Aromatic heterocyclic compound and its application

Abstract

Disclosed are an aromatic heterocyclic compound and its application. The present invention provides an aromatic heterocyclic compound as shown in Formula I, which has good LSD1 enzyme inhibitory activity and can be used as a LSD1 inhibitor for the treatment of tumors and the like.

Description

[0001] This application claims the priority of Chinese Patent Application No. 2021113320188 filed on November 11, 2021. This application cites the entire text of the above Chinese Patent Application. Technical Field

[0002] The invention relates to an aromatic heterocyclic compound and application thereof. Background Art

[0003] Histone methylation is an important type of histone covalent modification in epigenetic regulation. It was previously considered to be a relatively stable epigenetic modification. Until 2004, Shi Yang et al. discovered the first specific lysine demethylase 1 (LSD1, KDM1A), people gradually realized that histone methylation and demethylation are a dynamic equilibrium process [Cell, 2004, 119: 941-53.]. Structurally, LSD1 can be divided into three parts: Tower domain, C-terminal amino oxidase (AOL) domain, and N-terminal SWIRM domain. The Tower domain is composed of a group of reverse parallel α helices, which plays a very important role in the catalytic function of LSD1. The N-terminal domain contains an α helix, which can form a protein-protein complex with certain proteins, such as CoREST, NuRD and other proteins. This form is conducive to maintaining protein stability, so that the protein is not easy to deconstruct and inactivate while exercising higher-level functions. The C-terminal AOL domain is the structural center of the entire LSD1 catalytic function. It is the hub for recognizing FAD and the site for specific binding to FAD. The reduction in LSD1 enzyme activity is likely to be caused by the allosteric inactivation of this domain to a large extent [PLoS Computational Biology, 2013, 9: e1003158.]. LSD1 belongs to the amine oxidase family, which relies on FAD to catalyze the oxidation reaction of H3K4 and H3K9 to produce formaldehyde and a demethylated lysine residue to remove the methyl group.

[0004] LSD1 regulates many cell signaling pathways, and its dysfunction is closely related to the occurrence and development of many diseases, such as cancer, neurodegenerative diseases, cardiovascular diseases, inflammation, viral infections, etc. Abnormal LSD1 overexpression occurs in human blood tumors and solid tumor cells, such as acute myeloid leukemia [Cancer Res. 2016, 76 (7), 1975-1988.], small cell lung cancer [Cancer Cell 2015, 28 (1), 57-69.], breast cancer, neuroblastoma, colorectal cancer, prostate cancer [Am. J. Clin. Exp. Urol. 2014, 2 (4), 273-285.], liver cancer, gastric cancer, oral cancer, etc. [Future Med. Chem., 2017, 9: 1227-1242.]. Inhibiting the activity of LSD1 can inhibit the differentiation, proliferation, migration, invasion and tumor growth of cancer cells [Epigenomics 2016, 8(8), 1103-1116.]. In addition, the inhibition of LSD1 can enhance the tumor immunotherapy effect of PD-1 antibodies, which provides theoretical support for the combination of small molecule LSD1 inhibitors and tumor immunotherapy [Cell, 2018, 174: 549-563.e19.]. Therefore, LSD1 is a very potential therapeutic target.

[0005] Currently, no LSD1 inhibitor has been approved for marketing, and 8 compounds are in the early clinical stage, 6 of which have a trans-phenylcyclopropylamine skeleton. In this field, LSD1 inhibitor molecules with new structural skeletons are needed. Summary of the invention

[0006] The technical problem to be solved by the present invention is that the existing LSD1 inhibitors have defects such as a single structure. The present invention provides an aromatic heterocyclic compound and its application. The compound has good inhibitory activity on LSD1 and can be used as an LSD1 inhibitor for the treatment of tumors and the like.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides an aromatic heterocyclic compound as shown in Formula I, and a pharmaceutically acceptable salt, stereoisomer, racemate, prodrug, co-crystallized complex, hydrate or solvate thereof;

[0009]

[0010] in, represents a single bond or a double bond;

[0011] A is a substituted 5-14 membered heteroaryl or a substituted 6-14 membered aryl; wherein the substituted 5-14 membered heteroaryl and the substituted 6-14 membered aryl are independently substituted by 1, 2 or 3 R a Substitution; the heteroatoms in the 5-14 membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0012] R a are independently CN, F, Cl, Br, I or C 1-3 Alkyl, at least one of which is CN;

[0013] R 1 is hydrogen, halogen, substituted or unsubstituted (amino)-(C1-C4 alkylene)-, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 14 aryl or substituted or unsubstituted 5-14 membered heteroaryl, wherein the substituted (amino)-(C1-C4 alkylene)-, substituted C 3-12 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 14 Aryl and substituted 5-14 membered heteroaryl are independently substituted with 1, 2 or 3 R 1a Substitution; the heteroatoms in the 5-14 membered heteroaryl are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; the heteroatoms in the saturated 3-10 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0014] R 2 is halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted saturated or unsaturated C 3-10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclic-(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted N(R 3 )2-(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclyl-O-, substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O-, substituted or unsubstituted N(R 3 )2-(C1-C4 alkylene)-O-, substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-; wherein the substituted C 1-4 Alkyl, substituted saturated or unsaturated C3-10 Cycloalkyl, substituted C6-C 14 Aryl, substituted 3-10 membered heterocyclic group, substituted 5-14 membered heteroaryl, substituted 3-10 membered heterocyclic group-N(R 3 )-, substituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-N(R 3 )-, substituted N(R 3 )2-(C1-C4 alkylene)-N(R 3 )-, substituted 3-10 membered heterocyclyl-O-, substituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O- and substituted N(R 3 )2-(C1-C4 alkylene)-O- is independently substituted by 1, 2 or 3 R 1c substituted; the heteroatoms in the 5-14 membered heteroaryl are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; the 3-10 membered heterocyclic group is a saturated or unsaturated 3-10 membered heterocyclic group, wherein the heteroatoms are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0015] Each R 1a and R 1c are independently F, Cl, Br, I, OH, N(R 3 )2, CN, COOH, CON(R 3 )2、SO2N(R 3 2. C 1-3 Alkyl, C 3-12 Cycloalkyl, C 1-3 Alkyl-O- or C 3-12 Cycloalkyl-O-, wherein the C 1-3 Alkyl, C 3-12 Cycloalkyl, C 1-3 Alkyl-O- and C 3-12 The cycloalkyl-O- is optionally substituted with 1, 2 or 3 R 1b replace;

[0016] Each R 1b are independently F, Cl, Br, I, OH or NH2;

[0017] Each R 3 are independently hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl; the substituted C 1-4 Alkyl and substituted C 3-12 Cycloalkyl is independently substituted by 1, 2 or 3 R 1b replace;

[0018] L is -NH-, -N(C1-C3 alkyl)-, -O- or absent (i.e., the connecting bond, R1 Directly connected to M);

[0019] X and Y are each independently N or C(R 4 );

[0020] M is C, CH or N;

[0021] Z 1 , Z 2 and Z 3 are independently a linker, N, N(R 4 )、C(H)(R 4 )、C(R 4 ), -(C=O)- or -(C=S)-; and Z 1 , Z 2 and Z 3 At most one of them is a connection key;

[0022] R 4 is hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl; the substituted C 1-4 Alkyl and substituted C 3-12 Cycloalkyl is independently substituted by 1, 2 or 3 R 1b replace.

[0023] In a certain embodiment, the aromatic heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, stereoisomer, racemate, prodrug, co-crystal complex, hydrate or solvate,

[0024] in, represents a single bond or a double bond;

[0025] A is a substituted 5-14 membered heteroaryl or a substituted 6-14 membered aryl; wherein the substituted 5-14 membered heteroaryl and the substituted 6-14 membered aryl are independently substituted by 1, 2 or 3 R a Substitution; the heteroatoms in the 5-14 membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0026] R a are independently CN, F, Cl, Br, I or C 1-3 Alkyl, at least one of which is CN;

[0027] R 1 is hydrogen, halogen, substituted or unsubstituted (amino)-(C1-C4 alkylene)-, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 14aryl or substituted or unsubstituted 5-14 membered heteroaryl, wherein the substituted (amino)-(C1-C4 alkylene)-, substituted C 3-12 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 14 Aryl and substituted 5-14 membered heteroaryl are independently substituted with 1, 2 or 3 R 1a Substitution; the heteroatoms in the 5-14 membered heteroaryl are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; the heteroatoms in the saturated 3-10 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0028] R 2 is halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted saturated or unsaturated C 3-10 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclic-(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted N(R 3 )2-(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclyl-O-, substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O-, substituted or unsubstituted N(R 3 )2-(C1-C4 alkylene)-O-, substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-; wherein the substituted C 1-4 Alkyl, substituted saturated or unsaturated C 3-10 Cycloalkyl, substituted C6-C 14 Aryl, substituted 3-10 membered heterocyclic group, substituted 5-14 membered heteroaryl, substituted 3-10 membered heterocyclic group-N(R 3 )-, substituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-N(R 3 )-, substituted N(R 3 )2-(C1-C4 alkylene)-N(R 3 )-, substituted 3-10 membered heterocyclyl-O-, substituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O- and substituted N(R 3 )2-(C1-C4 alkylene)-O- is independently substituted by 1, 2 or 3 R 1csubstituted; the heteroatoms in the 5-14 membered heteroaryl are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; the 3-10 membered heterocyclic group is a saturated or unsaturated 3-10 membered heterocyclic group, wherein the heteroatoms are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0029] Each R 1a and R 1c are independently F, Cl, Br, I, OH, N(R 3 )2, CN, COOH, CON(R 3 )2、SO2N(R 3 2. C 1-3 Alkyl, C 3-12 Cycloalkyl, C 1-3 Alkyl-O- or C 3-12 Cycloalkyl-O-, wherein the C 1-3 Alkyl, C 3-12 Cycloalkyl, C 1-3 Alkyl-O- and C 3-12 The cycloalkyl-O- is optionally substituted with 1, 2 or 3 R 1b replace;

[0030] Each R 1b are independently F, Cl, Br, I, OH or NH2;

[0031] Each R 3 are independently hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl; the substituted C 1-4 Alkyl and substituted C 3-12 Cycloalkyl is independently substituted by 1, 2 or 3 R 1b replace;

[0032] L is -NH-, -N(C1-C3 alkyl)-, -O- or absent (i.e., the connecting bond, R 1 Directly connected to M);

[0033] X and Y are each independently N or C(R 4 );

[0034] M is C, CH or N;

[0035] Z 1 , Z 2 and Z 3 are independently a linker, N, N(R 4 )、C(H)(R 4 )、C(R 4 ) or -(C=O)-; and Z 1 , Z 2and Z 3 At most one of them is a connection key;

[0036] R 4 is hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl; the substituted C 1-4 Alkyl and substituted C 3-12 Cycloalkyl is independently substituted by 1, 2 or 3 R 1b replace.

[0037] In a certain embodiment, in the aromatic heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, stereoisomer, racemate, prodrug, co-crystallized complex, hydrate or solvate, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment"),

[0038] Wherein, the aromatic heterocyclic compound as shown in Formula I is as follows:

[0039] Formula I-1 is also for example For example

[0040] in, R 1 , R 2 , L, X, Y, Z 1 , Z 2 and Z 3 As described in any one of the embodiments of the present invention; 1 and W 2 are each independently N, C(H) or C(R a ), where R a Can be F, Cl, Br, I or C 1-3 alkyl.

[0041] In one embodiment, A is a substituted 6-14 membered aryl group, R 1 is substituted or unsubstituted C6-C 14 Aryl, and R 2 is substituted or unsubstituted C6-C 14 In the aryl group, the C6-C 14 Aryl is independently phenyl or naphthyl.

[0042] In one embodiment, A is a substituted 5-14 membered heteroaryl group, R 1 is a substituted or unsubstituted 5-14 membered heteroaryl group, and R 2is a substituted or unsubstituted 5-14 membered heteroaryl group, wherein the 5-14 membered heteroaryl group is a 5-10 membered heteroaryl group, the heteroatom is selected from N, O and S, and the number of the heteroatom is 1 or 2; for example Another example

[0043] In one scenario, R 1 , R 2 and R 4 is halogen, wherein the halogen is independently F, Cl, Br, I, such as Br.

[0044] In one scenario, R 1 is substituted or unsubstituted (amino)-(C1-C4 alkylene)-, and R 2 is a substituted or unsubstituted 3-10 membered heterocyclic group -(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted N(R 3 )2-(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclyl-O-, substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O-, or substituted or unsubstituted N(R 3 )2-(C1-C4 alkylene)-O-, the (C1-C4 alkylene) is -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2- or -C(CH3)2-.

[0045] In one scenario, R 1 is substituted or unsubstituted C 3-12 Cycloalkyl, R 1a and R 1c Independently for C 3-12 Cycloalkyl or C 3-12 Cycloalkyl-O-, R 3 is substituted or unsubstituted C 3-12 Cycloalkyl, and R 4 is substituted or unsubstituted C 3-12 In the cycloalkyl group, the C 3-12 The cycloalkyl groups are independently C 3-7 Monocyclic cycloalkyl, C 4-12 Bridged or fused cycloalkyl, C 7-12 Spirocyclic cycloalkyl;

[0046] The C 3-7 A monocyclic cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0047] In one scenario, R 1is a substituted or unsubstituted 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is independently C 3-7 Monocyclic heterocycloalkyl, C 4-12 Bridged or fused heterocycloalkyl, C 7-12 Spirocyclic heterocycloalkyl, wherein the heteroatom may be selected from N, O and S, and the number of heteroatoms may be 1 or 2;

[0048] The C 3-7 The monocyclic heterocycloalkyl group may be pyrrolidinyl (For example ), piperidinyl (For example ), piperazinyl (For example ), (For example );

[0049] The C 4-12 The bridged or fused heterocycloalkyl group may be (For example ), (For example For example or Another example ), (For example ),

[0050] The C 7-12 The spirocyclic heterocycloalkyl group may be (For example ).

[0051] In one scenario, R 2 is substituted or unsubstituted C 1-4 Alkyl, R 3 is substituted or unsubstituted C 1-4 Alkyl, and R 4 is substituted or unsubstituted C 1-4 In the alkyl group, the C 1-4 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0052] In one scenario, R 2 is substituted or unsubstituted saturated or unsaturated C 3-12 In the cyclic hydrocarbon group, the saturated C 3-12 The cycloalkyl group is C 3-12 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0053] In one scenario, R 2is a substituted or unsubstituted 3-10 membered heterocyclic group, a substituted or unsubstituted 3-10 membered heterocyclic group-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclic-(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclyl-O- or substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O-, when the 3-10 membered heterocyclyl is independently a 3-10 membered heterocycloalkyl, the 3-10 membered heterocycloalkyl is independently C 3-7 Monocyclic heterocycloalkyl, C 4-12 Bridged or fused heterocycloalkyl, C 7-12 The heterocyclic alkyl group is a spirocyclic heterocyclic alkyl group, wherein the heteroatom may be selected from N, O and S, and the number of the heteroatom may be 1 or 2; the C 3-7 The monocyclic heterocycloalkyl group may be pyrrolidinyl (For example ), piperidinyl (For example ), piperazinyl (For example ), (For example );

[0054] The C 4-12 The bridged or fused heterocycloalkyl group may be (For example ), (For example For example or Another example ), (For example ),

[0055] The C 7-12 The spirocyclic heterocycloalkyl group may be (For example ).

[0056] In one scenario, R a Independently for C 1-3 Alkyl, R 1a and R 1c Independently for C 1-3 Alkyl or C 1-3 alkyl-O-, and L is -N(C1-C3 alkyl)-, wherein the C 1-3 Alkyl groups are independently methyl, ethyl, n-propyl or isopropyl.

[0057] In one scheme, A is W 1 and W 2are each independently N, C(H) or C(R a );

[0058] Among them, R a Can be F, Cl, Br, I or C 1-3 alkyl;

[0059] For example, W 1 N, CH or CF; W 2 For CH.

[0060] In one scenario, R a are independently CN or F, and at least one is CN.

[0061] In one embodiment, the R a At least one of them is a CN and is located in The counterpoint.

[0062] In one scenario, R 1 is halogen, substituted or unsubstituted C6-C 14 aryl or substituted or unsubstituted 5-14 membered heteroaryl.

[0063] In one scenario, R 2 is a substituted or unsubstituted 3-10 membered N-containing heterocyclic group, a substituted or unsubstituted 3-10 membered heterocyclic group-(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O-.

[0064] In one scheme, each R 1a and R 1c are independently F, Cl, OH, N(R 3 )2.CON(R 3 )2、SO2N(R 3 2. C 1-3 Alkyl or C 1-3 Alkyl-O-, wherein the C 1-3 Alkyl and C 1-3 Alkyl-O- is optionally substituted with 1, 2 or 3 R 1b Substituted, for example by halogen.

[0065] In one scheme, each R 1b is independently F or NH2.

[0066] In one scenario, R 3 is hydrogen or substituted or unsubstituted C 1-4 Alkyl groups, such as hydrogen or C 1-4 Alkyl; for example, hydrogen or methyl.

[0067] In one embodiment, L is -NH-, -O-, or absent; for example, absent.

[0068] In one embodiment, X and Y are each independently N; that is, for

[0069] In one embodiment, X and Y are each independently N or CH; for example for

[0070] In one scenario, Z 1 , Z 2 and Z 3 are independently N, C(H)(R 4 ) or CR 4 .

[0071] In one scenario, Z 1 , Z 2 and Z 3 Each independently is N, N(R 4 )、C(H)(R 4 ),CR 4 or -(C=O)-. In one embodiment, R 4 is hydrogen or halogen; for example, H or F.

[0072] In one scenario, R 4 is hydrogen, halogen or C 1-4 Alkyl; for example H, F or methyl.

[0073] In one scenario, R 1a and R 1c are independently F, Cl, methyl, isopropyl, methyl-O-, SO2NH2, CF3-O-, CF3-, OH- or CONH2.

[0074] In one scenario, R 1 for Br,

[0075] For example, for Br, Best More preferred

[0076] In one scenario, R 1 for Br,

[0077] For example, for Br, Best More preferred

[0078] In one scheme, A is For example Best

[0079] In one plan, for For example

[0080] For example, for

[0081] In one plan, for For example

[0082] For example, for

[0083] In one scenario, R 2 for For example Best

[0084] In one scenario, R 2 for For example Best

[0085] In one embodiment, the aromatic heterocyclic compound or a pharmaceutically acceptable salt thereof as shown in Formula I is a compound having the following structure or a hydrochloride thereof (Table 1):

[0086] Table 1:

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] The present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of substance A and a pharmaceutically acceptable carrier (pharmaceutical excipient); the substance A is one or more of the aromatic heterocyclic compound represented by formula I as described above, and its pharmaceutically acceptable salts, stereoisomers, racemates, prodrugs, co-crystallized complexes, hydrates or solvent compounds.

[0097] The present invention also provides an application of a substance A in the preparation of an LSD1 inhibitor, wherein the substance A is an aromatic heterocyclic compound as shown in Formula 1, or one or more of its pharmaceutically acceptable salts, stereoisomers, racemates, prodrugs, co-crystallized complexes, hydrates or solvent compounds. In the application, the LSD1 inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting LSD1.

[0098] The present invention also provides an application of a substance A in the preparation of a drug, wherein the substance A is an aromatic heterocyclic compound represented by formula I as described above, or one or more of its pharmaceutically acceptable salts, stereoisomers, racemates, prodrugs, co-crystallized complexes, hydrates or solvent compounds; the substance A is in a therapeutically effective amount; and the drug is used to treat or prevent LSD1-mediated diseases.

[0099] The present invention also provides an application of a substance A in the preparation of a drug, wherein the drug is a drug for treating or preventing cancer; the substance A is one or more of the aromatic heterocyclic compound represented by formula I as described above, or its pharmaceutically acceptable salts, stereoisomers, racemates, prodrugs, co-crystallized complexes, hydrates or solvent compounds; the substance A is in a therapeutically effective amount.

[0100] The present invention also provides a method for inhibiting LSD1, which comprises administering a therapeutically effective amount of substance A to a patient; the substance A is one or more of the aromatic heterocyclic compound represented by formula 1 as described above, or a pharmaceutically acceptable salt, stereoisomer, racemate, prodrug, co-crystallized complex, hydrate or solvent compound thereof.

