Substituted pyrimidine ring inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a substituted aminopyrimidine ring inhibitor as well as a preparation method and application thereof. Specifically, the compound has a structure as shown in a formula (I0), the invention further discloses a preparation method of the compound and application of the compound as a KRAS mutation inhibitor, and the compound has a very good inhibition effect on KRAS mutation and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a substituted pyrimidocyclic inhibitor and a preparation method and application thereof. Background Art

[0002] About a quarter of all human tumors are caused by RAS mutations, and nearly one million people lose their lives each year. In the RAS family, KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mainly non-small cell lung cancer).

[0003] KRAS protein is a small GTPase encoded by the KRAS gene and is an important regulatory protein for cell growth. Once KRAS is activated, it can activate multiple signaling pathways and promote cell proliferation. The most common sites for gene mutations in KRAS protein are codons 12, 13, and 61, among which mutations in codon 12 are the most common. The most important mutations in KRAS G12 mutations are G12A, G12C, G12D, G12V, G12S, etc., among which G12C, G12D, G12V, etc. mutations mainly occur in NSCLC, CRC, and pancreatic cancer. So far, there are still no drugs approved for marketing that target multiple KRAS mutations at the same time.

[0004] Since KRAS mutant target proteins are pathologically associated with a variety of diseases, especially lung cancer, pancreatic cancer, colorectal cancer, etc., new KRAS mutant inhibitors are currently needed for clinical treatment. Highly active KRAS mutant inhibitors can more effectively treat diseases such as cancer caused by KRAS mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need. Summary of the invention

[0005] The object of the present invention is to provide a novel class of compounds having an inhibitory effect on KRAS mutation and / or better pharmacodynamic properties and uses thereof.

[0006] In the first aspect of the present invention, there is provided a compound of formula (I0), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs

[0007]

[0008] In the formula,

[0009] Select from the following group:

[0010] In another preferred embodiment, a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug is provided:

[0011]

[0012] in,

[0013] Select from the following group: Preferably, Select from the following group:

[0014] In another preferred embodiment, ring B is selected from the following substituted or unsubstituted groups: C6-C 14 Aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more R;

[0015] R 1a are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C 10 Alkyl, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclic C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0016] R 1b are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C1-C 10 Alkoxy C1-C6 alkylene, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclic C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0017] R 1c Independently selected from the following substituted or unsubstituted groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C1-C 10 Alkoxy C1-C6 alkylene, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclic C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0018] or R 1a and R 1c Connected to form 4-7 membered rings;

[0019] R 2 Selected from the following substituted or unsubstituted groups: C6-C 14 Aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more R;

[0020] R 3 Each is independently selected from the following substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R;

[0021] m is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0022] X is selected from: bond, O, NH, N(C1-C3 alkyl), C≡C;

[0023] Y is selected from: a bond, a substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0024] 1) Z is selected from:

[0025] Wherein, ring W1 is selected from the following substituted or unsubstituted groups: C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0026] R 4Selected from: H, deuterium, alkenyl, fluoroalkenyl, ethynyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, (C3-C6 cycloalkyl)C1-C6 alkyl, (4-6 membered heterocyclyl)C1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C3-C6 cycloalkyloxy)C1-C6 alkyl, (4-6 membered heterocyclyloxy)C1-C6 alkyl, (C1-C6 alkyl)vinyl, deuterated (C1-C6 alkyl) )vinyl, halogenated (C1-C6 alkyl)vinyl, (C1-C6 alkyl)ethynyl, deuterated (C1-C6 alkyl)ethynyl, halogenated (C1-C6 alkyl)ethynyl, (C3-C6 cycloalkyl)ethynyl, (4-6 membered heterocyclyl)ethynyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, halogen, nitro, hydroxy, oxo (═O), cyano, ester, amine, amide, sulfone or urea;

[0027] n is an integer selected from: 0, 1, 2, 3, 4, 5 or 6;

[0028] or

[0029] 2) Z is selected from: -L4-Q2 or

[0030] Wherein, ring W2 is selected from the following group of substituted or unsubstituted groups: C3-C6 cycloalkylene, 4-6 membered saturated or unsaturated heterocyclylene; wherein, the substitution refers to substitution by one or more R;

[0031] Each L4 is independently selected from the group consisting of a substituted or unsubstituted bond, a C1-C6 alkylene group, and a deuterated C1-C6 alkylene group; wherein the substitution refers to substitution by one or more R;

[0032] Each Q2 is independently selected from the following groups: substituted or unsubstituted: C1-C6 alkoxy, C3-C 10 Cycloalkyloxy, 4-10 membered heterocyclyloxy, C3-C 10 Cycloalkyl C1-C6 alkyleneoxy, 4-10 membered heterocyclic C1-C6 alkyleneoxy, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, NHR 9 NR 9 R 10 ; R 9 and R 10 Each is independently selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, (C3-C10 cycloalkyl)C1-C6 alkylene, (4-10 membered heterocyclic)C1-C6 alkylene, or R 9 and R 10 The N atom connected thereto together forms a substituted or unsubstituted 4-10 membered heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0033] Each R is the same or different and is independently selected from the group consisting of: H, deuterium, alkenyl, fluoroalkenyl, ethynyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylene, halogenated C1-C6 alkylene, (C3-C6 cycloalkyl)C1-C6 alkyl, (4-6 membered heterocyclyl)C1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C3-C6 cycloalkyloxy)C1-C6 alkyl, (4-6 membered heterocyclyloxy)C1-C6 alkyl, (C1-C6 alkyl)vinyl , deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl (such as -C≡C-CH3), deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C6 cycloalkyl) ethynyl, (4-6 membered heterocyclyl) ethynyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 aryl, 5-10 membered heteroaryl, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amine, amide, sulfone or urea.

