 1,3-cyclopentanediol (i.e. compound 22, 340.1 mg, 3.33 mmol) was added. The reaction solution was stirred at room temperature overnight. TLC (PE / EA=3:1) analysis showed that the raw material was completely consumed and a new product point was generated. After the reaction was completed, the resulting mixture was concentrated and the solvent was removed. The crude product was separated by silica gel column to obtain compound 23 (210 mg) with a yield of 71.5%, which was a light yellow solid.

[0392] LCMS product RT = 2.76 min, m / z = 265.1 (M+H) +

[0393] 9.2 Synthesis of Compound DD02002H

[0394] Under nitrogen protection, compound 23 (200 mg, 0.76 mmol) was dissolved in isopropanol (5 mL), p-aminobenzenesulfonamide (260.2 mg, 1.51 mmol) was added, and the reaction was heated to 90°C overnight. Thin layer chromatography analysis showed that some raw materials remained and new product spots were generated. LCMS showed that the molecular weight of the target product was detected. After the reaction was completed, the product was concentrated and the crude product was separated by silica gel column to obtain the target molecule DD02002H (104 mg), with a yield of 34%, as a white solid. The structure was 1 H NMR and LCMS confirmed.

[0395] LCMS product RT = 3.46 min, m / z = 401.1 (M+H) +

[0396] 1 H NMR(400MHz,MeOD)δ9.21(s,1H),8.23-8.25(m,2H),7.87-7.89(m,2H),7.48(d ,J=7.6Hz,1H),7.33-7.37(m,2H),4.36(m,1H),4.20(m,1H),1.76-2.10(m,6H).

[0397] Example 10: Synthesis of Compound DD02019H: 3-((8-((4-hydroxycyclohexyl)oxy)quinazolin-2-yl)amino)benzenesulfonamide

[0398] Fig.10 The synthetic route of compound DD02019H is shown.

[0399] 10.1 Synthesis of Compound 26

[0400] Under nitrogen protection, compound 11 (200 mg, 1.11 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), triphenylphosphine (581 mg, 2.22 mmol) and DIAD (449 mg, 2.22 mmol) were added in sequence, the resulting mixture was stirred for 15 min, and finally 1,4-cyclohexanediol (387 mg, 3.33 mmol) was added. The resulting reaction solution was stirred at room temperature overnight. TLC (PE / EA=3:1) analysis showed that the raw material was completely consumed and new product spots were generated. LCMS detected the molecular weight of the target product (RT=4.03 min). The reaction solution was concentrated, and the crude product was separated by silica gel column to obtain compound 26 (197 mg), with a yield of 70.7%, and a light yellow solid. LCMS product RT=4.03 min, m / z=279.1 (M+H) +

[0401] 10.2 Synthesis of Compound DD02019H

[0402] Under nitrogen protection, compound 26 (150 mg, 0.54 mmol) was dissolved in isopropanol (5 mL), and m-aminobenzenesulfonamide (185.4 mg, 1.1 mmol) was added. The reaction was heated to 90 ° C and reacted overnight. TLC analysis showed that the raw material was left and new product spots were generated. LC-MS detected the molecular weight of the target product. The reaction solution was concentrated and the crude product was separated by silica gel column to obtain the target molecule DD02019H (27 mg) with a yield of 12.1%. It was a white solid. The structure was confirmed by LC-MS and 1 H NMR confirmed. LCMS product RT = 3.54 min, m / z = 415.2 (M+H) +

[0403] 1 H NMR (400MHz, MeOD) δ9.19(s,1H),8.51(m,2H),7.34-7.55(m,5H),4.62(m,1H),3.73(m,1H),1.57-1.94(m,8H).

[0404] Example 11: In vitro testing of compounds for inhibiting HPK1 kinase activity

[0405] Table 1 lists the reagents and their sources required for the experiment

[0406]

[0407]

[0408] All compounds were tested at a starting concentration of 10 μM, with three-fold serial dilutions for a total of 10 concentration points, and each concentration was replicated once.

[0409] 11.1 In vitro test of HPK1 kinase activity inhibition by compounds

[0410] Before the experiment, prepare 50 μM DTT and enzymatic reaction system buffer.

[0411] The compound dilution was transferred to a 384-well plate with a pipette. After addition, the 384-well plate was sealed and centrifuged at 1000g for 1 min. A 2-fold concentration of HPK1 solution was prepared in the kinase buffer, and then 2.5 μL of the prepared 2-fold concentration of HPK1 solution was added to the 384 wells, centrifuged at 1000g for 30s, and incubated at room temperature for 10 min. A 2-fold concentration of MBP and ATP mixed solution was prepared in the kinase buffer, and 2.5 μL of the prepared 2-fold concentration of MBP and ATP mixed solution was added to the above reaction system. The reaction started, centrifuged at 1000g for 30s, and then incubated at room temperature for 1h. 5 μL of ADP-Glo ​​reagent was added to the reaction system and incubated at room temperature for 40 min. 10 μL of kinase detection reagent was added and incubated at room temperature for 40 min. The luminescent signal was then read on the Envision 2104plate reader, and the inhibition rate was calculated according to the following formula:

[0412] %inhibition=100-(Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )×100

[0413] In the above formula, cmpd refers to the test compound, PC refers to the positive control, and VC refers to the negative control. The positive control used in the HPK1 experiment is Sunitinib.

[0414] Table 2 lists the inhibitory ability of the compounds described in each example on HPK1 kinase activity

[0415]

[0416]

Claims

1. Compounds of formula I: or a pharmaceutically acceptable salt thereof, wherein R a for R b , R c , R d is H; R e Selected from H; X is selected from —O—, —NH—, —S—, —SO—, —SO2—, carbonyl, carbonylamino and aminocarbonyl; R 1 for m is 0, 1, 2, 3, 4 or 5, R 14 C 1-6 Alkyl, or R 1 for Where n is 1, 2, 3 or 4; R 3 for—OR 4 or—NR 5 R 6 , where R 4 For H, R 5 and R 6 independently H; The A-Ring-R 2 The moiety is selected from the following substituted aromatic rings: R 2 Select from the following substituents: Where Y is C or N, R 7 H or C 1-6 Alkyl, R 8 H, C 1-6 Alkyl, R 9 and R 10 Independently H, C 1-6 Alkyl, R 11 For H, R 12 is a substituent selected from the following:

2. The compound of formula I according to claim 1, wherein the compound of formula I is as shown in formula I-1-1 or I-1-2, or a pharmaceutically acceptable salt thereof, wherein R b , R c , R d , R e ,X,n,m,R 14 , A ring, R 2 , Y, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 As described in claim 1.

3. The compound of formula I according to claim 1, wherein the compound of formula I is selected from the following compounds:

4. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

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