[0101] The present invention also provides a method for treating or preventing LSD1-mediated diseases, which comprises administering a therapeutically effective amount of substance A to a patient; the substance A is one or more of the aromatic heterocyclic compounds shown in formula I as described above, and pharmaceutically acceptable salts, stereoisomers, racemates, prodrugs, co-crystallized complexes, hydrates or solvent compounds thereof.

[0102] The present invention also provides a method for treating or preventing cancer, which comprises administering a therapeutically effective amount of substance A to a patient; the substance A is one or more of the aromatic heterocyclic compound represented by formula I as described above, or a pharmaceutically acceptable salt, stereoisomer, racemate, prodrug, co-crystallized complex, hydrate or solvent compound thereof.

[0103] The LSD1-mediated disease may be cancer.

[0104] The cancers described above are selected from, but not limited to, bladder cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, liver cancer, colon cancer, rectal cancer, esophageal cancer, cervical cancer, ovarian cancer, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, chondrosarcoma, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, large cell lymphoma, fibrosarcoma, testicular germ cell cancer, glioma, lymphoma (Hodgkin's or non-Hodgkin's), multiple myeloma, lymphoma, myeloma, neuroblastoma, neuroblastoma, non-small cell lung cancer, and one or more of small cell lung cancer.

[0105] In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0106] In the present application, when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof.

[0107] The term "plurality" refers to 2, 3, 4 or 5.

[0108] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes an inorganic acid, an organic acid (e.g., trifluoroacetic acid, hydrochloric acid). For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0109] As used herein, the compound shown in Formula I of the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound comprises enantiomers. The present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be separated by methods known in the profession, such as methods such as crystallization and chiral chromatography. When the compound of Formula I contains more than one chiral center, diastereomers may exist. The present invention includes optically pure specific isomers that have been separated and mixtures of diastereomers. Diastereomers can be separated by methods known in the profession, such as crystallization and preparative chromatography. The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore cover all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis isomers and trans isomers, and any combination thereof. The atropisomers of the present invention are stereoisomers of axial or planar chirality generated based on restricted intramolecular rotation. Regarding the atropisomers of the present invention, wherein the compound has a structure of formula I, or the compound of formula I has an isomer generated by an asymmetric carbon, etc., it represents any one of a pair of atropisomers present in each isomeric compound. And as a drug, atropisomers with excellent activity are preferred. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral separation by bonding or salt formation with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%. The compound of formula I has optical isomers derived from asymmetric carbon, axial asymmetry, etc., and a single isomer can be obtained by separation by methods known in the art, such as crystallization or chromatography (e.g., chiral chromatography) and the like when necessary.

[0110] As mentioned above, the present invention provides compounds represented by the above-mentioned structures, or their cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, wherein "their mixtures" include any form of mixtures between any of the aforementioned stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, atropisomers) and / or mixtures (meso-isomers, racemates), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of atropisomers, or mixtures of cis-trans isomers and racemates, mixtures of enantiomers and mixtures of diastereomers, mixtures of atropisomers and mixtures of diastereomers, etc.

[0111] The compounds of formula I, their stereoisomers and their pharmaceutically acceptable salts are intended to encompass any isotopically labeled (or "radiolabeled") variants of the compounds of formula I, their pharmaceutically acceptable salts, stereoisomers, racemates, prodrugs, cocrystallized complexes, hydrates or solvates. Such variants are compounds of formula I, their pharmaceutically acceptable salts, stereoisomers, racemates, prodrugs, cocrystallized complexes, hydrates or solvates in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The radionuclide used will depend on the specific application of the radiolabeled variant. For example, for in vitro receptor labeling and competition assays, 3 H or 14 C is often useful. For radiographic applications, 11 C or 18 F is often useful.

[0112] Certain isotopic variants of the compounds of the invention, particularly those into which one or more radioactive isotopes have been incorporated, can be useful, for example, in studying the mechanism of action or the distribution of the active ingredient in vivo; 3 H or 14 Compounds containing C isotopes are particularly suitable for this purpose. In addition, the inclusion of isotopes such as deuterium can produce special therapeutic benefits due to the better metabolic stability of the compound, such as extending the half-life in the body or reducing the effective dose required; therefore, such modifications of the compounds of the present invention may also constitute preferred embodiments of the present invention in some cases. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, such as by the methods described below and by the methods described in the operating examples, by using corresponding isotopically modified specific reagents and / or starting compounds.

[0113] In this application, "pharmaceutical composition" refers to a preparation comprising a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0114] In this application, "pharmaceutically acceptable" refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0115] The term "pharmaceutical excipient" or "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations except the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredients at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredients after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0116] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0117] When used as a drug, the compound as shown in Formula I, its pharmaceutically acceptable salt, stereoisomer, racemate, prodrug, co-crystallized complex, hydrate or solvent compound can be administered in any form of a pharmaceutical composition. These compositions can be prepared according to methods well known in the pharmaceutical field and can be administered in various ways, depending on the local or systemic treatment and the area to be treated. Administration can be local (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (for example, by inhalation or insufflation of powder or aerosol, including by sprayer; intratracheal or intranasal), oral (solid and liquid preparations) or parenteral administration. Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, emulsions, ointments, gels, drops, suppositories, sprays, liquids, and powders. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols: such as nasal sprays or inhalers. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial administration such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be by continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, etc. may be necessary or required. The pharmaceutical composition of the present invention may also be a controlled release or delayed release dosage form (e.g., liposomes or microspheres).

[0118] The term "treat" refers to therapeutic treatment or palliative measures. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

[0119] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0120] The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0121] The term "patient" refers to any animal that is about to or has been administered the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

[0122] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0123] In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.

[0124] Certain chemical groups defined herein are preceded by simplified notations to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl group refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5, or 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group.

[0125] As used herein, numerical ranges defined in substituents such as 0 to 4, 1-4, 1 to 3, etc. indicate integers within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

[0126] In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0127] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0128] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.

[0129] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other, that is, the more than one substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

[0130] In various parts of this specification, substituents of compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. The term "C x -C y "Alkyl" refers to a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, the term "C1-C6 alkyl" or "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently; "C 1-4 The term "alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl (i.e. propyl, including n-propyl and isopropyl), C4 alkyl (i.e. butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

[0131] As used herein, the terms "part", "moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0132] When a substituent is listed without indicating the atom through which it is attached to a chemical formula (including but not specifically mentioned compounds), such a substituent may be bonded via any atom thereof. Combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0133] When any variable (such as R 1a ) appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other.1a group-substituted, that is, the group may be replaced by up to 3 R 1a Replace, the position R 1a Definition and other positions R 1a In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0134] When there is no explicit indication that a group has a substituent, such group refers only to unsubstituted groups. For example, when "C1-C4 alkyl" is not preceded by "substituted or unsubstituted", it only refers to "C1-C4 alkyl" itself or "unsubstituted C1-C4 alkyl".

[0135] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", it should be understood that the "alkyl" represents a linked alkylene group.

[0136] In some specific structures, when an alkyl group is clearly indicated as a linking group, the alkyl group represents a linked alkylene group, for example, the C1-C6 alkyl in the group "halo-C1-C6 alkyl" should be understood as a C1-C6 alkylene.

[0137] The term "halogen" refers to fluorine, chlorine, bromine or iodine, in particular to F or Cl.

[0138] In this application, as a group or as part of other groups (e.g., in groups such as halogenated hydrocarbon groups), the term "hydrocarbon group" refers to saturated or unsaturated aliphatic hydrocarbon groups including branched and straight chains with a specified number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, and connected to the rest of the molecule by a single bond, such as "alkyl", "alkenyl" or "alkynyl".

[0139] In this application, as a group or as part of other groups (for example, in groups such as haloalkyl), the term "alkyl" refers to a saturated aliphatic hydrocarbon group including branched and straight chains having a specified number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, and connected to the rest of the molecule by a single bond, for example, having 1 to 10 (preferably 1 to 6, more preferably 1 to 4) carbon atoms. Among them, propyl is a C3 alkyl group (including isomers, such as n-propyl or isopropyl); butyl is a C4 alkyl group (including isomers, such as n-butyl, sec-butyl, isobutyl or tert-butyl); pentyl is a C5 alkyl group (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); hexyl is a C6 alkyl group (including isomers, such as n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl). For example, it includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl and decyl and the like alkyl groups.

[0140] In the present application, as a group or part of other groups, the term "alkylene" means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight or branched hydrocarbon group; that is, one hydrogen in an alkyl group is replaced, and the definition of alkyl group is as described above. Examples of alkylene groups include methylene (-CH2-), ethylene {including-CH2CH2- or-CH(CH3)-}, isopropylene {including-CH(CH3)CH2- or-C(CH3)2-}, and the like.

[0141] In the present application, as a group or part of other groups, the term "alkenyl" refers to a straight or branched hydrocarbon chain group having at least one double bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, for example, including but not limited to vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2,2-dimethylpropenyl, n-hexenyl, heptenyl, 2-methylhexenyl, 3-methylhexenyl, octenyl, nonenyl and decenyl, etc.

[0142] In the present application, as a group or part of other groups, the term "alkynyl" refers to a straight or branched hydrocarbon chain group having at least one triple bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, 2-methylbutynyl, 2,2-dimethylpropynyl, n-hexynyl, heptynyl, 2-methylhexynyl, 3-methylhexynyl, octynyl, nonynyl and decynyl, etc.

[0143] In the present application, as a group or part of other groups, the term "cycloalkyl" means a saturated or unsaturated (non-aromatic) monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) carbocyclic substituent, and it can be connected to the rest of the molecule through a single bond via any suitable carbon atom. For example, a 3-12-membered cycloalkyl group having 3 to 12 carbon atoms, another example is a 3-12-membered cycloalkyl or cycloalkenyl group, and another example is C 3-7 Monocyclic cycloalkyl, C 4-12 Bridged or fused cyclic hydrocarbon groups, C 7-12 Spirocyclic cycloalkyl. In some embodiments, 3-10-membered cycloalkyl with 3 to 10 carbon atoms is preferred, for example, 3-10-membered cycloalkyl with 3 to 10 carbon atoms, preferably 3-6-membered cycloalkyl with 3 to 6 carbon atoms; or 3-10-membered cycloalkenyl with 3 to 10 carbon atoms, preferably 3-6-membered cycloalkenyl with 3 to 6 carbon atoms. In a certain embodiment, typical monocyclic cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some embodiments, "cycloalkenyl" is a monocyclic, unsaturated carbocyclic alkenyl group with 5 to 6 ring atoms ("5-6-membered cycloalkenyl"). The term includes, but is not limited to, cyclopentenyl (e.g. ), cyclopentadienyl (e.g. ), cyclohexenyl (e.g. ) or cyclohexadienyl, and stereoisomers thereof.

[0144] In the present application, as a group or part of other groups, the term "heterocyclyl" means a stable, saturated or unsaturated (non-aromatic) monocyclic or polycyclic (e.g. bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) heterocyclic hydrocarbon group consisting of carbon atoms and one or more heteroatoms or heteroatoms selected from O, S, N (e.g. C(=O), S(=O), S(=O)2), and which can be connected to the rest of the molecule by a single bond via any suitable carbon atom. For example, a 3-10 membered heterocyclyl having 2 to 9 carbon atoms, preferably a 3-6 membered heterocyclyl having 3 to 5 carbon atoms, and another example is a 3-10 membered heterocycloalkyl having 2 to 9 carbon atoms, preferably a 3-6 membered heterocycloalkyl having 3 to 5 carbon atoms, or a 3-10 membered heterocycloalkenyl having 2 to 9 carbon atoms, preferably a 3-6 membered heterocycloalkenyl having 3 to 5 carbon atoms. The ring system of the heterocyclyl bicyclic ring may include one or more heteroatoms in one or both rings; and is saturated or unsaturated. The heterocyclyl group may be connected to the rest of the molecule via a carbon atom and by a single bond; in a heterocyclyl group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom; or, it may be connected to the rest of the molecule in parallel rings; as long as the valence permits. In some embodiments, "heterocycloalkyl" is a 5- to 7-membered monocyclic heterocycloalkyl, a 6- to 8-membered parallel ring-connected heterocycloalkyl, a 6- to 8-membered bridge-connected heterocycloalkyl, or a 7- to 10-membered spirocyclic heterocycloalkyl. Exemplary 3-membered heterocycloalkyl groups include, but are not limited to, aziridine, oxiranyl, and thiirane, or stereoisomers thereof; exemplary 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxiranyl, thiirane, or isomers and stereoisomers thereof; exemplary 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl (For example Another example ), thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl (For example ), tetrahydropyranyl, cyclopentylsulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl (For example ), triazine alkyl, (For example ), or isomers and stereoisomers thereof. Exemplary 7-membered heterocycloalkyl groups include, but are not limited to, (For example ), (For example ), (For example ), (For example For example Another example )or (For example For example Another example ), or isomers and stereoisomers thereof. Exemplary 8-membered heterocycloalkyl groups include, but are not limited to, (For example ), (For example ), (For example Another example ), (For example For example Another example )or (For example For example Another example ), or isomers and stereoisomers thereof. Exemplary 9-membered heterocycloalkyl groups include, but are not limited to, (For example )or (For example ), (For example ) or isomers and stereoisomers thereof. Exemplary 10-membered heterocycloalkyl groups include, but are not limited to, (For example )or (For example ), or isomers and stereoisomers thereof. ("*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof). In some embodiments, "heterocycloalkenyl" is a 5-7-membered monocyclic heterocycloalkenyl, a 6-8-membered and ring-connected heterocycloalkenyl, a 6-8-membered bridge-connected heterocycloalkenyl or a 7-10-membered spiro-connected heterocycloalkenyl. Examples of heterocycloalkenyl include, but are not limited to, pyranyl, 2,3-dihydropyrrolyl, 2,3-dihydrofuranyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,4-dihydro-2H-pyranyl, For example For example Another example “*” indicates that when the carbon atom marked with “*” is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof.

[0145] In the present application, as a group or part of other groups, the term "aryl" means a conjugated hydrocarbon ring system group that satisfies the 4n+2 rule. For example, a conjugated hydrocarbon ring system group that satisfies the 4n+2 rule has 6 to 20 carbon atoms (preferably 6 to 10 carbon atoms). For the purposes of the present invention, the aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group as defined above, provided that the aryl group is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. In a certain embodiment, the term "aryl" refers to an aromatic group composed of carbon atoms, each ring having aromaticity. Examples of aryl include, but are not limited to, phenyl, naphthyl (e.g. ).

[0146] In the present application, as a group or part of other groups, the term "heteroaryl" means a conjugated ring system group having carbon atoms and at least one heteroatom selected from O, S, and N in the ring. For example, a 5- to 14-membered conjugated ring system group having 1 to 13 carbon atoms (preferably 2 to 9 carbon atoms) and 1 to 6 heteroatoms selected from O, N, and S in the ring. Unless otherwise specifically indicated in this specification, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or more ring system, and may also be fused with a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as defined above, provided that the heteroaryl group is connected to the rest of the molecule via a single bond via an atom on the aromatic ring. For the purposes of the present invention, the heteroaryl group preferably comprises a stable 5- to 14-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, and further preferably comprises a stable 5- to 10-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In one embodiment, the term "heteroaryl" refers to an aromatic group containing heteroatoms, each ring having aromaticity; preferably an aromatic 5-6-membered monocyclic or 9-10-membered bicyclic ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, benzoxazolyl or benzisoxazolyl.

[0147] It should be understood that as used herein, the singular forms, such as "a," and "an," include plural references unless otherwise specified.

[0148] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0149] Unless otherwise specified, the present invention adopts conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operating steps and conditions in the art.

[0150] Unless otherwise indicated, the present invention adopts standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance testing.

[0151] In addition, it should be noted that, unless otherwise explicitly stated, the description method "... independently are" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can independently be the same or different specific groups. In more detail, the description method "... independently are" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

[0152] Those skilled in the art will appreciate that, according to the conventions used in the art, the structural formulas used in this application to describe groups and It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0153] Those skilled in the art will appreciate that, according to the conventions used in the art, the structural formulas used in this application to describe groups Indicates a single bond or a double bond.

[0154] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0155] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0156] The reagents and raw materials used in the present invention are commercially available.

[0157] The positive and progressive effect of the present invention is that as a reversible LSD1 inhibitor with a novel structural skeleton, the compound of the present invention has significant inhibitory activity on LSD1. DETAILED DESCRIPTION

[0158] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0159] In the present invention, room temperature refers to ambient temperature, which is 10° C. to 35° C. Overnight refers to 8 to 15 hours. Reflux refers to the reflux temperature of the solvent under normal pressure.

[0160] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS). MS was measured using a Finnigan LCQ / Deca (ESI) mass spectrometer. High performance liquid chromatography (HPLC) analysis used a Gilson-215 high pressure liquid chromatograph.

[0161] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0162] The known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd., Bid Pharmaceuticals, etc. Unless otherwise specified in the examples, the reactions can be carried out under argon atmosphere or nitrogen atmosphere.

[0163] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include a dichloromethane / methanol system and a petroleum ether / ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0164] Example 1

[0165] Preparation of 4-(2-(4-aminopiperidin-1-yl)-6-(3-fluoro-4-methoxyphenyl)quinazolin-4-yl)-2-fluorobenzonitrile 1

[0166]

[0167] first step

[0168] 4-(6-Bromo-2-chloroquinazolin-4-yl)-2-fluorobenzonitrile 1b

[0169] To a mixture of compound 6-bromo-2,4-dichloroquinazoline 1a (4.0 g, 11.03 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.), bis(triphenylphosphine)palladium(II) chloride (0.77 g, 1.10 mmol), sodium carbonate aqueous solution (2.0 M, 5 mL) and acetonitrile (40 mL), (4-cyano-3-fluorophenyl)boric acid (1.82 g, 11.03 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) was added. Under nitrogen protection, the stirred reaction mixture was heated at 100 ° C for 15 minutes. After cooling, the reaction solution was concentrated under reduced pressure. Ethyl acetate was slurried, filtered and dried. The title compound 1b (3.74 g) (white solid) was obtained with a yield of 72%.

[0170] 1 H NMR (400MHz, DMSO-d6) δ8.28 (dd, J=9.0, 2.1Hz, 1H), 8.23-8.17 (m, 2H), 8.05 (d, J=9.0Hz, 1H), 7.97 (d, J=9.8Hz, 1H), 7.80 (d, J=8.0Hz, 1H).

[0171] Step 2

[0172] tert-Butyl (1-(6-bromo-4-(4-cyano-3-fluorophenyl)quinazolin-2-yl)piperidin-4-yl)carbamate 1c

[0173] Compound 4-(6-bromo-2-chloroquinazoline-4-yl)-2-fluorobenzonitrile 1b (2.0 g, 5.5 mmol), diisopropylethylamine (1.82 mL, 11 mmol) and tert-butyl piperidine-4-carbamate (1.65 g, 8.25 mmol, Bid Pharmaceuticals) were dissolved in N, N-dimethylformamide (20 ml). The reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 50 mL of water and 50 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA: PE; 1: 10 to 1: 5) gave the title compound 1c (2.48 g) (yellow solid), yield: 85%. 1H NMR (400MHz, Chloroform-d) δ7.81 (dd, J=8.1, 6.3Hz, 1H), 7.75 (d, J=2.2Hz, 1H), 7.70 (dd, J=9.0, 2.2Hz, 1H), 7.61-7.55 (m, 2H), 7.51 (d, J=9.0Hz, 1H), 4.84 (dt, J=13.6, 3.9Hz, 2H), 4.52 (d, J=7.9Hz, 1H), 3.76 (s, 1H), 3.14 (t, J=12.5Hz , 2H), 2.07 (dd, J=13.1, 3.7Hz, 2H), 1.45 (s, 9H), 1.39 (qd, J=11.8, 5.4Hz, 2H).

[0174] MS m / z(ESI):526.01[M+1] + .