[0034] In another preferred embodiment, R 1a are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C 10 Alkyl, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclic C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; R 1b are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C1-C 10 Alkoxy C1-C6 alkylene, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclic C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; R 1cIndependently selected from the following substituted or unsubstituted groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C1-C 10 Alkoxy C1-C6 alkylene, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclyl C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; the remaining variables are as defined above.

[0035] In another preferred embodiment, the compound has a structure shown in formula (II-A) or formula (II-B):

[0036]

[0037] In the formula,

[0038] Ring B, R 1a , R 1b , R 1c , R 2 , R 3 , X, Y, Z and m are defined as above.

[0039] In another preferred embodiment, the compound has a structure shown by formula (III-A1), formula (III-A2) or formula (III-B1), formula (III-B2):

[0040]

[0041] In the formula, ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , X, Y, W1, W2, L4, Q2, m and n are defined as above.

[0042] In another preferred embodiment, the compound has a structure represented by formula (III-A1) or formula (III-B1).

[0043] In another preferred embodiment, X is O.

[0044] In another preferred embodiment, the compound has a structure shown by formula (IV-A1), formula (IV-A2) or formula (IV-B1), formula (IV-B2):

[0045]

[0046]

[0047] In the formula,

[0048] Ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , Y, W1, W2, L4, Q2, m and n are defined as above.

[0049] In another preferred embodiment, the compound has a structure shown by formula (IV-A1) or formula (IV-B1).

[0050] In another preferred embodiment, R 1a C1-C 10 Alkyl; R 1b is hydrogen; and R 1c C1-C 10 Alkyl; preferably, R 1a is a C1-C4 alkyl group; R 1b is hydrogen; and R 1c is C1-C4 alkyl; more preferably, R 1a is methyl; R 1b is hydrogen; and R 1c It is methyl.

[0051] In another preferred embodiment, the compound has a structure shown by formula (V-A1), formula (V-A2) or formula (V-B1), formula (V-B2):

[0052]

[0053] In the formula, ring B, R 2 , R 3 , R 4 , Y, W1, W2, L4, Q2, m and n are as defined in claim 1;

[0054] In another preferred embodiment, the compound has a structure represented by formula (V-A1) or formula (V-B1).

[0055] In another preferred embodiment, the compound has a structure represented by formula (VI-A1) or formula (VI-B1):

[0056]

[0057] In the formula, ring B, R 2 , R 3 , m and n are as defined in claim 1, each R 5 are the same or different and are each independently selected from hydrogen or deuterium.

[0058] In another preferred embodiment, the compound has a structure shown in formula (VII-A1) or formula (VII-B1):

[0059]

[0060] In the formula,

[0061] P 1 , P 2 , P 3 Each independently selected from CH, CF, C-Cl, C-CN, C-CF 3 , or N;

[0062] Ring B, R 1a , R 1b , R 1c , R 3 , R 4 , X, Y, W1, W2, L4, Q2, m and n are defined as in claim 1;

[0063] In another preferred embodiment, the compound has a structure shown in formula (VII-B1).

[0064] In another preferred embodiment, Y is CH2 or CD2.

[0065] In another preferred embodiment, for and / or for

[0066] In another preferred embodiment, R 3 The same or different, each independently selected from the following group: H, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy.

[0067] In another preferred embodiment, W1 is selected from: substituted or unsubstituted 4-7 membered monocyclic heterocyclic group, substituted or unsubstituted C3-C7 monocyclic cycloalkyl group, substituted or unsubstituted 6-10 membered bicyclic heterocyclic group, substituted or unsubstituted C6-C 10 bicyclic cycloalkyl, substituted or unsubstituted 7-12 membered tricyclic heterocyclic group, substituted or unsubstituted C7-C 12 tricyclic cycloalkyl, preferably, W1 is a substituted or unsubstituted 8-12 membered N-containing heterocyclic group, wherein the substitution refers to substitution by one or more R, and R is defined as above;

[0068] Preferably, Selected from:

[0069]

[0070]

[0071] wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R 4 and n are defined as above, R, R 4 It can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring);

[0072] More preferably, Selected from:

[0073]

[0074] wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, R 4 and n are as defined above, and R may be substituted on any one of the polycyclic (eg, bridged or spiro) rings.