[0175] Step 3

[0176] tert-Butyl (1-(4-(4-cyano-3-fluorophenyl)-6-(3-fluoro-4-methoxyphenyl)quinazolin-2-yl)piperidin-4-yl)carbamate 1d

[0177] To a mixture of compound (tert-butyl 1-(6-bromo-4-(4-cyano-3-fluorophenyl)quinazolin-2-yl)piperidin-4-yl)carbamate 1c (50 mg, 0.09 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7.3 mg, 0.009 mol), sodium carbonate (28.6 mg, 0.27 mmol) and tetrahydrofuran / water (5:1) (2 mL), (3-fluoro-4-methoxyphenyl)boric acid (30.6 mg, 0.18 mmol Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) was added. The reaction mixture was stirred at 70°C for 16 h under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure, 15 mL of water and 15 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA:PE; 1:8 to 1:4) gave the title compound 1d (42 mg) as a yellow solid. Yield: 77%. 1H NMR (400MHz, Chloroform-d) δ7.87 (dd, J=8.8, 2.1Hz, 1H), 7.82 (dd, J=8.1, 6.3Hz, 1 H), 7.74-7.68 (m, 2H), 7.68-7.59 (m, 2H), 7.30-7.22 (m, 2H), 7.02 (t, J=8.8Hz, 1H), 4 .88 (d, J=13.4Hz, 2H), 4.52 (d, J=7.9Hz, 1H), 3.92 (s, 3H), 3.77 (s, 1H), 3.16 (t, J=1 2.4Hz, 2H), 2.09 (dd, J=12.9, 3.8Hz, 2H), 1.46 (s, 9H), 1.39 (qd, J=11.7, 4.0Hz, 2H).

[0178] MS m / z(ESI):571.15[M+1] + .

[0179] Step 4

[0180] 4-(2-(4-aminopiperidin-1-yl)-6-(3-fluoro-4-methoxyphenyl)quinazolin-4-yl)-2-fluorobenzonitrile 1

[0181] Compound (1-(4-(4-cyano-3-fluorophenyl)-6-(3-fluoro-4-methoxyphenyl)quinazolin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester 1d (42 mg) was dissolved in 2 mL of dichloromethane, and 2 mL of 4N hydrogen chloride-1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of the title compound 1 (30 mg) as a yellow solid, with a yield of 88%. 1 H NMR (400MHz, DMSO-d6) δ8.21-8.13 (m, 2H), 8.00 (d, J=9.7Hz, 2H), 7.84 (dd, J=10.2, 1.9Hz, 2H), 7.59 (dd, J=12.9, 2.2Hz, IH), 7.47 (dd, J=8.5, 2.2 Hz, 1H), 7.23 (t, J=8.8Hz, 1H), 4.93 (d, J=13.3Hz, 2H), 3.46-3.34 (m, 1H) , 3.24 (t, J=13.0Hz, 2H), 2.11 (d, J=12.1Hz, 2H), 1.64 (q, J=12.2Hz, 2H).

[0182] Example 2

[0183] 4-(2-(4-aminopiperidin-1-yl)-6-bromo-quinazolin-4-yl)-2-fluorobenzonitrile

[0184] The second step product 1c in the synthetic route of Example 1 was used as the raw material, and the method was similar to the fourth step reaction in the example to obtain the title compound 2 hydrochloride (20 mg). MS m / z (ESI): 426.05 [M+1] + .

[0185] Example 3

[0186] 4-(2-(4-aminopiperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-2-fluorobenzonitrile 3

[0187] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 3 (29 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boric acid with ((3,5-dimethylisoxazol-4-yl)boric acid. 1 H NMR (400MHz, DMSO-d6) δ8.16 (t, J=7.3Hz, 1H), 8.00-7.93 (m, 1H), 7.88 (dd, J=8.7, 1.9Hz, 1H), 7.84-7 .78 (m, 2H), 7.65 (d, J=1.8Hz, 1H), 4.20 (d, J=5.2Hz, 4H), 3.26-3.18 (m, 4H), 2.40 (s, 3H), 2.21 (s, 3H).

[0188] Example 4

[0189] 4-(2-(4-aminopiperidin-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)quinazolin-4-yl)-2-fluorobenzonitrile

[0190] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 4 (31 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boric acid with (5-methyl-1H-pyrazol-4-yl)boric acid. 1 H NMR (400MHz, DMSO-d6) δ8.17 (t, J=7.3Hz, 1H), 8.07 (s, 1H), 8.01 (t, J=8.7Hz, 2H), 7.90 (d, J=8.8Hz, 1H), 7.84 (d, J=7.9Hz, 1H), 7.7 1 (s, 1H), 4.91 (d, J = 13.2Hz, 2H), 3.44-3.32 (m, 1H), 3.19 (t, J = 12.6Hz, 2H), 2.37 (s, 3H), 2.09 (d, J = 12.2Hz, 2H), 1.69-1.55 (m, 2H).

[0191] Example 5

[0192] 3-(2-(4-aminopiperidin-1-yl)-4-(4-cyano-3-fluorophenyl)quinazolin-6-yl)benzenesulfonamide 5

[0193] The synthetic route of Example 1 was used to replace the raw material (3-fluoro-4-methoxyphenyl)boronic acid in the third step with 3-(aminosulfonyl)phenylboronic acid to prepare the hydrochloride salt of the title compound 5 (28 mg). MS m / z (ESI): 503.16 [M+1] + .

[0194] Example 6

[0195] 4-(2-(4-aminopiperidin-1-yl)-6-(o-tolyl)quinazolin-4-yl)-2-fluorobenzonitrile

[0196] The hydrochloride salt of the title compound 4 (26 mg) was prepared by adopting the synthetic route of Example 1, replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with o-methylphenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.14 (t, J=7.2Hz, 1H), 8.07 (d, J=8.6Hz, 1H), 7.95 ( d, J=9.7Hz, 1H), 7.92-7.89 (m, 1H), 7.79 (d, J=7.8Hz, 1H), 7.60 (d, J=1.7Hz, 1H), 7.32-7.21(m, 4H), 4.95(d, J=13.1Hz, 2H), 3.43-3.39(m, 1H), 3.28(t, J=12.8Hz, 2H), 2.22 (s, 3H), 2.12 (d, J=12.2Hz, 2H), 1.66 (d, J=11.9Hz, 2H).

[0197] Example 7

[0198] 4-(2-(4-aminopiperidin-1-yl)-6-(2-isopropylphenyl)quinazolin-4-yl)-2-fluorobenzonitrile 7

[0199] The hydrochloride salt of the title compound 7 (26 mg) was prepared by adopting the synthetic route of Example 1, replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2-isopropylphenylboronic acid. 1H NMR (400MHz, DMSO-d6) δ8.12 (t, J=6.9Hz, 1H), 8.00 (d, J=7.7Hz, 1H), 7.94 (d, J=9.6Hz, 1H), 7.79 (t, J=8.2Hz, 2H), 7.52 (s, 1H), 7.41 (d, J=7.5Hz, 1H), 7.34 (t, J=7.0Hz, 1H), 7. 19 (q, J=7.9Hz, 2H), 4.93 (d, J=12.5Hz, 2H), 3.43-3.34 (m, 1H), 3.22 (d, J=12.5Hz, 2H), 3 .06-2.88(m, 1H), 2.11(d, J=11.9Hz, 2H), 1.64(t, J=11.8Hz, 2H), 1.08(d, J=6.4Hz, 6H).

[0200] Example 8

[0201] 4-(2-(4-aminopiperidin-1-yl)-6-(m-tolyl)quinazolin-4-yl)-2-fluorobenzonitrile 8

[0202] The synthetic route of Example 1 was adopted, and the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid was replaced by 3-methylphenylboronic acid to prepare the hydrochloride salt of the title compound 8 (16 mg). 1 H NMR (400MHz, DMSO-d6) δ8.21-8.12 (m, 2H), 8.01 (d, J=9.8Hz, 1H), 7.93-7.81 (m, 3H), 7.49-7.41 (m, 2H), 7.34 (t, J=7.5Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 4.91 (d, J=13.2Hz, 2H), 3.40-3.36 (m, 1H), 3.19 (t, J=12.6Hz, 2H), 2.35 (s, 3H), 2.09 (d, J=12.1Hz, 2H), 1.61 (q, J=12.4, 11.2Hz, 2H).

[0203] Example 9

[0204] 4-(2-(4-aminopiperidin-1-yl)-6-(1-methyl-1H-indazol-5-yl)quinazolin-4-yl)-2-fluorobenzonitrile 9

[0205] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 9 (26 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 1-methylindazole-5-boronic acid. 1H NMR (400MHz, Methanol-d4) δ8.40 (d, J=8.5Hz, 1H), 8.15-8.03 (m, 5H), 7.91 (d, J=7.8Hz, 1H), 7.73 (d, J=8.7Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 5.07-5.02 (m, 2H), 4.09 (s, 3H), 3.67-3.59 (m, 1H), 3.52 (d, J=11.5Hz, 2H), 2.30 (d, J=11.3Hz, 2H), 1.88 (d, J=12.2Hz, 2H).

[0206] Example 10

[0207] 4-(2-(4-aminopiperidin-1-yl)-6-(1-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2-fluorobenzonitrile 10

[0208] The synthetic route of Example 1 was adopted, and the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid was replaced by 1-methylindazole-4-boronic acid to prepare the hydrochloride salt of the title compound 36 (22 mg). 1 H NMR (400MHz, Methanol-d4) δ8.43 (dd, J=8.7, 1.8Hz, 1H), 8.17 (d, J=1.7Hz, 1H), 8.13 (d, J =8.7Hz, 1H), 8.07 (dd, J=7.9, 6.4Hz, 1H), 8.03 (s, 1H), 7.98 (d, J=9.5Hz, 1H), 7.92 (d, J=7 .9Hz, 1H), 7.88-7.81 (m, 2H), 7.44 (d, J=8.4Hz, 1H), 5.05 (d, J=11.6Hz, 2H), 4.11 (s, 3H), 3.64 (d, J=12.4Hz, 1H), 3.50 (t, J=12.9Hz, 2H), 2.34-2.27 (m, 2H), 1.88 (d, J=12.5Hz, 2H).

[0209] Embodiment 11

[0210] 4-(2-(4-aminopiperidin-1-yl)-6-(1-methyl-1H-indazol-7-yl)quinazolin-4-yl)-2-fluorobenzonitrile 11

[0211] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 11 (23 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 1-methylindazole-7-boronic acid. 1H NMR (400MHz, Methanol-d4) δ8.25-8.17 (m, 2H), 8.09 (d, J=1.5Hz, 1H), 8.06-7.92 (m, 3H), 7.88 (d, J=7.9Hz, 1H), 7.83 (dd, J=7.9, 1.5H z, 1H), 7.31 (d, J=6.9Hz, 1H), 7.23 (t, J=7.5Hz, 1H), 5.10-5.02 (m, 2H), 3.70-3.55 (m, 6H), 2.33 (d, J=11.2Hz, 2H), 2.01-1.83 (m, 2H).

[0212] Example 12

[0213] 4-(2-(4-aminopiperidin-1-yl)-6-(2,6-dimethylphenyl)quinazolin-4-yl)-2-fluorobenzonitrile 12

[0214] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 12 (18 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2,6-dimethylbenzeneboronic acid. 1 H NMR (400MHz, Methanol-d4) δ8.18 (d, J=8.2Hz, 1H), 7.98 (d, J=6.3Hz, 1H), 7.89-7.76 (m, 3H), 7.65 (s, 1H), 7.19-7.05 (m , 3H), 5.10-5.03(m, 2H), 3.70-3.64(m, 1H), 3.56-3.50(m, 2H), 2.33(d, J=11.3Hz, 2H), 2.01(s, 6H), 1.96-1.86(m, 2H).

[0215] Example 13

[0216] 4-(2-(4-aminopiperidin-1-yl)-6-(2-(trifluoromethoxy)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 13

[0217] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 13 (16 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2-(trifluoromethoxy)phenylboronic acid. 1H NMR (400MHz, Methanol-d4) δ8.20 (s, 2H), 8.07 (t, J=7.1Hz, 1H), 8.03 (s, 1H), 7.93 (d, J=9.4Hz, 1H), 7.88 (d, J=8.1Hz, 1H), 7.62 (d, J=7.2Hz, 1H), 7.59-7.44 (m, 3H), 5.10-5.03 (m, 2H), 3.68 (s, 1H), 3.57 (t, J=10.7Hz, 2H), 2.34 (d, J=12.0Hz, 2H), 2.01-1.83 (m, 2H).

[0218] Embodiment 14

[0219] 4-(2-(4-aminopiperidin-1-yl)-6-(2-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 14

[0220] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 14 (20 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2-(trifluoromethyl)phenylboronic acid. 1 H NMR (400MHz, Methanol-d4) δ8.13 (d, J=8.5Hz, 1H), 8.03 (t, J=6.9Hz, 2H), 7.88 (dd, J=16.5, 8.4Hz, 4H), 7.73 (t, J=7.4Hz, 1H), 7.65 (t, J=7 .7Hz, 1H), 7.48 (d, J = 7.4Hz, 1H), 5.10-5.03 (m, 2H), 3.71-3.64 (m, 1H), 3.53 (d, J = 13.3Hz, 2H), 2.39-2.27 (m, 2H), 1.92 (d, J = 12.7Hz, 2H).

[0221] Embodiment 15

[0222] 4-(2-(4-aminopiperidin-1-yl)-6-(2-fluorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 15

[0223] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 15 (30 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2-fluorophenylboronic acid. 1H NMR (400MHz, Methanol-d4) δ8.24 (d, J=9.2Hz, 1H), 8.13-8.01 (m, 3H), 7.93 (d, J=9.5Hz, 1H), 7.87 (d, J=7.9Hz, 1H), 7.57 (td, J=7.9, 1.7Hz, 1H), 7.45 (t dd, J=7.2, 5.0, 1.7Hz, 1H), 7.35-7.20 (m, 2H), 5.05 (d, J=12.5Hz, 2H), 3.66 -3.60 (m, 1H), 3.55-3.39 (m, 2H), 2.29 (d, J=12.0Hz, 2H), 1.95-1.77 (m, 2H).

[0224] Example 16

[0225] 4-(2-(4-aminopiperidin-1-yl)-6-(2-chlorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 16

[0226] The synthetic route of Example 1 was adopted, and the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid was replaced by 2-chlorophenylboronic acid to prepare the hydrochloride salt of the title compound 16 (32 mg). 1 H NMR (400MHz, Methanol-d4) δ8.13 (q, J=8.7Hz, 2H), 8.04 (t, J=7.0Hz, 1H), 7.98 (s, 1H), 7.93 (d, J=9.5Hz, 1H), 7.87 (d, J=7.8Hz, 1H), 7. 58-7.52 (m, 1H), 7.50-7.37 (m, 3H), 5.08-5.02 (m, 2H), 3.72-3.60 (m, IH), 3.58-3.41 (m, 2H), 2.31 (d, J=11.0Hz, 2H), 1.93-1.86 (m, 2H).

[0227] Embodiment 17

[0228] 4-(2-(4-aminopiperidin-1-yl)-6-(2,3-difluorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 17

[0229] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 17 (19 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2,3-difluorophenylboronic acid. 1H NMR (400MHz, Methanol-d4) δ8.26 (d, J=8.8Hz, 1H), 8.17-8.02 (m, 3H), 7.96 (d, J=9.5Hz, 1H), 7.90 (d, J=8.2Hz, 1H), 7 .43-7.25 (m, 3H), 5.12-5.03 (m, 2H), 3.71-3.58 (m, 1H), 3.57-3.40 (m, 2H), 2.32 (d, J=12.3Hz, 2H), 1.97-1.78 (m, 2H).

[0230] Embodiment 18

[0231] 4-(2-(4-aminopiperidin-1-yl)-6-(2,6-bis(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 18

[0232] The synthesis route of Example 1 was used to replace the raw material (3-fluoro-4-methoxyphenyl)boronic acid in the third step with 2,6-bis(trifluoromethyl)phenylboronic acid to obtain the hydrochloride salt of the title compound 18 (14 mg). MS m / z (ESI): 560.23 [M+1] + .

[0233] Embodiment 19

[0234] 4-(2-(4-aminopiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 19

[0235] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 19 (23 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2-fluoro-6-(trifluoromethyl)phenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.13 (t, J=7.3Hz, 1H), 7.95 (d, J=8.7Hz, 1H), 7.84-7.76 (m, 2H), 7.73-7.61 (m, 5H), 4.93 ( d, J=13.5Hz, 2H), 3.46-3.37 (m, 1H), 3.24 (t, J=12.7Hz, 2H), 2.11 (dd, J=13.0, 3.9Hz, 2H), 1.63 (d, J=12.5Hz, 2H).

[0236] Embodiment 20

[0237] 4-(2-(4-aminopiperidin-1-yl)-6-(2,6-dichlorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 20

[0238] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 20 (32 mg), by replacing the raw material (3-fluoro-4-methoxyphenyl)boronic acid in the third step with 2,6-dichlorophenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.15 (dd, J=8.0, 6.6Hz, 1H), 7.99 (d, J=8.7Hz, 1H), 7.86 (dd, J= 9.8, 1.5Hz, 1H), 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.73 (dd, J=8.0, 1.5Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.59 (d, J=8.0Hz, 2H), 7.44 (dd, J=8.7, 7.5Hz, 1H), 4.94 (d, J=13.4Hz, 2H), 3.4 3-3.34 (m, 1H), 3.25 (t, J=12.7Hz, 2H), 2.14-2.09 (m, 2H), 1.64 (qd, J=12.5, 4.1Hz, 2H).

[0239] Embodiment 21

[0240] 4-(2-(4-aminopiperidin-1-yl)-6-(2-chloro-6-methylphenyl)quinazolin-4-yl)-2-fluorobenzonitrile 21

[0241] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 21 (22 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2-chloro-6-methylphenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.13 (dd, J=8.0, 6.7Hz, 1H), 7.88 (dd, J=9.8, 1.5Hz, 1H), 7. 80 (d, J=8.7Hz, 1H), 7.72 (dd, J=8.0, 1.5Hz, 1H), 7.66 (dd, J=8.7, 1.9Hz, 1H), 7.50 (d , J=1.9Hz, 1H), 7.39 (dd, J=5.4, 3.9Hz, 1H), 7.35-7.27 (m, 2H), 4.90 (d, J=13.4Hz, 2 H), 3.44-3.32 (m, 1H), 3.16 (t, J=12.7Hz, 2H), 2.07-2.05 (s, 5H), 1.64-1.51 (m, 2H).

[0242] Embodiment 22

[0243] 4-(2-(4-aminopiperidin-1-yl)-6-(2-chloro-6-fluorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 22

[0244] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 22 (12 mg), by replacing the raw material in the third step (3-fluoro-4-methoxyphenyl)boronic acid with 2-chloro-6-fluorophenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.15 (t, J=7.3Hz, 1H), 7.97 (d, J=8.7Hz, 1H), 7.87 (dd, J=15.4, 9.3Hz, 2H), 7.78-7.71 (m, 2H), 7.47 (t, J=5.3Hz, 2H), 7. 39-7.30 (m, 1H), 4.94 (d, J=13.2Hz, 2H), 3.50-3.33 (m, 1H), 3.24 (t, J=12.6Hz, 2H), 2.11 (dd, J=13.0, 3.9Hz, 2H), 1.64 (qd, J=12.0, 4.0Hz, 2H).

[0245] Embodiment 23

[0246] 4-(2-(4-aminopiperidin-1-yl)-6-(3-fluoro-2-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 23

[0247] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 23 (32 mg), by replacing the raw material (3-fluoro-4-methoxyphenyl)boronic acid in the third step with 3-fluoro-2-(trifluoromethyl)phenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.18-8.10 (m, 1H), 7.96-7.88 (m, 2H), 7.78 (ddt, J=13.5, 10.3, 5.3Hz, 3H), 7.66 (d, J=1.9Hz, 1H), 7.54 (dd, J=11.6, 8.5Hz, 1H) , 7.31 (d, J = 7.7Hz, 1H), 4.93 (d, J = 13.5Hz, 2H), 3.40 (dt, J = 13.5, 4.9Hz, 1H ), 3.23 (t, J=12.7Hz, 2H), 2.14-2.08 (m, 2H), 1.64 (qd, J=12.2, 4.1Hz, 2H).

[0248] Embodiment 24

[0249] 5-(2-(4-aminopiperidin-1-yl)-6-(3-fluoro-4-methoxyphenyl)quinazolin-4-yl)pyridinecarbonitrile 24

[0250] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 24 (10 mg), by replacing the first step raw material (4-cyano-3-fluorophenyl)boric acid with (6-cyanopyridin-3-yl)boric acid.1 H NMR (400MHz, Methanol-d4) δ9.21 (d, J=2.1Hz, 1H), 8.55 (dd, J=8.0, 2.2Hz, 1H), 8.31 (dd , J=8.8, 2.0Hz, 1H), 8.17 (d, J=8.0Hz, 1H), 8.08 (dd, J=8.8, 2.2Hz, 1H), 8.04 (d, J=2.0Hz, 1H), 7.51-7.42 (m, 2H), 7.20 (t, J=8.9Hz, 1H), 5.03 (d, J=12.7Hz, 2H), 3.92 (s, 3H), 3.61 ( d, J=11.1Hz, 1H), 3.49 (t, J=13.0Hz, 2H), 2.29 (d, J=12.4Hz, 2H), 1.86 (q, J=12.1Hz, 2H).

[0251] Embodiment 25

[0252] 4-(2-(4-aminopiperidin-1-yl)-6-(3-fluoro-4-methoxyphenyl)quinazolin-4-yl)benzonitrile 25

[0253] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 25 (24 mg), by replacing the first step raw material (4-cyano-3-fluorophenyl)boric acid with (4-cyanophenyl)boric acid. 1 H NMR (400MHz, Methanol-d4) δ8.27 (dd, J=8.8, 2.0Hz, 1H), 8.11-8.00 (m, 6H), 7.48-7.38 (m, 2H), 7.20 (t, J=8.9Hz, 1H), 5.04 (d, J= 14.3Hz, 2H), 3.92 (s, 3H), 3.64-3.55 (m, 2H), 3.44 (t, J=13.2Hz, 2H), 2.27 (d, J=12.6Hz, 2H), 1.82 (qd, J=12.3, 10.4, 2.2Hz, 2H)...

[0254] Embodiment 26

[0255] 2-Fluoro-4-(6-(3-fluoro-4-methoxyphenyl)-2-(piperazin-1-yl)quinazolin-4-yl)benzonitrile 26

[0256] The hydrochloride salt of the title compound 24 (29 mg) was prepared by using the synthetic route of Example 1, replacing the second step raw material tert-butyl piperidin-4-ylcarbamate with tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, DMSO-d6) δ8.21-8.12 (m, 2H), 8.01 (dd, J=9.9, 1.4Hz, 1H), 7.89 (d, J=2.0Hz, 1H), 7.85 (dd, J=7.9, 1.4Hz, 1H), 7.80 (d, J= 8.8Hz, 1H), 7.60 (dd, J=12.9, 2.2Hz, 1H), 7.47 (dd, J=8.4, 2.2Hz, 1H), 7.23 (t, J=8.8Hz, 1H), 4.18 (t, J=5.1Hz, 4H), 3.26-3.19 (m, 4H).

[0257] Embodiment 27

[0258] (S)-4-(2-(3-aminopyrrolidin-1-yl)-6-(3-fluoro-4-methoxyphenyl)quinazolin-4-yl)-2-fluorobenzonitrile 27

[0259] The hydrochloride salt of the title compound 27 (32 mg) was prepared by adopting the synthetic route of Example 1, except that the raw material in the second step, tert-butyl piperidin-4-ylcarbamate, was replaced by (S)-3-tert-butyloxycarbonylaminopyrrolidine. 1 H NMR (400MHz, DMSO-d6) δ8.24-8.15 (m, 2H), 8.01 (d, J=9.7Hz, 2H), 7.90 (s, 1H), 7.85 (d, J=7.7Hz, 1H), 7.61 (d, J=1 2.6Hz, 1H), 7.48 (d, J=8.2Hz, 1H), 7.24 (t, J=8.7Hz, 1H), 4.03-3.85 (m, 5H), 2.43-2.35 (m, 1H), 2.28-2.17 (m, 1H).

[0260] Embodiment 28

[0261] (R)-4-(2-(3-aminopyrrolidin-1-yl)-6-(3-fluoro-4-methoxyphenyl)quinazolin-4-yl)-2-fluorobenzonitrile 28

[0262] The hydrochloride salt of the title compound 28 (20 mg) was prepared by adopting the synthetic route of Example 1, except that the raw material in the second step, tert-butyl piperidin-4-ylcarbamate, was replaced by (R)-3-tert-butyloxycarbonylaminopyrrolidine. 1H NMR (4000Hz, DMSO-d6) δ8.20 (q, J=7.5, 6.8Hz, 2H), 8.01 (d, J=9.7Hz, 2H), 7.94-7.89 (m, 1H), 7.85 (d, J=7.8Hz, 1H), 7.62 (d, J=12.7Hz, 1H), 7.49 (d, J=8.4Hz, 1H), 7.24 (t, J=8.7Hz, 1H), 3.94-3.79 (m, 5H), 2.42-2.36 (m, 1H), 2.27-2.18 (m, 1H).

[0263] Embodiment 29

[0264] 2-Fluoro-4-(6-(3-fluoro-4-methoxyphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)benzonitrile 29

[0265] The hydrochloride salt of the title compound 29 (35 mg) was prepared by using the synthetic route of Example 1, replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine. 1 H NMR (400MHz, Methanol-d4) δ8.21 (s, 1H), 8.05 (t, J=7.2Hz, 1H), 7.97-7.83 (m, 3H), 7.46-7.37 (m, 2H), 7.18 (t, J=8.9Hz, 1H), 3.91 (s, 3H ), 3.80-3.76(m, 2H), 3.59-3.41(m, 2H), 3.36-3.32(m, 1H), 3.20-3.12(m, 1H), 2.92-2.84(m, 1H), 2.32-2.28(m, 1H), 1.96-1.87(m, 1H).

[0266] Embodiment 30

[0267] 2-Fluoro-4-(6-(3-fluoro-4-methoxyphenyl)-2-((piperidin-4-ylmethyl)amino)quinazolin-4-yl)benzonitrile 30

[0268] The hydrochloride salt of the title compound 30 (29 mg) was prepared by adopting the synthetic route of Example 1, replacing the second step raw material tert-butyl piperidin-4-ylcarbamate with 1-tert-butyloxycarbonyl-4-aminomethylpiperidine. 1H NMR (400MHz, DMSO-d6) δ8.40-8.22 (m, 2H), 8.21 (t, J=7.2Hz, 1H), 7.97 (d, J=9 .7Hz, 1H), 7.92-7.79 (m, 2H), 7.63 (d, J=12.7Hz, 1H), 7.49 (d, J=8.3Hz, 1H), 7. 25(t, J=8.8Hz, 1H), 3.87(s, 3H), 3.63-3.58(m, 2H), 3.54-3.50(m, 1H), 3.28(d , J=12.2Hz, 2H), 2.83 (q, J=11.7Hz, 2H), 2.05-1.99 (m, 2H), 1.57-1.41 (m, 2H).

[0269] Embodiment 31

[0270] (S)-4-(6-(3-fluoro-4-methoxyphenyl)-2-(pyrrolidin-3-ylmethoxy)quinazolin-4-yl)benzonitrile 31

[0271] The synthetic route of Example 1 was used to replace the first step raw material (4-cyano-3-fluorophenyl)boric acid with (4-cyanophenyl)boric acid. The second step raw material piperidin-4-ylcarbamic acid tert-butyl ester was replaced with (S)-1-tert-butyloxycarbonyl-3-hydroxymethylpyrrolidine to prepare the hydrochloride salt of the title compound 31 (20 mg). 1 H NMR (400MHz, Methanol-d4) δ8.22 (dd, J=8.8, 2.0Hz, 1H), 8.01 (s, 5H), 7.96 (d, J= 8.8Hz, 1H), 7.44-7.40 (m, 1H), 7.39 (d, J=1.7Hz, 1H), 7.17 (t, J=8.6Hz, 1H), 4.69 (dd, J=10.9, 5.1Hz, 1H), 4.62 (dd, J=10.9, 6.0Hz, 1H), 3.91 (s, 3H), 3.68-3.44 (m , 2H), 3.42-3.32 (m, 2H), 2.35 (ddt, J=21.6, 14.7, 7.6Hz, 1H), 2.18-1.99 (m, 2H).

[0272] Embodiment 32

[0273] 4-(6-(3-fluoro-4-methoxyphenyl)-2-(piperidin-4-ylmethoxy)quinazolin-4-yl)benzonitrile 32

[0274] The synthetic route of Example 1 was used to replace the first step raw material (4-cyano-3-fluorophenyl)boric acid with (4-cyanophenyl)boric acid. The second step raw material piperidin-4-ylcarbamic acid tert-butyl ester was replaced with 1-tert-butyloxycarbonyl-4-piperidinol to prepare the hydrochloride salt of the title compound 32 (13 mg). 1 H NMR (400MHz, Methanol-d4) δ8.21 (dd, J=8.8, 2.0Hz, 1H), 8.05-7.96 (m, 5H), 7.96 (d, J=8.9Hz, 1H), 7.44-7.37 (m, 2H), 7.18 (t, J=8.8Hz, 1H), 5 .34 (t, J=4.8Hz, 2H), 4.51 (d, J=5.9Hz, 2H), 3.91 (s, 3H), 3.48 (d, J=12.3Hz, 2H), 3.13-3.03 (m, 2H), 2.30 (q, J=7.2Hz, 1H), 1.80-1.65 (m, 2H).

[0275] Embodiment 33

[0276] 4-(6-(3,5-dimethylisoxazol-4-yl)-2-(pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 33

[0277] The synthetic route of Example 1 was adopted, and the raw material of the second step, piperidin-4-ylcarbamic acid tert-butyl ester, was replaced by 1-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine. The raw material of the third step, (3-fluoro-4-methoxyphenyl)boric acid, was replaced by 3,5-dimethylisoxazole-4-boric acid to prepare the hydrochloride salt of the title compound 33 (20 mg). MS m / z (ESI): 443.31 [M+1] + .

[0278] Embodiment 34

[0279] 2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(o-tolyl)quinazolin-4-yl)benzonitrile 34

[0280] The synthetic route of Example 1 was used, and the raw material in the second step, tert-butyl piperidin-4-ylcarbamate, was replaced by 1-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine. The raw material in the third step, (3-fluoro-4-methoxyphenyl)boronic acid, was replaced by o-methylphenylboronic acid to prepare the hydrochloride salt of the title compound 34 (18 mg). 1H NMR (400MHz, Methanol-d4) δ8.26-7.70(m, 6H), 7.38-7.14(m, 4H), 3.94-3.82(m, 2H), 3.66-3.43(m, 2H), 3 .37-3.32(m, 1H), 3.22-3.15(m, 1H), 3.01-2.86(m, 1H), 2.41-2.25(m, 1H), 2.26(s, 3H), 1.97-1.87(m, 1H).

[0281] Embodiment 35

[0282] (S)-2-Fluoro-4-(6-(3-fluoro-4-methoxyphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)benzonitrile 35

[0283] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 35 (15 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine. 1 H NMR (400MHz, Methanol-d4) δ8.21 (s, 1H), 8.05 (t, J=7.2Hz, 1H), 7.97-7.83 (m, 3H), 7.46-7.37 (m, 2H), 7.18 (t, J=8.9Hz, 1H), 3.91 (s, 3H ), 3.81-3.77(m, 2H), 3.59-3.41(m, 2H), 3.36-3.32(m, 1H), 3.20-3.12(m, 1H), 2.92-2.84(m, 1H), 2.32-2.27(m, 1H), 1.96-1.87(m, 1H).

[0284] Embodiment 36

[0285] (R)-2-Fluoro-4-(6-(3-fluoro-4-methoxyphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)benzonitrile 36

[0286] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 36 (30 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (S)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine. 1H NMR (400MHz, Methanol-d4) δ8.29 (s, 1H), 8.18-7.83 (m, 5H), 7.43 (t, J=9.2Hz, 2H), 7.19 (t, J=8.6Hz, 1H), 3.91 (s, 3H), 3.85-3 .79(m, 2H), 3.65-3.41(m, 2H), 3.38-3.33(m, 1H), 3.20-3.13(m, 1H), 2.92-2.84(m, 1H), 2.35-2.29(m, 1H), 1.96-1.88(m, 1H).

[0287] Embodiment 37

[0288] (S)-2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(o-tolyl)quinazolin-4-yl)benzonitrile 37

[0289] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 37 (25 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with o-methylphenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.28-7.63 (m, 6H), 7.39-7.17 (m, 4H), 3.87 (t, J=7.7Hz, 2H), 3.71-3.3 2(m, 3H), 3.26-3.10(m, IH), 3.02-2.82(m, 1H), 2.46-2.30(m, 1H), 2.27(s, 3H), 2.01-1.86(m, 1H).

[0290] Embodiment 38

[0291] (R)-2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(o-tolyl)quinazolin-4-yl)benzonitrile 38

[0292] The synthetic route of Example 1 was used to replace the raw material of the second step, tert-butyl piperidin-4-ylcarbamate, with (S)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and the raw material of the third step, (3-fluoro-4-methoxyphenyl)boronic acid, with o-methylphenylboronic acid to prepare the hydrochloride salt of the title compound 38 (16 mg). MS m / z (ESI): 438.45 [M+1] + .

[0293] Embodiment 39

[0294] (S)-2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(2-(trifluoromethoxy)phenyl)quinazolin-4-yl)benzonitrile 39

[0295] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 39 (36 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-(trifluoromethoxy)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.31-7.78 (m, 6H), 7.67-7.40 (m, 4H), 3.97-3.79 (m, 2H), 3.67 -3.40(m, 3H), 3.25-3.08(m, 1H), 3.01-2.81(m, 1H), 2.45-2.24(m, 1H), 2.00-1.83(m, 1H).

[0296] Embodiment 40

[0297] (S)-2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(2-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 40

[0298] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 40 (16 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ 8.20-8.17 (m, 1H), 8.05-8.01 (m, 2H), 7.95-7.77 (m, 4H), 7.71 (t, J=7.3Hz, 1H), 7.63 (t, J=7.7Hz, 1H), 7. 46(d, J=7.6Hz, 1H), 3.98-3.78(m, 2H), 3.70-3.32(m, 3H), 3.26-3.08(m, 1H), 3.02-2.83(m, 1H), 2.48-2.23(m, 1H), 2.00-1.84(m, 1H).

[0299] Embodiment 41

[0300] (S)-2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(2-fluorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 41

[0301] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 41 (30 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluorophenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.32-7.84 (m, 6H), 7.57 (t, J=7.7Hz, 1H), 7.45 (q, J=7.5Hz, 1H), 7.31 (t, J=7.5Hz, 1H), 7.24 (dd, J=11.1, 8.2Hz , 1H), 3.94-3.87(m, 2H), 3.68-3.43(m, 2H), 3.41-3.33(m, 1H), 3.27- 3.12(m, 1H), 2.99-2.87(m, 1H), 2.45-2.25(m, 1H), 2.06-1.87(m, 1H).

[0302] Embodiment 42

[0303] (S)-2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(2-chlorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 42

[0304] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 42 (18 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-chlorobenzeneboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.29-7.82 (m, 6H), 7.54 (dq, J=6.6, 3.9, 3.2Hz, 1H), 7.50-7.40 (m, 3H), 3.93-3.87 (m, 2H ), 3.68-3.43(m, 2H), 3.40-3.32(m, 1H), 3.26-3.11(m, 1H), 2.98-2.87(m, 1H), 2.44-2.24(m, 1H), 2.05-1.86(m, 1H).

[0305] Embodiment 43

[0306] (S)-2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(2,3-difluorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 43

[0307] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 43 (20 mg), by replacing the second step raw material piperidin-4-ylcarbamic acid tert-butyl ester with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material (3-fluoro-4-methoxyphenyl)boric acid with 2,3-difluorophenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.33-7.86(m, 6H), 7.41-7.23(m, 3H), 3.94-3.88(m, 2H), 3.68-3.43(m, 2H), 3.40-3.33(m, 1H), 3.25-3.13(m, 1H), 2.98-2.88(m, 1H), 2.43-2.25(m, 1H), 2.05-1.86(m, 1H).

[0308] Embodiment 44

[0309] (S)-2-Fluoro-4-(6-(4-methylthiophen-3-yl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)benzonitrile 44

[0310] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 44 (24 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 4-methyl-3-thiopheneboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.29-7.79(m, 6H), 7.48(s, 1H), 7.18(s, 1H), 3.90-3.84(m, 2H), 3.70-3.41(m, 2H ), 3.36-3.30(m, 1H), 3.22-3.16(m, 1H), 2.98-2.89(m, 1H), 2.48-2.28(m, 1H), 2.27(s, 3H), 2.07-1.87(m, 1H).

[0311] Embodiment 45

[0312] (S)-4-(6-(2,6-dimethylphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 45

[0313] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 45 (25 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2,6-dimethylphenylboric acid.1 H NMR (400MHz, Methanol-d4) δ8.36-7.57(m, 6H), 7.20-7.07(m, 3H), 3.94-3.88(m, 2H), 3.70-3.44(m, 2H), 3 .39-3.33(m, 1H), 3.24-3.18(m, 1H), 3.01-2.90(m, 1H), 2.48-2.27(m, 1H), 2.01(s, 6H), 2.08-1.87(m, 1H).

[0314] Embodiment 46

[0315] (S)-4-(6-(2,4,6-trimethylphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 46

[0316] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 46 (20 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2,4,6-trimethylphenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.29-7.56(m, 6H), 6.96-6.92(m, 2H), 3.92-3.86(m, 2H), 3.59-3.42(m, 2H), 3.39-3. 32(m, 1H), 3.23-3.16(m, 1H), 3.02-2.90(m, 1H), 2.48-2.23(m, 1H), 2.28(s, 3H), 1.98(s, 6H), 2.08-1.88(m, 1H).

[0317] Embodiment 47

[0318] (S)-2-Fluoro-4-(6-(3-fluoro-2-methylphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)benzonitrile 47

[0319] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 47 (22 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 3-fluoro-2-methylphenylboric acid. 1H NMR (400MHz, Methanol-d4) δ8.37-7.74 (m, 6H), 7.29 (q, J=7.1Hz, 1H), 7.12 (dt, J=8.8, 5.2Hz, 2H), 3.94-3.88 (m, 2H), 3.72-3.4 5 (m, 2H), 3.38-3.33 (m, 1H), 3.25-3.17 (m, 1H), 3.03-2.90 (m, 1H), 2.49-2.24 (m, 1H), 2.19 (d, J=2.4Hz, 3H), 2.08-1.87 (m, 1H).

[0320] Embodiment 48

[0321] (S)-2-Fluoro-4-(6-(2-fluoro-6-methylphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)benzonitrile 48

[0322] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 48 (12 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluoro-6-methylphenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.38-7.68 (m, 6H), 7.37-7.29 (m, 1H), 7.17 (d, J=7.6Hz, 1H), 7.04 (t, J=9.0Hz, 1H), 3.95-3.89 (m, 2H ), 3.71-3.44(m, 2H), 3.39-3.34(m, 1H), 3.24-3.17(m, 1H), 3.04-2.91(m, 1H), 2.44-2.28(m, 1H), 2.21(s, 3H), 2.08-1.86(m, 1H).

[0323] Embodiment 49

[0324] (S)-2-Fluoro-4-(2-((pyrrolidin-3-ylmethyl)amino)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-4-yl)benzonitrile 49

[0325] The synthetic route of Example 1 was used, and the second step raw material, piperidin-4-ylcarbamic acid tert-butyl ester was replaced by (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid was replaced by (1,3,5-trimethyl-1H-pyrazol-4-yl)boric acid to prepare the hydrochloride salt (15 mg) of the title compound 49. 1H NMR (400MHz, Methanol-d4) δ8.43-7.72(m, 6H), 4.00(s, 3H), 3.96-3.87(m, 2H), 3.72-3.41(m, 2H ), 3.41-3.35(m, 1H), 3.25-3.17(m, 1H), 3.05-2.91(m, 1H), 2.50-2.26(m, 7H), 2.06-1.86(m, 1H).

[0326] Embodiment 50

[0327] (S)-4-(6-(2,6-difluorophenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 50

[0328] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 50 (29 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2,6-difluorophenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.33-7.78 (m, 6H), 7.47 (t, J=7.1Hz, 1H), 7.13 (t, J=7.9Hz, 2H), 3.96-3.88 (m, 2H), 3 .69-3.44(m, 2H), 3.38-3.32(m, 1H), 3.25-3.14(m, 1H), 3.02-2.88(m, 1H), 2.45-2.25(m, 1H), 2.04-1.89(m, 1H).

[0329] Embodiment 51

[0330] (S)-4-(6-(2,6-dichlorophenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 51

[0331] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 51 (35 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2,6-dichlorobenzeneboric acid. 1H NMR (400MHz, Methanol-d4) δ8.10-7.78 (m, 6H), 7.53 (d, J=8.0Hz, 2H), 7.41 (t, J=8.0Hz, 1H), 3.97-3.88 (m, 2H), 3 .68-3.42(m, 2H), 3.38-3.32(m, 1H), 3.26-3.14(m, 1H), 3.02-2.89(m, 1H), 2.45-2.25(m, 1H), 2.03-1.87(m, 1H).

[0332] Embodiment 52

[0333] (S)-4-(6-(2-chloro-6-(trifluoromethyl)phenyl)-2-(pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 52

[0334] The synthetic route of Example 40 was used to prepare the hydrochloride salt of the title compound 52 (35 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-chloro-6-trifluoromethylphenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.36-7.85(m, 6H), 7.74(q, J=8.2Hz, 2H), 3.97-3.88(m, 2H), 3.71-3.44( m, 2H), 3.39-3.33 (m, 1H), 3.28-3.16 (m, 1H), 3.02-2.89 (m, 1H), 2.47-2.27 (m, 1H), 2.03-1.93 (m, 1H).

[0335] Embodiment 53

[0336] (S)-4-(6-(2-chloro-6-methylphenyl)-2-(pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 53

[0337] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 53 (35 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-chloro-6-methylphenylboric acid. 1H NMR (400MHz, Methanol-d4) δ8.34-7.69 (m, 6H), 7.38-7.32 (m, 1H), 7.28 (d, J=4.8Hz, 2H), 3.95-3.86 (m, 2H), 3.70-3.4 4(m, 2H), 3.38-3.32(m, 1H), 3.27-3.13(m, 1H), 3.01-2.87(m, 1H), 2.45-2.25(m, 1H), 2.11(s, 3H), 2.03-1.87(m, 1H).

[0338] Embodiment 54

[0339] (S)-4-(6-(2-fluoro-6-(trifluoromethylphenyl)-2-(pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 54

[0340] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 54 (36 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluoro-6-trifluoromethylphenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.32-7.74 (m, 6H), 7.69 (d, J=3.5Hz, 2H), 7.58-7.49 (m, 1H), 3.95-3.86 (m, 2H), 3.70 -3.43 (m, 2H), 3.35 (d, J=8.8Hz, 1H), 3.25-3.14 (m, 1H), 3.00-2.87 (m, 1H), 2.40-2.28 (m, 1H), 2.05-1.88 (m, 1H).

[0341] Embodiment 55

[0342] (S)-4-(6-(2-chloro-6-fluorophenyl)-2-(pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 55

[0343] The synthetic route of Example 1 was used to replace the raw material of the second step, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and the raw material of the third step, (3-fluoro-4-methoxyphenyl)boric acid, with 2-chloro-6-fluorophenylboric acid to prepare the hydrochloride salt of the title compound 55 (40 mg). MS m / z (ESI): 476.48 [M+1] + .

[0344] Embodiment 56

[0345] (S)-4-(6-(5-fluoro-2-(trifluoromethyl)-2-(pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 56

[0346] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 56 (36 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 5-fluoro-2-trifluoromethylphenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.30-7.78 (m, 7H), 7.38 (td, J=8.4, 2.4Hz, 1H), 7.29 (dd, J=9.0, 2.6Hz, 1H), 3.95-3.86 (m, 2 H), 3.69-3.42(m, 2H), 3.37(d, J=8.6Hz, 1H), 3.25-3.14(m, 1H), 2.98-2.85(m, 1H), 2.40-2.28(m, 1H), 2.02-1.88(m, 1H).

[0347] Embodiment 57

[0348] (S)-4-(6-(3-fluoro-2-(trifluoromethylphenyl)-2-(pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 57

[0349] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 57 (26 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 3-fluoro-2-trifluoromethylphenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.29-7.77 (m, 6H), 7.72 (d, J=6.4Hz, 1H), 7.41 (dd, J=11.3, 8.1Hz, 1H), 7.27 (d, J=7.3Hz, 1H), 3.96-3 .87 (m, 2H), 3.70-3.43 (m, 2H), 3.35 (d, J=7.9Hz, 1H), 3.25-3.15 (m, 1H), 3.01-2.89 (m, 1H), 2.42-2.30 (m, 1H), 2.04-1.88 (m, 1H).

[0350] Embodiment 58

[0351] (S)-4-(6-(2,5-bis(trifluoromethyl)phenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 58

[0352] The synthetic route of Example 1 was used to prepare the hydrochloride salt (18 mg) of the title compound 58 by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2,5-bis(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.33-7.72(m, 9H), 3.97-3.88(m, 2H), 3.68-3.44(m, 2H), 3.37 -3.31(m, 1H), 3.24-3.14(m, 1H), 3.00-2.87(m, 1H), 2.41-2.30(m, 1H), 1.98-1.87(m, 1H).

[0353] Embodiment 59

[0354] (S)-2-Fluoro-4-(6-(3-methyl-2-(trifluoromethyl)phenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)benzonitrile 59

[0355] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 59 (17 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 3-methyl-2-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ7.91 (d, J=81.3Hz, 6H), 7.52 (t, J=6.5Hz, 1H), 7.45 (d, J=7.2Hz, 1H), 7.21 (s, 1H), 3.96-3.87 (m, 2H) , 3.68-3.41(m, 2H), 3.38-3.32(m, 1H), 3.25-3.15(m, 1H), 3.01-2.88(m, 1H), 2.56(s, 3H), 2.41-2.30(m, 1H), 1.99-1.89(m, 1H).

[0356] Embodiment 60

[0357] ((S)-4-(6-(2,6-difluoro-3-hydroxyphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)-2-fluorobenzonitrile 60

[0358] The synthetic route of Example 1 was used, and the second step raw material, piperidin-4-ylcarbamic acid tert-butyl ester was replaced by (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid was replaced by 6-(2,6-difluoro-3-hydroxyphenylboric acid) to prepare the hydrochloride salt of the title compound 60 (30 mg). 1 H NMR (400MHz, Methanol-d4) δ8.23-7.80 (m, 6H), 7.05-6.88 (m, 2H), 3.88 (q, J=6.5, 6.1Hz, 2H), 3.65-3.4 2(m, 2H), 3.36-3.31(m, 1H), 3.26-3.16(m, 1H), 3.02-2.89(m, 1H), 2.43-2,29(m, 1H), 2.00-1.89(m, 1H).

[0359] Embodiment 61

[0360] (S)-2-Fluoro-4-(6-(2-fluoro-3-hydroxyphenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-4-yl)benzonitrile 61

[0361] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 61 (13 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 6-(2-fluoro-3-hydroxy)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.34-7.75 (m, 6H), 7.08 (t, J=7.7Hz, 1H), 7.02-6.93 (m, 2H), 3.95-3.86 (m, 2H), 3. 69-3.43(m, 2H), 3.39-3.33(m, 1H), 3.24-3.14(m, 1H), 3.02-2.89(m, 1H), 2.41-2.29(m, 1H), 2.01-1.91(m, 1H).

[0362] Embodiment 62

[0363] (S)-3-(4-(4-cyano-3-fluorophenyl)-2-((pyrrolidin-3-ylmethyl)amino)quinazolin-6-yl)benzamide 62

[0364] The synthetic route of Example 1 was used to replace the raw material of the second step, tert-butyl piperidin-4-ylcarbamate, with (R)-N-tert-butyloxycarbonyl-3-(aminomethyl)pyrrolidine, and the raw material of the third step, (3-fluoro-4-methoxyphenyl)boronic acid, with 3-carbamoylphenylboronic acid to obtain the hydrochloride salt of the title compound 62 (13 mg). MS m / z (ESI): 467.46 [M+1] + .

[0365] Embodiment 63

[0366] 4-(2-(4-amino-4-methylpiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 63

[0367] The synthetic route of Example 1 was used to prepare the hydrochloride salt (20 mg) of the title compound 63 by replacing the second step raw material (tert-butyl piperidin-4-ylcarbamate) with (4-methylpiperidin-4-yl)carbamate, and replacing the third step raw material (3-fluoro-4-methoxyphenyl)boric acid with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, DMSO-d6) δ8.13 (t, J=7.3Hz, 1H), 7.89 (d, J=8.7Hz, 1H), 7.84-7.74 (m, 2H), 7.68 (dt, J =11.3, 3.0Hz, 5H), 4.43 (dt, J = 14.6, 5.1Hz, 2H), 3.81-3.76 (m, 2H), 1.91-1.81 (m, 4H), 1.42 (s, 3H).

[0368] Embodiment 64

[0369] 4-(2-(4-amino-3,3-difluoropiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 64

[0370] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 64 (26 mg), by replacing the second step raw material (3-fluoro-4-methoxyphenyl)boronic acid with tert-butyl (3,3-difluoropiperidin-4-yl)boronic acid, and replacing the third step raw material (3-fluoro-4-methoxyphenyl)boronic acid with 2-fluoro-6-(trifluoromethyl)phenylboronic acid. 1H NMR (400MHz, DMSO-d6) δ8.15 (dd, J=8.0, 6.7Hz, 1H), 7.84 (dd, J=9.8, 1.5Hz, 1H), 7.78 (s, 2H), 7.74-7.62 (m, 5H), 5.32-5.21 (m, 1H), 4 .93 (d, J=13.6Hz, 1H), 4.13-4.00 (m, 1H), 3.71 (dd, J=31.2, 14.1Hz, 1H), 3.38-3.29 (m, 1H), 2.30 (d, J=12.9Hz, 1H), 1.88-1.71 (m, 1H).

[0371] Embodiment 65

[0372] 4-(2-(6-amino-3-azabicyclo[3.1.0]hexane-3-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 65

[0373] The synthetic route of Example 1 was used, and the second step raw material, piperidin-4-ylcarbamic acid tert-butyl ester was replaced by (3-azabicyclo[3.1.0]-6-hexyl)-carbamic acid tert-butyl ester, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid was replaced by 2-fluoro-6-(trifluoromethyl)phenylboric acid to prepare the hydrochloride salt of the title compound 65 (13 mg). 1 H NMR (400MHz, DMSO-d6) δ8.17-8.12 (m, 1H), 8.06 (d, J=8.7Hz, 1H), 7.84 (dd, J=8.8, 1.8Hz, 1H), 7.79 (d, J=9.8Hz, 1 H), 7.74-7.62 (m, 5H), 4.13 (d, J=11.9Hz, 2H), 3.80 (dd, J=11.9, 4.0Hz, 2H), 2.51-2.44 (m, 1H), 2.33-2.19 (m, 2H).

[0374] Embodiment 66

[0375] 2-Fluoro-4-(6-(2-fluoro-6-(trifluoromethyl)phenyl)-2-(4-(methylamino)piperidin-1-yl)quinazolin-4-yl)benzonitrile 66

[0376] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 66 (16 mg), by replacing the second step raw material (tert-butyl piperidin-4-ylcarbamate) with 4-N-tert-butyloxycarbonyl-4-N-methylaminopiperidine, and replacing the third step raw material (3-fluoro-4-methoxyphenyl)boric acid with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1H NMR (400MHz, DMSO-d6) δ8.14 (dd, J=8.0, 6.7Hz, 1H), 7.85-7.80 (m, 2H), 7.76 (dd, J=8.8, 1.8Hz, 1H), 7.74-7.64 (m, 5H), 4.97 ( d, J=13.4Hz, 2H), 3.38-3.27 (m, 1H), 3.13 (t, J=12.2Hz, 2H), 2.56 (t, J=5.3Hz, 3H), 2.18 (d, J=12.2Hz, 2H), 1.69-1.55 (m, 2H).

[0377] Embodiment 67

[0378] 4-(2-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 67

[0379] The synthetic route of Example 1 was adopted, and the second step raw material, tert-butyl piperidin-4-ylcarbamate, was replaced by tert-butyl N-[(3R,4S)-3-fluoropiperidin-4-yl]carbamate, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, was replaced by 2-fluoro-6-(trifluoromethyl)phenylboric acid to prepare the hydrochloride salt (20 mg) of the title compound 67. 1 H NMR (400MHz, Methanol-d4) δ8.18 (d, J=8.6Hz, 1H), 8.05-7.97 (m, 2H), 7.91 (d, J=1.8Hz, 1H), 7.80 (dd, J=15.6, 8.6Hz, 2H), 7.68 (dd, J=6.8, 3.8H z, 2H), 7.58-7.49 (m, 1H), 5.51-5.49 (m, 1H), 5.27 (d, J=48.6Hz, 1H), 5.1 7-5.14(m, 1H), 4.00-3.68(m, 2H), 3.65-3.52(m, 1H), 2.30-2.12(m, 2H).

[0380] Embodiment 68

[0381] 4-(2-((3R,4R)-4-amino-3-methylpiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 68

[0382]

[0383] The synthetic route of Example 1 was used, the raw material of the second step, tert-butyl piperidin-4-ylcarbamate was replaced by tert-butyl N-[(3R, 4R)-3-methylpiperidin-4-yl]carbamate, and the raw material of the third step, (3-fluoro-4-methoxyphenyl)boronic acid, was replaced by 2-fluoro-6-(trifluoromethyl)phenylboronic acid to prepare the hydrochloride salt of the title compound 68 (16 mg). MS m / z (ESI): 524.28 [M+1] + .

[0384] Embodiment 69

[0385] 4-(2-(3-amino-8-azabicyclo[3.2.1]octan-8-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 69

[0386] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 69 (36 mg), by replacing the second step raw material (3-fluoro-4-methoxyphenyl)boronic acid with 2-fluoro-6-(trifluoromethyl)phenylboronic acid, tert-butyl piperidin-4-ylcarbamate with 3-tert-butoxyaminodemethyltropane. 1 H NMR (400MHz, DMSO-d6) δ8.21-8.13 (m, 1H), 8.05 (d, J=8.7Hz, 2H), 7.85 (dd, J=8.8, 1.8Hz, 1H), 7.81 (d, J=9.7Hz , 1H), 7.76-7.63(m, 4H), 5.17-5.07(m, 1H), 5.06-4.90(m, 1H), 3.69(dq, J=12.0, 6.7Hz, 1H), 2.22-1.75(m, 8H).

[0387] Embodiment 70

[0388] 4-(2-(3-aminopiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 70

[0389] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 70 (16 mg), by replacing the second step raw material tert-butyl piperidin-4-ylcarbamate with 3-tert-butyloxycarbonylaminopiperidine, and replacing the third step raw material (3-fluoro-4-methoxyphenyl)boric acid with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1H NMR (400MHz, DMSO-d6) δ8.18-8.10 (m, 1H), 7.86 (t, J=9.9Hz, 2H), 7.78 (dd, J=8.8, 1.8Hz, 1H), 7.69 (tdd, J=11.0, 7.2, 2.3Hz, 5H), 4.76-4. 60 (m, 1H), 4.40 (d, J=10.8Hz, 1H), 3.75-3.4l (m, 3H), 3.29 (dd, J=9.4, 4.9Hz, 1H), 2.11-2.07 (m, 1H), 1.93-1.70 (m, 2H), 1.64-1.54 (m, 1H).

[0390] Embodiment 71

[0391] 4-(2-(4-amino-3,3-dimethylpiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 71

[0392] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 71 (18 mg), by replacing the second step raw material (3-fluoro-4-methoxyphenyl)boronic acid with 2-fluoro-6-(trifluoromethyl)phenylboronic acid, tert-butyl piperidin-4-ylcarbamate. 1 H NMR (400MHz, DMSO-d6) δ8.13 (t, J=7.3Hz, 1H), 7.91 (d, J=8.7Hz, 1H), 7.77 (t, J=8.4Hz, 2H), 7.73-7.62 (m, 5H), 4.87 (d, J=13.3Hz, 1H), 4.64-4.61 (m, 1H), 3.27 (t, J=13.0Hz, 1H), 3.20 (p, J=5.2Hz, 1H), 3.11 (d, J=13.5Hz, 1H), 2.03-1.97 (m, 1H), 1.80 (tt, J=12.1, 6.3Hz, 1H), 1.13 (s, 3H), 0.93 (s, 3H).

[0393] Embodiment 72

[0394] 4-(2-(4-aminoazepan-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 72

[0395] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 72 (18 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with 4-tert-butyloxycarbonyl-1H-azepine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.23 (d, J=9.5Hz, 1H), 8.02 (t, J=7.2Hz, 2H), 7.91 (s, 1H), 7.83 (dd, J=17.1, 8.5Hz, 2H), 7.73-7.63 (m, 2H) , 7.54 (td, J=8.8, 3.3Hz, 1H), 4.60 (d, J=14.5Hz, 1H), 4.39-4.22 (m, 1H), 4.15-3.90 (m, 2H), 3.50 (d, J=12.0Hz, 1H), 2.58-1.77 (m, 6H).

[0396] Embodiment 73

[0397] 4-(2-(4-(dimethylamino)piperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 73

[0398] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 73 (16 mg), by replacing the second step raw material tert-butyl piperidin-4-ylcarbamate with 4-dimethylaminopiperidine, and replacing the third step raw material (3-fluoro-4-methoxyphenyl)boric acid with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, DMSO-d6) δ8.14 (dd, J=8.0, 6.7Hz, 1H), 7.89-7.74 (m, 3H), 7.73-7.63 (m, 5H), 5.06 (d, J=13.3Hz , 2H), 3.58-3.48 (m, 1H), 3.12-3.03 (m, 2H), 2.70 (d, J=4.9Hz, 6H), 2.18 (d, J=11.8Hz, 2H), 1.75-1.61 (m, 2H).

[0399] Embodiment 74

[0400] (R)-4-(2-(3-aminopiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 74

[0401] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 74 (26 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-3-tert-butyloxycarbonylaminopiperidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.14 (t, J=8.2Hz, 1H), 8.00 (q, J=8.9, 8.0Hz, 2H), 7 .92-7.84(m, 2H), 7.81(d, J=7.6Hz, 1H), 7.68(dd, J=7.3, 3.8Hz, 2H), 7.61-7.46 (m, 1H), 4.87-4.76 (m, 1H), 4.45-4.27 (m, 1H), 4.10-3.98 (m, 1H), 3.94-3.84 (m, 1H), 3.67-3.58(m, 1H), 2.31-2.25(m, 1H), 2.17-2.06(m, 1H), 1.97-1.88(m, 2H).

[0402] Embodiment 75

[0403] (S)-4-(2-(3-aminopiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 75

[0404] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 74 (15 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (S)-3-tert-butyloxycarbonylaminopiperidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.14 (d, J=8.2Hz, 1H), 7.99 (t, J=8.0Hz, 2H), 7.9 3-7.85 (m, 2H), 7.81 (d, J = 6.7Hz, 1H), 7.72-7.63 (m, 2H), 7.54 (d, J = 8.0Hz, 1H ), 5.08-5.02(m, 1H), 4.43-4.35(m, 1H), 4.07-3.98(m, 1H), 3.93-3.84(m, 1H) , 3.69-3.55(m, 1H), 2.37-2.19(m, 1H), 2.14-2.06(m, 1H), 2.00-1.85(m, 2H).

[0405] Embodiment 76

[0406] 2-Fluoro-4-(6-(2-fluoro-6-(trifluoromethyl)phenyl)-2-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)quinazolin-4-yl)benzonitrile 76

[0407] The synthetic route of Example 1 was adopted, and the second step raw material, piperidin-4-ylcarbamic acid tert-butyl ester was replaced by octahydro-1H-pyrrolo[3,2-C]pyridine-1-carboxylic acid tert-butyl ester, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid was replaced by 2-fluoro-6-(trifluoromethyl)phenylboric acid to prepare the hydrochloride salt of the title compound 76 (28 mg). 1 H NMR (400MHz, Methanol-d4) δ8.15 (t, J=7.9Hz, 1H), 8.04-7.94 (m, 2H), 7.89 (d, J=5.3 Hz, 1H), 7.85-7.76 (m, 2H), 7.68 (t, J=4.1Hz, 2H), 7.54 (dt, J=12.3, 5.2Hz, 1H), 4.53- 4.42(m, 1H), 4.36-4.21(m, 2H), 4.13-4.04(m, 1H), 3.95-3.80(m, 1H), 3.58-3.49(m, 1H), 3.40 (d, J=16.4Hz, 1H), 2.95-2.84 (m, 1H), 2.45-2.17 (m, 3H), 2.07-1.94 (m, 1H).

[0408] Embodiment 77

[0409] 2-Fluoro-4-(6-(2-fluoro-6-(trifluoromethyl)phenyl)-2-(1,8-diazaspiro[4.5]dec-8-yl)quinazolin-4-yl)benzonitrile 77

[0410] The synthetic route of Example 1 was used, and the second step raw material, piperidin-4-ylcarbamic acid tert-butyl ester was replaced by 1,8-diazaspiro[4.5]decane-1-carboxylic acid tert-butyl ester, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid was replaced by 2-fluoro-6-(trifluoromethyl)phenylboric acid to prepare the hydrochloride salt of the title compound 77 (18 mg). 1 H NMR (400MHz, Methanol-d4) δ8.04 (d, J=8.0Hz, 1H), 7.97 (s, 1H), 7.91-7.71 (m, 3H), 7.67-7.64 (m, 1H) ), 7.51 (d, J=7.4Hz, 1H), 4.68-4.63 (m, 2H), 3.92-3.87 (m, 2H), 3.49-3.45 (m, 2H), 2.15-2.14 (m, 8H).

[0411] Embodiment 78

[0412] 4-(2-(4-aminopiperidin-1-yl)-7-fluoro-6-(2-fluorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 78

[0413]

[0414] first step

[0415] 6-Bromo-7-fluoroquinazoline-2,4(1H,3H)-dione 78b

[0416] Compound 2-amino-5-bromo-4-fluorobenzoic acid 78a (1 g, 4.27 mmol, Bidex Pharmaceuticals) and urea (2.56 g, 42.73 mmol) were ground to obtain a uniform mixture, which was heated to 180°C under nitrogen protection for 3 hours. After cooling, the obtained solid mixture was ground with water, filtered, washed with water, and dried to obtain a crude product 78b (1.1 g) (light yellow solid). No purification was required and it was directly used for the next step.

[0417] Step 2

[0418] 6-Bromo-2,4-dichloro-7-fluoroquinazoline 78c

[0419] The crude product 78b (1.1 g, 4.25 mmol) was dissolved in phosphorus oxychloride (2.38 mL, 25.5 mmol) and N,N-diethylaniline (2.03 mL, 12.75 mmol) was added. The reaction mixture was refluxed at 110°C for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure. Poured into cold water, extracted with dichloromethane 3 times, the organic layers were combined, washed with saturated sodium chloride solution, dried and concentrated. Purified by silica gel column chromatography (EA: PE; 1: 100 to 1: 60) to obtain the title compound 78c (0.56 g) (light yellow solid), yield: 45%. 1 H NMR (400MHz, Chloroform-d) δ 8.54 (d, J=7.0Hz, 1H), 7.70 (d, J=8.4Hz, 1H).

[0420] Step 3

[0421] 4-(6-Bromo-2-chloro-7-fluoroquinazolin-4-yl)-2-fluorobenzonitrile 78d

[0422] To a mixture of compound 6-bromo-2,4-dichloro-7-fluoroquinazoline 78c (300 mg, 1.01 mmol,), bis(triphenylphosphine)palladium(II) chloride (42.5 mg, 0.06 mmol), potassium phosphate (430 mg, 2.02 mmol) and MeCN / H2O (8:1) (40 mL), (4-cyano-3-fluorophenyl)boric acid (167.2 mg, 1.01 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) was added. Under nitrogen protection, the reaction mixture was heated at 100°C for 15 minutes. After cooling, the reaction solution was concentrated under reduced pressure. The ethyl acetate was slurried, filtered and dried. The title compound 78d (235 mg) (white solid) was obtained with a yield of 61%. 1 H NMR (400MHz, Chloroform-d) δ8.24 (d, J=7.0Hz, 1H), 7.90 (dd, J=8.2, 6.3Hz, 1H), 7.79 (d, J=8.5Hz, 1H), 7.69-7.67 (m, 1H), 7.66 (q, J=1.6Hz, 1H).

[0423] Step 4

[0424] Tert-butyl (1-(6-bromo-4-(4-cyano-3-fluorophenyl)-7-fluoroquinazolin-2-yl)piperidin-4-yl)carbamate 78e

[0425] Compound 78d (235 mg, 0.62 mmol), diisopropylethylamine (0.216 mL, 1.24 mmol) and tert-butyl piperidin-4-ylcarbamate (186 mg, 0.93 mmol, Bid Pharmaceuticals) were dissolved in N, N-dimethylformamide (6 ml). The reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 15 mL of water and 15 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA: PE; 1: 10 to 1: 5) gave the title compound 78e (214 mg) (yellow solid), yield: 64%. 1H NMR (400MHz, Chloroform-d) δ7.83 (t, J=3.3Hz, 1H), 7.82-7.80 (m, 1H), 7.57 (dd, J=4.4, 1.6Hz, 1H), 7.55 (dd, J=5.7, 1.3Hz, 1H), 7.30 (d, J=9.9Hz, 1H), 4 .83 (dd, J=13.6, 3.9Hz, 2H), 4.52 (d, J=7.9Hz, 1H), 3.76 (s, 1H), 3.14 (ddd, J =14.0, 11.6, 2.7Hz, 2H), 2.10-2.03(m, 2H), 1.45(s, 9H), 1.42-1.34(m, 2H).

[0426] Step 5

[0427] tert-Butyl (1-(4-(4-cyano-3-fluorophenyl)-7-fluoro-6-(2-fluorophenyl)quinazolin-2-yl)piperidin-4-yl)carbamate 78f

[0428] To a mixture of compound 78e (50 mg, 0.09 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7.3 mg, 0.009 mol), sodium carbonate (28.6 mg, 0.27 mmol) and tetrahydrofuran / water (5:1) (2 mL), (2-fluorophenyl)boric acid (25.7 mg, 0.18 mmol) was added. The reaction mixture was stirred at 70°C for 16 h under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure, 15 mL of water and 15 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA:PE; 1:8 to 1:4) gave the title compound 78f (34 mg) (yellow solid) with a yield of 66%. 1 H NMR (400MHz, Chloroform-d) δ7.78 (dd, J=8.1, 6.3Hz, 1H), 7.68 (d, J=7.9Hz, 1H), 7.62 (dd, J=4.9, 1.6Hz, 1H), 7.60 (dd, J=6.3, 1.4Hz, 1H), 7.42-7.31 (m, 3H) , 7.25-7.12(m, 2H), 4.89(d, J=13.4Hz, 2H), 4.49(s, 1H), 3.78(s, 1H), 3.18(td , J=12.5, 11.3, 2.7Hz, 2H), 2.12-2.05(m, 2H), 1.46(s, 9H), 1.44-1.36(m, 2H).

[0429] Step 6

[0430] 4-(2-(4-aminopiperidin-1-yl)-7-fluoro-6-(2-fluorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 78

[0431] Compound 78f (34 mg) was dissolved in 2 mL of dichloromethane, and 2 mL of 4N hydrogen chloride-1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride of the title compound 78 (26 mg) (yellow solid), with a yield of 88%. 1 H NMR (400MHz, Methanol-d4) δ8.02 (t, J=6.6Hz, 1H), 7.96 (d, J=7.1Hz, 1H), 7.91 (d, J=9.2Hz, 1H), 7.85 (d, J=7.0Hz, 1H), 7.80 (d, J=10.4Hz, 1H), 7.50 (p, J=6.6 , 6.0Hz, 2H), 7.31 (t, J=7.2Hz, 1H), 7.25 (dd, J=10.3, 8.2Hz, 1H), 5.09 (s, 2H), 3.71-3.59 (m, 1H), 3.46 (t, J=12.4Hz, 2H), 2.30 (d, J=10.8Hz, 2H), 1.88 (s, 2H).

[0432] Embodiment 79

[0433] 4-(2-(4-aminopiperidin-1-yl)-7-fluoro-6-(2-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 79

[0434] The hydrochloride salt of the title compound 79 (30 mg) was prepared by adopting the synthetic route of Example 78, replacing the raw material 2-fluorophenylboric acid in the fifth step with 2-trifluoromethylphenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ7.96 (t, J=6.9Hz, 1H), 7.86-7.60 (m, 7H), 7.46 (d, J=7.2Hz, 1H), 5.08 (d, J =12.8Hz, 2H), 3.59 (t, J = 4.6Hz, 1H), 3.35 (d, J = 12.6Hz, 2H), 2.29-2.16 (m, 2H), 1.80 (d, J = 11.9Hz, 2H).

[0435] Embodiment 80

[0436] 4-(2-(4-aminopiperidin-1-yl)-7-fluoro-6-(2-fluorophenyl)quinazolin-4-yl)-2-fluorobenzonitrile 80

[0437]

[0438] first step

[0439] 6-Bromo-8-fluoroquinazoline-2,4(1H,3H)-dione 80b

[0440] Compound 2-amino-5-bromo-3-fluorobenzoic acid 80a (1 g, 4.27 mmol, Bidex Pharmaceuticals) and urea (2.56 g, 42.73 mmol) were ground to obtain a uniform mixture, which was heated to 180°C for 3 hours under nitrogen protection. After cooling, the obtained solid mixture was ground with water, filtered, washed with water, and dried to obtain a crude product 80b (1.05 g) (light yellow solid). No purification was required and it was directly used for the next step.

[0441] Step 2

[0442] 6-Bromo-2,4-dichloro-8-fluoroquinazoline 80c

[0443] The crude product 80b (1.05 g, 4.05 mmol) was dissolved in phosphorus oxychloride (2.27 mL, 24.32 mmol), and N, N-diethylaniline (1.93 mL, 12.16 mmol) was added. The reaction mixture was refluxed at 110°C for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure. Poured into cold water, extracted with dichloromethane 3 times, the organic layers were combined, washed with saturated sodium chloride solution, dried, and concentrated. Purified by silica gel column chromatography (EA: PE; 1: 100 to 1: 60) to obtain the title compound 80c (0.81 g) (light yellow solid), yield: 68%. 1 H NMR (400MHz, Chloroform-d) δ 8.18 (d, J=2.0Hz, 1H), 7.78 (dd, J=8.8, 2.9Hz, 1H).

[0444] Step 3

[0445] 4-(6-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-2-fluorobenzonitrile 80d

[0446] To a mixture of compound 6-bromo-2,4-dichloro-8-fluoroquinazoline 80c (600 mg, 2.02 mmol,), bis(triphenylphosphine)palladium(II) chloride (85 mg, 0.12 mmol), potassium phosphate (860 mg, 4.04 mmol) and MeCN / H2O (8:1) (18 mL), (4-cyano-3-fluorophenyl)boric acid (334.4 mg, 2.02 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) was added. Under nitrogen protection, the stirred reaction mixture was heated at 100°C for 15 minutes. After cooling, the reaction solution was concentrated under reduced pressure. The ethyl acetate was slurried, filtered and dried. The title compound 80d (490 mg) (white solid) was obtained with a yield of 64%. 1 H NMR (400MHz, Chloroform-d) δ7.95 (t, J=1.6Hz, 1H), 7.90 (dd, J=8.1, 6.3Hz, 1H), 7.82 (dd, J=8.7, 1.9Hz, 1H), 7.69 (s, 1H), 7.67 (s, 1H).

[0447] Step 4

[0448] tert-Butyl (1-(6-bromo-4-(4-cyano-3-fluorophenyl)-8-fluoroquinazolin-2-yl)piperidin-4-yl)carbamate 80e

[0449] Compound 4-(6-bromo-2-chloro-8-fluoroquinazoline-4-yl)-2-fluorobenzonitrile 80d (300 mg, 0.79 mmol), diisopropylethylamine (0.274 mL, 1.58 mmol) and tert-butyl piperidin-4-ylcarbamate (237 mg, 1.18 mmol, Bid Pharmaceuticals) were dissolved in N, N-dimethylformamide (8 ml). The reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 15 mL of water and 15 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA: PE; 1: 10 to 1: 5) gave the title compound 80e (210 mg) (yellow solid), yield: 49%. 1H NMR (400MHz, Chloroform-d) δ7.82 (dd, J=8.2, 6.3Hz, 1H), 7.61-7.53 (m, 3H), 7.48 (dd, J=9.6, 2.0Hz, 1H), 4.86 (d, J=1 3.5Hz, 2H), 4.51 (s, 1H), 3.76 (s, 1H), 3.22-3.11 (m, 2H), 2.08 (dd, J=13.0, 3.7Hz, 2H), 1.45 (s, 9H), 1.43-1.34 (m, 2H).

[0450] Step 5

[0451] tert-Butyl (1-(4-(4-cyano-3-fluorophenyl)-8-fluoro-6-(2-trifluoromethylphenyl)quinazolin-2-yl)piperidin-4-yl)carbamate 80f

[0452] To a mixture of compound (tert-butyl 1-(6-bromo-4-(4-cyano-3-fluorophenyl)-8-fluoroquinazolin-2-yl)piperidin-4-yl)carbamate 80e (50 mg, 0.09 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7.3 mg, 0.009 mol), sodium carbonate (28.6 mg, 0.27 mmol) and tetrahydrofuran / water (5:1) (2 mL), (2-trifluoromethylfluorophenyl)boric acid (34.9 mg, 0.18 mmol Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) was added. The reaction mixture was stirred at 70°C for 16 h under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure, 15 mL of water and 15 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA:PE; 1:8 to 1:4) gave the title compound 80f (42 mg) (yellow solid). Yield: 75%. 1 H NMR (400MHz, Chloroform-d) δ7.80-7.71 (m, 2H), 7.70-7.47 (m, 3H), 7.43-7.36 (m, 2H), 7.31 (d, J=7.6Hz, 1H), 4.92 (d, J= 13.6Hz, 2H), 4.52 (s, 1H), 3.77 (s, 1H), 3.25-3.15 (m, 2H), 2.09 (dd, J=13.2, 3.8Hz, 2H), 1.46 (s, 9H), 1.43-1.36 (m, 2H).

[0453] Step 6

[0454] 4-(2-(4-aminopiperidin-1-yl)-8-fluoro-6-(2-trifluoromethylphenyl)quinazolin-4-yl)-2-fluorobenzonitrile 80

[0455] Compound (1-(4-(4-cyano-3-fluorophenyl)-8-fluoro-6-(2-trifluoromethylphenyl)quinazolin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester 80f (42 mg) was dissolved in 2 mL of dichloromethane, and 2 mL of 4N hydrogen chloride-1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of the title compound 80 (34 mg) (yellow solid), with a yield of 97%. 1 H NMR (400MHz, Methanol-d4) δ7.93 (dd, J=8.0, 6.5Hz, 1H), 7.80 (dd, J=7.9, 1.3Hz, 1H), 7.74 (dd, J =9.7, 1.4Hz, 1H), 7.71 (dd, J=8.0, 1.5Hz, 1H), 7.67 (td, J=7.7, 1.3Hz, 1H), 7.58 (t, J=7.7Hz, 1H), 7.50 (dd, J=11.0, 1.8Hz, 1H), 7.47-7.42 (m, 2H), 5.15 (dt, J=13.6, 2.7Hz, 2H), 3.50 (tt, J=11.6, 4.2Hz, 1H), 3.17 (ddd, J=14.2, 12.3, 2.6Hz, 2H), 2.19-2.12 (m, 2H), 1.65 (qd, J=12.3, 4.3Hz, 2H).

[0456] Embodiment 81

[0457] 4-(2-(4-aminopiperidin-1-yl)-8-fluoro-6-(2-fluoro)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 81

[0458] The hydrochloride salt of the title compound 81 (40 mg) was prepared by adopting the synthetic route of Example 80 and replacing the raw material in the fifth step 2-trifluoromethylbenzeneboronic acid with 2-fluorobenzeneboronic acid. 1H NMR (400MHz, Methanol-d4) δ7.98 (t, J=7.1Hz, 1H), 7.84-7.74 (m, 3H), 7.73 (s, 1H), 7.51 (t, J=7.8Hz, 1H), 7.39 (t, J=6.8Hz, 1H), 7.26 (t, J=7.6Hz , 1H), 7.20 (dd, J=11.3, 8.2Hz, 1H), 5.12 (d, J=13.4Hz, 2H), 3.57-3.44 (m , 1H), 3.21 (t, J=12.8Hz, 2H), 2.18 (d, J=12.3Hz, 2H), 1.77-1.60 (m, 2H).

[0459] Embodiment 82

[0460] 4-(2-(4-aminopiperidin-1-yl)-8-fluoro-6-(2-fluoro-6-trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 82

[0461] The hydrochloride salt of the title compound 82 (24 mg) was prepared by adopting the synthetic route of Example 80 and replacing the raw material in the fifth step 2-trifluoromethylbenzeneboronic acid with 2-fluoro-6-trifluoromethylbenzeneboronic acid. 1 H NMR (400MHz, Methanol-d4) δ7.93 (ddd, J=8.3, 6.5, 1.9Hz, 1H), 7.74-7.58 (m, 4H), 7.53-7.44 (m, 3H), 5.15 (d , J=13.7Hz, 2H), 3.50 (dq, J=11.7, 5.9, 4.3Hz, 1H), 3.22-3.11 (m, 2H), 2.20-2.13 (m, 2H), 1.72-1.60 (m, 2H).

[0462] Embodiment 83

[0463] 4-(2-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 83

[0464] The synthetic route of Example 1 was used, and the second step raw material, tert-butyl piperidin-4-ylcarbamate, was replaced by tert-butyl N-[(3S,4R)-3-fluoropiperidin-4-yl]carbamate, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, was replaced by 2-fluoro-6-(trifluoromethyl)phenylboric acid to prepare the hydrochloride salt of the title compound 83 (33 mg).

[0465] 1H NMR (400MHz, DMSO-d6) δ8.13 (t, J=7.3Hz, 1H), 7.80 (d, J=9.8Hz, 1H), 7.74 (s, 2H), 7.72-7.61 (m, 5H), 5.37-5.25 (m, 1H), 5.16 (d, J=49. 1Hz, 1H), 5.00 (d, J=13.5Hz, 1H), 3.40 (dd, J=40.2, 14.9Hz, 1H), 3.16 (t, J=12.8Hz, 1H), 1.99 (dq, J=9.5, 6.1Hz, 2H), 1.89-1.73 (m, 1H).

[0466] Embodiment 84

[0467] 4-(2-((3R,4R)-4-amino-3-fluoropiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 84

[0468] The synthetic route of Example 1 was adopted, and the second step raw material, tert-butyl piperidin-4-ylcarbamate, was replaced by tert-butyl N-[(3R,4R)-3-fluoropiperidin-4-yl]carbamate, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, was replaced by 2-fluoro-6-(trifluoromethyl)phenylboric acid to prepare the hydrochloride salt of the title compound 84 (36 mg). 1 H NMR (400MHz, Methanol-d4) δ8.08 (d, J=8.5Hz, 1H), 7.99 (t, J=7.0Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=9.5Hz, 1H), 7.77 (d, J=7.7Hz, 1H), 7.67 (qd, J=7.7, 3.3H z, 2H), 7.56-7.48 (m, 1H), 5.36 (d, J=12.0Hz, 1H), 5.05 (d, J=12.8Hz, 1H), 4.82 (s, 1H), 3 .77 (d, J=12.0Hz, 1H), 3.55-3.38 (m, 2H), 2.38 (d, J=12.4Hz, 1H), 1.99 (d, J=14.1Hz, 1H).

[0469] Embodiment 85

[0470] 4-(2-((3S,4S)-4-amino-3-fluoropiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 85

[0471] The synthetic route of Example 1 was used, and the second step raw material, tert-butyl piperidin-4-ylcarbamate, was replaced by tert-butyl N-[(3S,4S)-3-fluoropiperidin-4-yl]carbamate, and the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, was replaced by 2-fluoro-6-(trifluoromethyl)phenylboric acid to prepare the hydrochloride salt of the title compound 85 (32 mg).

[0472] 1 H NMR (400MHz, Methanol-d4) δ8.09 (d, J=8.7Hz, 1H), 7.99 (t, J=7.0Hz, 1H), 7.94 (d, J =8.4Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 9.5Hz, 1H), 7.77 (d, J = 7.7Hz, 1H), 7.67 (dd, J = 7.3, 3.7Hz, 2H), 7.56-7.48 (m, 1H), 5.42-5.30 (m, 1H), 5.05 (d, J=13.0Hz, 1H), 4.83 (s, 1H), 3.83-3.72 (m, 1H), 3.48 (d, J=12.7Hz, 2H), 2.38 (s, 1H), 2.09-1.92 (m, 1H).

[0473] Embodiment 86

[0474] (S)-4-(2-(3-aminoazepan-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 86

[0475] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 86 (18 mg), by replacing the second step raw material (3-fluoro-4-methoxyphenyl)boronic acid with 2-fluoro-6-(trifluoromethyl)phenylboronic acid, tert-butyl piperidin-4-ylcarbamate with (S)-azepan-3-ylcarbamate, and the third step raw material (3-fluoro-4-methoxyphenyl)boronic acid with 2-fluoro-6-(trifluoromethyl)phenylboronic acid.

[0476] 1 H NMR (400MHz, Methanol-d4) δ8.31 (d, J=8.4Hz, 1H), 8.10-8.00 (m, 2H), 7.91 (d, J=11.5Hz, 2H), 7.84 (d, J=7.7Hz, 1H), 7.72-7.63 (m, 2H), 7.54 (t, J=7.2Hz, 1H), 4.60 (d, J=14.3Hz, 1H), 4.32 (d, J=14.0Hz, 1H), 4.15-4.03 (m, 2H), 3.79-3.71 (m, 1H), 2.32-1.98 (m, 4H), 1.93-1.66 (m, 2H).

[0477] Embodiment 87

[0478] (R)-4-(2-(3-aminoazepan-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 87

[0479] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 87 (25 mg), by replacing the second step raw material (3-fluoro-4-methoxyphenyl)boronic acid with (R)-azepan-3-ylboronic acid, and replacing the third step raw material (3-fluoro-4-methoxyphenyl)boronic acid with 2-fluoro-6-(trifluoromethyl)phenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ8.37 (s, 1H), 8.13 (t, J = 7.3Hz, 1H), 8.00 (t, J = 10.8Hz, 1H), 7.91-7.57 (m, 6H), 4.41-4.3 1 (m, 1H), 4.18-3.75 (m, 3H), 3.57 (d, J=46.6Hz, 1H), 1.96 (d, J=8.1Hz, 2H), 1.92-1.61 (m, 3H), 1.48-1.43 (m, 1H).

[0480] Embodiment 88

[0481] (S)-4-(2-(4-aminoazepan-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 88

[0482] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 88 (22 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (S)-4-tert-butyloxycarbonyl-1H-azepine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.19 (d, J=8.4Hz, 1H), 8.06-7.98 (m, 2H), 7.92-7.89 (m, 1H), 7.81 (dd, J=16.7, 8.6H z, 2H), 7.68 (dd, J=6.9, 3.7Hz, 2H), 7.58-7.49 (m, 1H), 4.65-3.89 (m, 3H), 3.52-3.44 (m, 1H), 2.56-1.79 (m, 3H).

[0483] Embodiment 89

[0484] 4-(2-(4-aminoazepan-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 89

[0485] The synthetic route of Example 1 was used to prepare the hydrochloride salt of the title compound 89 (59 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (R)-4-tert-butyloxycarbonyl-1H-azepine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Methanol-d4) δ8.30-8.16 (m, 1H), 8.06-7.98 (m, 2H), 7.93-7.90 (m, 1H), 7.83 (dd, J=17.1, 8 .5Hz, 2H), 7.68 (dd, J=6.2, 3.8Hz, 2H), 7.54 (td, J=9.0, 3.3Hz, 1H), 4.69-3.89 (m, 4H), 2.56-1.78 (m, 2H).

[0486] Embodiment 90

[0487] (S)-4-(2-(3-aminopyrrolidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 90

[0488] The synthetic route of Example 1 was used to prepare the title compound 90 (30 mg), by replacing the second step raw material, tert-butyl piperidin-4-ylcarbamate, with (S)-3-tert-butyloxycarbonylaminopyrrolidine, and replacing the third step raw material, (3-fluoro-4-methoxyphenyl)boric acid, with 2-fluoro-6-(trifluoromethyl)phenylboric acid. 1 H NMR (400MHz, Chloroform-d) δ7.74 (dd, J=8.7, 6.0Hz, 2H), 7.63-7.55 (m, 5H), 7.47 (td, J=8.0, 5.1Hz, 1H), 7.33 (t, J=8.4H z, 1H), 3.94 (ddd, J=19.1, 15.3, 6.5Hz, 2H), 3.79 (q, J=11.2, 9.0Hz, 2H), 3.62-3.43 (m, 1H), 2.23 (dt, J=19.8, 7.0Hz, 2H).

[0489] Embodiment 91

[0490] (R)-4-(2-(3-aminopyrrolidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)quinazolin-4-yl)-2-fluorobenzonitrile 91

[0491] The synthetic route of Example 1 was used to replace the second step raw material tert-butyl piperidin-4-ylcarbamate with (R)-3-tert-butyloxycarbonylaminopyrrolidine, and the third step raw material (3-fluoro-4-methoxyphenyl)boric acid with 2-fluoro-6-(trifluoromethyl)phenylboric acid to obtain the title compound 91 (38 mg). 1 H NMR (400MHz, Chloroform-d) δ7.77-7.72 (m, 2H), 7.62 (q, J=1.5Hz, 1H), 7.60 (dd, J= 4.3, 1.4Hz, 2H), 7.58-7.56 (m, 2H), 7.47 (td, J=8.1, 5.2Hz, 1H), 7.33 (t, J=8.5Hz, 1H ), 3.94 (ddd, J=18.9, 12.6, 6.4Hz, 2H), 3.79 (td, J=11.9, 9.9, 6.5Hz, 2H), 3.50 (dd, J=11.4, 4.6Hz, 1H), 2.24 (dq, J=15.0, 7.8, 7.1Hz, 1H), 1.86 (dq, J=12.7, 6.1Hz, 1H).

[0492] Embodiment 92

[0493] 4-(2-(4-aminopiperidin-1-yl)-6-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-4-yl)-2-fluorobenzonitrile 92

[0494]

[0495] first step

[0496] 4-(6-Benzyl-2-chloro-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-4-yl)-2-fluorobenzonitrile 92b

[0497] To a mixture of compound 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyridine [4,3-d] pyrimidine 92a (1 g, 3.38 mmol), bis(triphenylphosphine)palladium(II) chloride (237 mg, 0.34 mmol), potassium phosphate (1.43 g, 6.75 mmol) and MeCN / H2O (8:1) (18 mL), (4-cyano-3-fluorophenyl)boric acid (612 mg, 3.71 mmol) was added (Shanghai Haohong Biopharmaceutical Technology Co., Ltd.). The reaction mixture was heated at 100°C for 15 minutes under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure. The mixture was slurried with ethyl acetate, filtered and dried. The title compound 92b (908 mg) (white solid) was obtained with a yield of 70.6%.

[0498] Step 2

[0499] tert-Butyl (1-(6-benzyl-4-(4-cyano-3-fluorophenyl)-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-2-yl)piperidin-4-ylcarbamate 92c

[0500] Compound 4-(6-benzyl-2-chloro-5,6,7,8-tetrahydropyridine [4,3-d] pyrimidin-4-yl) -2-fluorobenzonitrile 92b (600 mg, 1.58 mmol), diisopropylethylamine (0.55 mL, 3.15 mmol) and tert-butyl piperidin-4-ylcarbamate (473 mg, 2.36 mmol, Bid Pharmaceuticals) were dissolved in N, N-dimethylformamide (8 ml). The reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 15 mL of water and 15 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA: PE; 1: 10 to 1: 5) gave the title compound 92c (760 mg) (white solid), yield: 88.9%. 1 HNMR (400MHz, Chloroform-d) δ7.66 (t, J=7.1Hz, 1H), 7.39 (d, J=8.8Hz, 2H), 7.3 5-7.25(m, 5H), 4.66(d, J=13.3Hz, 2H), 4.46(s, 1H), 3.74-3.66(m, 1H), 3.64(s, 2H), 3.49 (s, 2H), 3.01 (t, J=11.9Hz, 2H), 2.85 (d, J=5.9Hz, 2H), 2.78 (d, J=6.1H z, 2H), 2.00 (d, J=12.4Hz, 2H), 1.45 (s, 9H), 1.32 (dtt, J=12.1, 8.7, 4.5Hz, 2H).

[0501] Step 3

[0502] tert-Butyl (1-(4-(4-cyano-3-fluorophenyl)-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-2-yl)piperidin-4-yl)carbamate 92d

[0503] A mixture of compound (tert-butyl 1-(6-benzyl-4-(4-cyano-3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)piperidin-4-ylcarbamate 92c (600 mg, 1.11 mmol), 10% Pd—C catalyst (60 mg) and methanol (10 mL) was stirred at room temperature under hydrogen until the absorption of hydrogen stopped. After filtering out the catalyst, the filtrate was evaporated. Purification by silica gel column chromatography (DCM: MeOH; 1:20 to 1:15) gave the title compound 92d (210 mg) (white solid), yield: 42.0%. 1 H NMR (400MHz, Chloroform-d) δ7.68 (t, J=7.1Hz, 1H), 7.39 (d, J=8.7Hz, 2H), 4.65 (d, J=13.6Hz, 1H), 4.51 (d, J=7.7Hz, 2H), 3.83 (s, 2H), 3. 69 (s, 1H), 3.19 (t, J=6.2Hz, 2H), 3.05-2.96 (m, 2H), 2.80 (t, J=6.1Hz, 2H), 2.03-1.96 (m, 2H), 1.44 (s, 9H), 1.33 (qd, J=11.8, 4.3Hz, 2H).

[0504] Step 4

[0505] Tert-butyl (1-(4-(4-cyano-3-fluorophenyl)-6-(2-(trifluoromethyl)phenyl)-4a,5,6,7,8,8a-hexahydroquinazolin-2-yl)piperidin-4-yl)carbamate 92e

[0506] To a mixture of compound (tert-butyl 1-(4-(4-cyano-3-fluorophenyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-2-yl)piperidin-4-yl)carbamate 92d (41 mg, 0.09 mmol), bis(dibenzylideneacetone palladium) (2.73 mg, 4.75 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (5.5 mg, 9.50 μmol), cesium carbonate (61.89 mg, 0.27 mmol) and dry dioxane (2 mL) was added o-bromotrifluorotoluene (30.6 mg, 0.18 mmol). Under nitrogen protection, the reaction mixture was stirred at 100° C. for 17 h. After cooling, the reaction solution was concentrated under reduced pressure, 15 mL of water and 15 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA:PE; 1:8 to 1:4) gave the title compound 92e (21 mg) (yellow solid). Yield: 36.9%.1 H NMR (400MHz, Chloroform-d) δ7.67-7.60 (m, 2H), 7.54 (t, J=8.1Hz, 1H), 7.43-7.34 (m, 3H), 7.31-7.21 (m, 1H), 4.70 (d, J=13.3Hz, 2H), 4.51-4.48 (m, 1H), 3.90-3.87 (m, 2H), 3.74-3.69 (m, 1H), 3.28 (t, J=5.9Hz, 2H), 3. 09-2.97 (m, 4H), 2.03 (d, J=11.3Hz, 2H), 1.46 (s, 9H), 1.43-1.30 (m, 2H).

[0507] Step 5

[0508] 4-(2-(4-aminopiperidin-1-yl)-6-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-4-yl)-2-fluorobenzonitrile 92

[0509] Compound tert-butyl (1-(4-(4-cyano-3-fluorophenyl)-6-(2-(trifluoromethyl)phenyl)-4a,5,6,7,8,8a-hexahydroquinazolin-2-yl)piperidin-4-yl)carbamate 92e (21 mg) was dissolved in 2 mL of dichloromethane, and 2 mL of 4N hydrogen chloride-1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of the title compound 92 (15 mg) (yellow solid), with a yield of 85.8%. 1 H NMR (600MHz, Methanol-d4) δ7.99-7.92 (m, 1H), 7.87 (t, J=6.9Hz, 1H), 7.63 ( p, J=9.7, 8.2Hz, 4H), 7.34 (t, J=7.3Hz, 1H), 4.01-3.97 (m, 2H), 3.52-3.48 (m , 1H), 3.34 (d, J=6.4Hz, 2H), 3.19 (t, J=12.7Hz, 2H), 3.15-3.11 (m, 2H), 2.30 -2.19(m, 1H), 2.14(d, J=12.0Hz, 2H), 2.05-1.99(m, 1H), 1.72-1.67(m, 2H).

[0510] Embodiment 93

[0511] 4-(2-(4-aminopiperidin-1-yl)-6-(2-fluoro-6-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-4-yl)-2-fluorobenzonitrile 93

[0512] The synthetic route of Example 92 was adopted, and the raw material of step 4, o-bromobenzotrifluoromethane, was replaced with 2-bromo-3-fluorobenzotrifluoromethane to prepare the hydrochloride salt of the title compound 93 (8 mg). MS m / z (ESI): 515.20 [M+1] + .

[0513] Embodiment 94

[0514] 4-(2-(4-aminopiperidin-1-yl)-6-(1-methyl-1H-indazol-7-yl)-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-4-yl)-2-fluorobenzonitrile 94

[0515] The synthetic route of Example 92 was adopted, and the raw material of step 4, o-bromotrifluorotoluene, was replaced by 7-bromo-1-methylindazole to prepare the hydrochloride salt of the title compound 94 (10 mg). MS m / z (ESI): 482.52 [M+1] + .

[0516] Embodiment 95

[0517] 4-(3-(4-aminopiperidin-1-yl)-7-(2-fluoro-6-(trifluoromethyl)phenyl)isoquinolin-1-yl)-2-fluorobenzonitrile 98

[0518]

[0519] first step

[0520] 4-(7-Bromo-3-chloroisoquinolin-1-yl)-2-fluorobenzonitrile 98b

[0521] To a mixture of compound 7-bromo-1,3-dichloroisoquinoline 98a (1.00 g, 3.61 mmol), bis(triphenylphosphine)palladium(II) chloride (127 mg, 180.54 μmol), potassium phosphate (1.53 g, 7.22 mmol) and acetonitrile / water (8:1) (18 mL) was added (4-cyano-3-fluorophenyl)boric acid (596 mg, 3.61 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.). Under nitrogen protection, the reaction mixture was heated at 100°C for 15 minutes. After the reaction was completed by TLC monitoring, the reaction solution was cooled and concentrated under reduced pressure. The mixture was slurried with ethyl acetate, filtered and dried. The title compound 98b (1.10 g) (white solid) was obtained with a yield of 84.3%. 1 H NMR (400MHz, Chloroform-d) δ 8.11 (s, 1H), 7.84 (td, J=5.9, 5.3, 2.6Hz, 2H), 7.80-7.74 (m, 2H), 7.61 (s, 1H), 7.59 (s, 1H).

[0522] Step 2

[0523] 4-(3-Chloro-7-(2-fluoro-6-(trifluoromethyl)phenyl)isoquinolin-1-yl)-2-fluorobenzonitrile 98c

[0524] 2-Fluoro-6-trifluoromethylphenylboronic acid (288 mg, 1.38 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) was added to a mixture of compound 4-(7-bromo-3-chloroisoquinolin-1-yl)-2-fluorobenzonitrile 98b (500 mg, 1.38 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (56 mg, 0.069 mol), sodium carbonate (293 mg, 2.77 mmol) and tetrahydrofuran / water (5:1) (35 mL). The reaction mixture was stirred at 70°C for 16 hours under nitrogen protection. After the reaction was completed by TLC monitoring, the reaction solution was cooled, concentrated under reduced pressure, 35 mL of water and 35 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA:PE; 1:20 to 1:15) gave the title compound 98c (420 mg) as a pale yellow solid. Yield: 68.3%. MS m / z (ESI): 445.35 [M+1] + .

[0525] Step 3

[0526] tert-Butyl (1-(1-(4-cyano-3-fluorophenyl)-7-(2-fluoro-6-(trifluoromethyl)phenyl)isoquinolin-3-yl)piperidin-4-yl)carbamate 98d

[0527] Palladium acetate (5 mg, 22.48 μmol) and BINAP (28 mg, 44.97 μmol) were added to a mixture of compound 4-(3-chloro-7-(2-fluoro-6-(trifluoromethyl)phenyl)isoquinolin-1-yl)-2-fluorobenzonitrile 98c (100 mg, 224.83 μmol), 4-tert-butyloxycarbonylaminopiperidine (90 mg, 449.65 μmol), cesium carbonate (147 mg, 449.65 μmol) and dry 1,4-dioxane (4 mL). The reaction mixture was stirred at 110°C for 12 hours under nitrogen protection. After the reaction was completed by TLC monitoring, the reaction solution was cooled and concentrated under reduced pressure, 15 mL of water and 15 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10M1×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA:PE; 1:10 to 1:5) gave the title compound 98d (57 mg) as a yellow solid. Yield: 41.7%. MS m / z (ESI): 609.13 [M+1] + .

[0528] Step 4

[0529] 4-(3-(4-aminopiperidin-1-yl)-7-(2-fluoro-6-(trifluoromethyl)phenyl)isoquinolin-1-yl)-2-fluorobenzonitrile 98

[0530] Compound (tert-butyl 1-(1-(4-cyano-3-fluorophenyl)-7-(2-fluoro-6-(trifluoromethyl)phenyl)isoquinolin-3-yl)piperidin-4-yl)carbamate 98d (57 mg) was dissolved in 2 mL of dichloromethane, and 2 mL of 4N hydrogen chloride-1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and washed with ethyl acetate solution to obtain the hydrochloride salt of the title compound 98 (41 mg) (yellow solid), with a yield of 80.6%. MS m / z (ESI): 509.21 [M+1] + .

[0531] Embodiment 96

[0532] 4-(2-(4-aminopiperidin-1-yl)-8-methyl-7-oxo-6-(2-trifluoromethylphenyl)-7,8-dihydropyridin[2,3-d]pyrimidin-4-yl)-2-fluorobenzonitrile 99

[0533]

[0534] first step

[0535] 4-Chloro-6-methylamino-2-methylthiopyrimidine-5-carbaldehyde 99b

[0536] Compound 4,6-dichloro-2-methylthiopyrimidine-5-carboxaldehyde 99a (5.00 g, 22.41 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) was dissolved in chloroform (40 mL), methylamine (40% aqueous solution) (1.83 g, 23.54 mmol) and triethylamine (4.67 mL, 33.62 mmol) were added dropwise, and stirred at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure. 60 mL of water and 60 mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA: PE; 1: 10 to 1: 5) gave the title compound 96b (4.50 g) (white solid), with a yield of 90.2%. 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 3.04 (d, J=4.9Hz, 3H), 2.53 (s, 3H).

[0537] Step 2

[0538] 2-Fluoro-4-(5-formyl-6-(methylamino)-2-(methylthio)pyrimidin-4-yl)benzonitrile 99c

[0539] To a mixture of compound 4-chloro-6-methylamino-2-methylthiopyrimidine-5-carboxaldehyde 99b (4.50 g, 20.67 mmol), tetrakis(triphenylphosphine)palladium (477 mg, 413.47 μmol), potassium carbonate (5.71 g, 41.35 mmol) and 1,4-dioxane / water (4:1) (40 mL), (4-cyano-3-fluorophenyl)boric acid (4.43 g, 26.88 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.) was added. Under nitrogen protection, the reaction mixture was heated at 110°C for 16 hours. After the reaction was completed, the reaction solution was cooled and concentrated under reduced pressure after monitoring by TLC. The mixture was slurried with ethyl acetate, filtered and dried. The title compound 99c (4.20 g) (white solid) was obtained with a yield of 67.2%. 1 H NMR (400MHz, Chloroform-d) δ9.73 (d, J=0.6Hz, 1H), 9.16 (s, 1H), 7.73 (dd, J=7.9, 6.3Hz, 1H), 7.44 (ddd, J=16.7, 8.4, 1.5Hz, 2H), 3.17 (d, J=4.9Hz, 3H), 2.59 (s, 3H).

[0540] Step 3

[0541] (E)-3-(4-(4-cyano-3-fluorophenyl)-6-(methylamino)-2-(methylthio)pyrimidin-5-yl)acrylate 99d

[0542] Compound 2-fluoro-4-(5-formyl-6-(methylamino)-2-(methylthio)pyrimidin-4-yl)benzonitrile 99c (4.00 g, 13.23 mmol) was dissolved in tetrahydrofuran (50 mL), and ethoxycarbonylmethylenetriphenylphosphine (5.99 g, 17.20 mmol) was added. The reaction mixture was heated to reflux for 1.5 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and directly purified by column chromatography (EA: PE; 1: 10 to 1: 5) to obtain the title compound 99d (4.10 g) (white solid) with a yield of 83.2%. 1 H NMR (400MHz, DMSO-d6) δ8.05-7.96 (m, 1H), 7.64 (dd, J=10.3, 1.5Hz, 1H), 7.51-7.44 (m, 2H), 7.36 (d, J=16.3Hz , 1H), 5.99 (d, J=16.3Hz, 1H), 4.11 (q, J=7.1Hz, 2H), 2.91 (d, J=4.4Hz, 3H), 2.48 (s, 3H), 1.20 (t, J=7.1Hz, 3H).

[0543] Step 4

[0544] 2-Fluoro-4-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)benzonitrile 99e

[0545] Compound (E)-ethyl 3-(4-(4-cyano-3-fluorophenyl)-6.(methylamino)-2-(methylthio)pyrimidin-5-yl)acrylate 99d (4.00 g, 10.74 mmol) was suspended in methanol, sodium methoxide (29 mg, 537.03 μmol) was added, and the reaction mixture was stirred and heated at 70°C for 6 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, and solids precipitated. The solids were filtered and dried to obtain the crude product of the title compound 99e, which was directly used for the next step without purification. MS m / z (ESI): 327.31 [M+1] + .

[0546] Step 5

[0547] 6-Bromo-8-methyl-2-methylthio-7-oxo-7,8-dihydropyridine-2,3-dihydroxypyrimidin-4-yl-2-fluorobenzonitrile 99f

[0548] Compound 2-fluoro-4-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)benzonitrile 99e (2.00 g, 6.13 mmol) was dissolved in dichloromethane (30 mL), and then bromine (1.96 g, 12.26 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed as monitored by TLC, the reaction solution was poured into a saturated sodium thiosulfate solution and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA:PE; 1:10 to 1:5) gave the title compound 99f (1.90 g) (white solid) in a yield of 76.5%. 1 H NMR (400MHz, Chloroform-d) δ 8.06 (s, 1H), 7.84 (dd, J=7.8, 6.3Hz, 1H), 7.58-7.49 (m, 2H), 3.88 (s, 3H), 2.66 (s, 3H).

[0549] Step 6

[0550] 4-Bromo-8-methyl-2-methanesulfonyl-7-oxo-7,8-dihydropyridin-[2,3-d]pyrimidin-4-yl)-2-fluorobenzonitrile 99g

[0551] The compound 6-bromo-8-methyl-2-methylthio-7-oxo-7,8-dihydropyridine-2,3-dihydroxypyrimidin-4-yl-2-fluorobenzonitrile 99f (1.90 g, 4.96 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperbenzoic acid (2.43 g, 14.07 mmol) was added in batches at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product of the title compound 99 g was obtained, which was directly carried out to the next step without purification.

[0552] Step 7

[0553] 1-(6-bromo-4-(4-cyano-3-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylpiperidin-4-carbamic acid tert-butyl ester 99h

[0554] The compound 4-bromo-8-methyl-2-methylsulfonyl-7-oxo-7,8-dihydropyridine [2,3-d] pyrimidin-4-yl)-2-fluorobenzonitrile 99g (2.05g, 4.96mmol) and 4-tert-butyloxycarbonylaminopiperidine (1.13g, 5.63mmol) were dissolved in acetonitrile (20mL), potassium carbonate (1.30g, 9.38mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure. 30mL of water and 30mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (30mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (MeOH: DCM; 1:100 to 1:50) gave the title compound 99h (2.40g) (yellow solid), with a yield of 91.8%. 1 H NMR (400MHz, Chloroform-d) δ7.89 (s, 1H), 7.81 (dd, J=8.1, 6.3Hz, 1H), 7.48 (ddd, J=8.2, 4.8, 1.4Hz, 2H), 4.84-4 .76(m, 2H), 4.51-4.43(m, 1H), 3.76(s, 3H), 3.22-3.11(m, 2H), 2.14-2.05(m, 2H), 1.46(s, 9H), 1.44-1.36(m, 2H).

[0555] Step 8

[0556] Tert-butyl 1-(4-(4-cyano-3-fluorophenyl)-8-methyl-7-oxo-6-(2-trifluoromethylphenyl)-7,8-dihydropyridin[2,3-d]pyrimidin-2-yl)carbamate 99i

[0557] To a mixture of compound 1-(6-bromo-4-(4-cyano-3-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylpiperidin-4-carbamic acid tert-butyl ester 99h (200 mg, 358.79 μmol), tetrakistriphenylphosphine palladium (20.73 mg, 17.94 μmol), potassium carbonate (149 mg, 1.08 mmol) and 1,4-dioxane / water (4:1) (5 mL) was added 2-trifluoromethylphenylboronic acid (102 mg, 538.1 9μmol). The reaction mixture was stirred at 110°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled and concentrated under reduced pressure. 15mL of water and 15mL of ethyl acetate were added, mixed evenly, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate (10mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (EA:PE; 1:4 to 1:2) gave the title compound 99i (181mg) (yellow solid) with a yield of 81.0%. 1 H NMR (400MHz, Chloroform-d) δ7.72 (dd, J=8.1, 6.3Hz, 2H), 7.58-7.52 (m, 1H), 7.51-7.43 (m, 4H), 7.32 (d, J=7.6Hz, 1H), 4 .88-4.80(m, 2H), 4.55-4.48(m, 1H), 3.75(s, 3H), 3.24-3.13(m, 2H), 2.14-2.06(m, 2H), 1.46(s, 9H), 1.44-1.35(m, 2H).

[0558] Step 9

[0559] 4-(2-(4-aminopiperidin-1-yl)-8-methyl-7-oxo-6-(2-trifluoromethylphenyl)-7,8-dihydropyridin[2,3-d]pyrimidin-4-yl)-2-fluorobenzonitrile 99

[0560] Compound 1-(4-(4-cyano-3-fluorophenyl)-8-methyl-7-oxo-6-(2-trifluoromethylphenyl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)carbamic acid tert-butyl ester 99i (181 mg) was dissolved in 4 mL of dichloromethane, and 4 mL of 4N hydrogen chloride-1,4-dioxane solution was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and washed with ethyl acetate solution to obtain the hydrochloride salt of the title compound 99 (152 mg) (yellow solid), with a yield of 93.8%. 1H NMR (400MHz, Methanol-d4) δ7.90 (dd, J=8.0, 6.5Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.67-7.62 (m, 2H), 7.61-7.53 (m, 3H), 7.39 ( d, J=7.6Hz, 1H), 5.13-5.06 (m, 2H), 3.77 (s, 3H), 3.54-3.43 (m, 1H), 3.23-3.12 (m, 2H), 2.21-2.11 (m, 2H), 1.70-1.57 (m, 2H).

[0561] Biological evaluation

[0562] Test Example 1: In vitro enzyme inhibition activity assay - LSD1

[0563] The purpose of this experiment is to detect the in vitro inhibitory activity of compounds on LSD1. The human recombinant LSD1 protein used in the experiment was purchased from Active Motif, and the enzyme level activity test of LSD1 was performed using the Lance Ultra LSD1 histone H3 lysine 4 demethylase assay kit (PerkinElmer). First, Tris buffer (50mM Tris-HCl, 50mMNaCl, 0.01% Tween-20, 1mM DTT, 10μM FAD, 10% glycerol, pH 9.0) needs to be prepared. After the preparation is completed, the LSD1 components required for the test need to be placed in the buffer and cultured at room temperature for one hour. The components include 4μL substrate solution (25μM Bio-H3K4me2, 1-24aa), 4μL enzyme solution (4nM LSD1) and 2μL inhibitor in a 384-well microplate. After these operations were completed, 5 μL of the detection mixture containing Eu-labeled H3K4me0 antibody and ULight-streptavidin was added to the system. After that, Envision (PerkinElmer) was used to detect the fluorescence intensity of the components to be tested. The test mode was set in TR-FRET mode (excitation wavelength of 320 nm, emission wavelength of 665 nm). To reduce the error, the test was repeated three times in total. The final IC 50 The data were calculated by GraphPad Prism 5 software, and the sigmoidal dose-response (variable slope) method was used to obtain the fitting curve.

[0564] The LSD1 inhibitory activities of representative compounds of the present application and the positive control compound CC90011 are provided in Table 2. All compounds were tested in the form of HCl salts.

[0565] Table 2

[0566]

[0567]

[0568]

[0569] Note: 1. Biochemical determination of IC 50 The data is specified in the following ranges:

[0570] A: ≤30nM

[0571] B:>30nM to ≤300nM

[0572] C:>300nM to ≤10000nM

[0573] D:>10000nM.

[0574] 2.CC90011 chemical structure:

[0575]

[0576] Test Example 2: In vivo efficacy evaluation in mouse transplanted tumor model

[0577] Experimental purpose: To test the in vivo efficacy of the compound in a mouse xenograft tumor model

[0578] Experimental materials: Female NU / NU nude mice, MV4-11 cell line

[0579] Experimental method: Female NU / NU nude mice, weighing 20±2g, were inoculated with MV4-11 cells subcutaneously in the right axilla of nude mice. The cell inoculation amount was 5×10 6 After the tumor is formed, the diameter of the transplanted tumor is measured with a vernier caliper. The tumor grows to 100-300 mm. 3 The animals were divided into a model control group and a drug administration group according to their body weight and tumor volume, with 6 animals in each group. The drug administration group was ground and suspended with 0.5% CMC-Na, while the model control group was given an equal amount of blank solvent. After grouping, the animals were orally administered every day at a dose of 20 mg / kg for 21 days. During the experiment, the diameter of the transplanted tumor and the weight of the mice were measured twice a week, and the tumor tissue was obtained after the animals were euthanized on the 21st day. Observation index: tumor volume TV = 1 / 2 × a × b 2 (Note: a and b represent length and width respectively.) Relative tumor volume RTV = TV t / TV0 (Note: TV0 is the tumor volume measured at the time of administration (i.e., d0), TV t is the tumor volume at each measurement. ), relative tumor proliferation rate T / C (%) = (T RTV / C RTV )×100%(Note: T RTV :RTV in treatment group; C RTV : Negative control group RTV), tumor weight inhibition rate % = (Wc-W T ) / Wc×100%(Note: Wc: tumor weight of control group, W T : Tumor weight in treatment group).

[0580] Experimental conclusion: Representative test compounds 19 and 89 showed significant in vivo antitumor activity (T / C was less than 50% at a dose of 20 mg / kg by oral administration).

Claims

1. An aromatic heterocyclic compound as shown in formula I, or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof; in, represents a single or double bond; A is W 1 and W 2 are each independently N, C(H) or C(R a ), where R a Can be F, Cl, Br, I or C 1-3 alkyl; R 1 is substituted or unsubstituted C6-C 10 aryl or substituted or unsubstituted 5-14 membered heteroaryl, wherein the substituted C6-C 10 Aryl and substituted 5-14 membered heteroaryl are independently substituted by 1, 2 or 3 R 1a Substitution; the heteroatoms in the 5-14 membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; R 2 N(R 3 )2 substituted saturated or unsaturated C 3-10 Cyclic hydrocarbon group, N(R 3 )2 substituted C6-C 14 Aryl, N(R 3 )2 substituted 3-10 membered heterocyclic group or unsubstituted 3-10 membered heterocyclic group containing 1, 2, 3 or 4 N atoms, N(R 3 )2 substituted 5-10 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-N(R 3 )-, substituted or unsubstituted N(R 3 )2-(C1-C4 alkylene)-N(R 3 )-、N(R 3 )2 substituted 3-10 membered heterocyclic group or unsubstituted 3-10 membered heterocyclic group containing 1, 2, 3 or 4 nitrogen atoms -O-, N(R 3 )2 substituted 3-10 membered heterocyclic group or unsubstituted 3-10 membered heterocyclic group containing 1, 2, 3 or 4 N atoms-(C1-C4 alkylene)-O-, substituted or unsubstituted N(R 3 )2-(C1-C4 alkylene)-O-, N(R 3 )2 substituted 3-10 membered heterocyclyl or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)- containing 1, 2, 3 or 4 N atoms; wherein the substituted 3-10 membered heterocyclyl-N(R 3 )-, substituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-N(R 3 )-, substituted N(R 3 )2-(C1-C4 alkylene)-N(R 3 )-, and substituted N(R 3 )2-(C1-C4 alkylene)-O- is independently substituted by 1, 2 or 3 R 1c substituted; the heteroatoms in the 5-10 membered heteroaryl are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; the 3-10 membered heterocyclic group is a saturated or unsaturated 3-10 membered heterocyclic group, wherein the heteroatoms are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each R 1a and R 1c are independently F, Cl, Br, I, OH, N(R 3 )2, CN, COOH, CON(R 3 )2、SO2N(R 3 2. C 1-3 Alkyl, or C 1-3 Alkyl-O-, wherein the C 1-3 Alkyl, and C 1-3 Alkyl-O- is optionally substituted with 1, 2 or 3 R 1b replace; Each R 1b are independently F, Cl, Br, I, OH or NH2; Each R 3 are independently hydrogen or unsubstituted C 1-4 alkyl; L is absent; X is N, Y is N or C (R 4 ); M is C, CH or N; Z 1 , Z 2 and Z 3 Each independently is N, N(R 4 )、C(H)(R 4 )、C(R 4 ), -(C=O)-; R 4 is hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, the substituted C 1-4 Alkyl and substituted C 3-6 Cycloalkyl is independently substituted by 1, 2 or 3 R 1b replace.

2. The aromatic heterocyclic compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt, stereoisomer, or racemate, characterized in that: The aromatic heterocyclic compound as shown in Formula I is Among them, Z 1 , Z 2 and Z 3 Each independently is N or C(R 4 ), R 4 is hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, the substituted C 1-4 Alkyl is independently substituted by 1, 2 or 3 R 1b Substitute, where each R 1b are independently F, Cl or Br; W 1 and W 2 are each independently N, C(H) or C(R a ), where R a Can be F, Cl, Br, I or C 1-3 alkyl; R 1 , R 2 and L as described in claim 1.

3. The aromatic heterocyclic compound as shown in formula I as claimed in claim 1 or 2, or its pharmaceutically acceptable salt, stereoisomer, racemate, characterized in that: The aromatic heterocyclic compound shown in Formula I is as follows: Among them, W 1 and W 2 are each independently N, C(H) or C(R a ), where R a is F, Cl, Br, I or C 1-3 alkyl; Z 1 N(R 4 ); Z 2 is -(C=O)-; Z 3 N or C (R 4 ); R 4 are independently hydrogen, substituted or unsubstituted C 1-4 Alkyl, the substituted C 1-4 Alkyl is independently substituted by 1, 2 or 3 R 1b Substitute, where each R 1b are independently F, Cl or Br; R 1 , R 2 , L, X and Y as described in claim 1.

4. The aromatic heterocyclic compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt, stereoisomer, or racemate, characterized in that: The aromatic heterocyclic compound shown in Formula I is as follows: Among them, W 1 and W 2 are each independently N, C(H) or C(R a ), where R a is F, Cl, Br, I or C 1-3 alkyl; Z 1 , Z 2 and Z 3 Each independently is N(R 4 ) or C(H)(R 4 );R 4 are independently hydrogen, halogen, substituted or unsubstituted C 1-4 Alkyl, the substituted C 1-4 Alkyl is independently substituted by 1, 2 or 3 R 1b Substitute, where each R 1b are independently F, Cl or Br; R 1 , R 2 and L as described in claim 1.

5. The aromatic heterocyclic compound as shown in formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof, characterized in that: R 2 N(R 3 )2 substituted 3-10 membered heterocyclic group or unsubstituted 3-10 membered heterocyclic group containing 1, 2 or 3 N atoms, substituted or unsubstituted 3-10 membered heterocyclic group-N(R 3 )-, substituted or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-N(R 3 )-, or N(R 3 )2 substituted 3-10 membered heterocyclyl or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O- containing 1, 2 or 3 N atoms; wherein the substituted 3-10 membered heterocyclyl-N(R 3 )-, substituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-N(R 3 )-is independently 1, 2 or 3 R 1c Substitution; 3-10 membered heterocyclic group is a saturated or unsaturated 3-10 membered heterocyclic group, wherein the heteroatom is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; R 3 and R c As described in claim 1.

6. The aromatic heterocyclic compound of formula I as claimed in claim 5, or its pharmaceutically acceptable salt, stereoisomer, racemate, characterized in that: R 2 The 3-10 membered heterocyclic group is selected from the following groups:

7. The aromatic heterocyclic compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt, stereoisomer, or racemate, characterized in that: The aromatic heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, stereoisomer, racemate satisfies one or more of the following conditions: (1) A is W 1 is C(H), and W 2 N, C(H) or C(R a ), where R a is F, Cl, Br or I; (2)R 1 is substituted or unsubstituted C6-C 10 aryl or substituted or unsubstituted 5-10 membered heteroaryl; wherein the substituted C6-C 10 Aryl and substituted 5-10 membered heteroaryl are independently substituted by 1, 2 or 3 R 1a Replacement; R 1a As claimed in claim 1; (3)R 2 N(R 3 )2 substituted or unsubstituted 3-10 membered heterocyclic group containing 1, 2 or 3 N atoms, substituted or unsubstituted 3-10 membered heterocyclic group-(C1-C4 alkylene)-N(R 3 )-、N(R 3 )2 substituted 3-10 membered heterocyclyl or unsubstituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-O- containing 1, 2 or 3 N atoms; wherein the substituted 3-10 membered heterocyclyl-(C1-C4 alkylene)-N(R 3 )-is independently 1, 2 or 3 R 1c substituted; 3-10 membered heterocyclic group is a saturated or unsaturated 3-10 membered heterocyclic group, wherein the heteroatom is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; R 3 and R 1c As claimed in claim 1; (4) Each R 1a and R 1c are independently F, Cl, OH, N(R 3 )2、SO2N(R 3 2. C 1-3 Alkyl or C 1-3 Alkyl-O-; (5) Each R 1b independently F or NH2; (6)R 3 is hydrogen or unsubstituted C 1-4 alkyl; (7) X and Y are N; (8) Z 1 , Z 2 and Z 3 are independently N, C(H)(R 4 ) or C(R 4 ); (9)R 4 is hydrogen or halogen.

8. The aromatic heterocyclic compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt, stereoisomer, or racemate, characterized in that: The aromatic heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, stereoisomer, racemate satisfies one or more of the following conditions: (1)R 1 for (2) A is (3) for (4)R 2 for 9. The aromatic heterocyclic compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt, stereoisomer, or racemate, wherein: The aromatic heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, stereoisomer, racemate satisfies one or more of the following conditions: (1)R 1 for (2) for (3)R 2 for (4)R 4 is H, F or methyl.

10. The aromatic heterocyclic compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer or racemate thereof, characterized in that: The aromatic heterocyclic compound as shown in formula I is selected from the following group:

11. A pharmaceutical composition comprising a therapeutically effective amount of substance A and a pharmaceutically acceptable carrier, characterized in that: The substance A is one or more of the aromatic heterocyclic compound represented by formula I as described in any one of claims 1 to 10, or its pharmaceutically acceptable salts, stereoisomers, and racemates.

12. Use of substance A in the preparation of LSD1 inhibitors, characterized in that: The substance A is one or more of the aromatic heterocyclic compound represented by formula I as described in any one of claims 1 to 10, or its pharmaceutically acceptable salts, stereoisomers, and racemates.

13. Use of substance A in preparing medicine, characterized in that: The substance A is one or more of the aromatic heterocyclic compound represented by formula I as described in any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof; The medicine is a medicine for treating or preventing LSD1-mediated diseases or cancers.

14. The use according to claim 13, characterized in that The LSD1-mediated disease is cancer; The cancer is selected from one or more of bladder cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, liver cancer, colon cancer, rectal cancer, esophageal cancer, cervical cancer, ovarian cancer, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute T-cell leukemia, chondrosarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, large cell lymphoma, fibrosarcoma, testicular germ cell cancer, glioma, lymphoma, multiple myeloma, lymphoma, bone marrow cancer, neuroblastoma, neuroblastoma, non-small cell lung cancer, and small cell lung cancer.

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