[0075] In another preferred embodiment, Selected from:

[0076] Or choose from:

[0077]

[0078] wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R 4 and n are defined as above, R, R 4 It can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring);

[0079] More preferably, Selected from:

[0080]

[0081] wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, R 4 and n are as defined above, and R may be substituted on any one of the polycyclic (eg, bridged or spiro) rings.

[0082] In another preferred embodiment, for Preferably, each R is independently hydrogen or deuterium.

[0083] In another preferred embodiment, L4 is selected from: bond, CH2, CD2, CH(CH3).

[0084] In another preferred embodiment, Q2 is selected from: NHCH3, N(CH3)2,

[0085] In another preferred embodiment, Selected from:

[0086] In another preferred embodiment, for Preferably, Selected from:

[0087]

[0088] In another preferred embodiment, R 2 is selected from the following substituted or unsubstituted groups: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyridyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following groups: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl (such as ethynyl or propynyl), ester, amine, amide, sulfone, urea, sulfonamide, C3-C6 cycloalkyl O-, 4-6 membered heterocyclyl O-, C3-C6 cycloalkyl OH (hydroxy substituted C3-C6 cycloalkyl), 4-6 membered heterocyclyl OH (hydroxy substituted 4-6 membered heterocyclyl); preferably, R 2 Selected from:

[0089]

[0090] Or choose from:

[0091]

[0092] Or choose from:

[0093]

[0094] Or choose from:

[0095]

[0096] In another preferred embodiment, R 2 is selected from the group consisting of substituted or unsubstituted phenyl, 5-6 membered monocyclic heteroaryl (preferably the 5-6 membered monocyclic heteroaryl contains only 1, 2 or 3 nitrogen as heteroatoms, such as pyridyl), or naphthyl, wherein the substitution is as defined above.

[0097] In another preferred embodiment, when R 2 If the carbon that is connected to the rest of the molecule is a chiral carbon, then the chiral carbon is in the R configuration or the S configuration.

[0098] In another preferred embodiment, ring B is selected from the following substituted or unsubstituted groups: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C 1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, ester, amine, amide, sulfone, urea, sulfonamide, C3-C6 cycloalkyl O-, 4-6 membered heterocyclyl O-, C3-C6 cycloalkyl OH (hydroxy substituted C3-C6 cycloalkyl), 4-6 membered heterocyclyl OH (hydroxy substituted 4-6 membered heterocyclyl); preferably, ring B is selected from:

[0099]

[0100]

[0101] In another preferred embodiment, ring B is selected from the following substituted groups: phenyl, 6-membered monocyclic heteroaryl (such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl); and the substitution refers to being substituted by one NH2 (preferably, the NH2 is substituted at the ortho position where the phenyl or 6-membered monocyclic heteroaryl ring B is connected to the rest of the molecule) and optionally one or more substituents selected from the following group: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 ring Alkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, ester, amine, amide, sulfone, urea, sulfonamide, C3-C6 cycloalkyl O-, 4-6 membered heterocyclyl O-, C3-C6 cycloalkyl OH, 4-6 membered heterocyclyl OH; preferably, the substitution refers to substitution with one NH2 and 0 or one or more substituents selected from the following group: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy.

[0102] In another preferred embodiment, ring B is selected from:

[0103]

[0104]

[0105] In another preferred embodiment, R 1ais selected from the following group: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogenated C3-C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, C1-C6 alkoxy C1-C6 alkylene, halogenated C1-C6 alkoxy C1-C6 alkylene, C3-C6 cycloalkyl C1-C6 alkylene, 4-6 membered heterocyclyl C1-C6 alkylene; preferably, R 1a is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CH2cyclopropyl, CH2CH2OCH3, CH(CH3)CH2OCH3. More preferably, R 1a Selected from the group consisting of methyl, ethyl.

[0106] In another preferred embodiment, R 1b is independently selected from the following group: H, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogenated C3-C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, C1-C6 alkoxy C1-C6 alkylene, halogenated C1-C6 alkoxy C1-C6 alkylene, C3-C6 cycloalkyl C1-C6 alkylene, 4-6 membered heterocyclyl C1-C6 alkylene; preferably, R 1b is independently selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl. More preferably, R 1b For H.

[0107] In another preferred embodiment, R 1c is independently selected from the following group: C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogenated C3-C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, C1-C6 alkoxy C1-C6 alkylene, halogenated C1-C6 alkoxy C1-C6 alkylene, C3-C6 cycloalkyl C1-C6 alkylene, 4-6 membered heterocyclyl C1-C6 alkylene; preferably, R 1c is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, oxetanyl. More preferably, R 1c It is a C1-C6 alkyl group (such as methyl, ethyl).

[0108] In another preferred embodiment, R 1a Selected from the group consisting of methyl, ethyl, R 1b Selected from H, and R 1c Selected from methyl.

[0109] In another preferred embodiment, when R 1b and R 1c If different, then R 1b and R 1cThe attached carbon is in the R configuration or the S configuration.

[0110] In another preferred embodiment, ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , X, Y, W1, W2, L4, Q2, m and n have the groups corresponding to the specific compounds in the embodiments.

[0111] In another preferred embodiment, the compound is selected from the following group:

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119] Or choose from:

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] Or choose from:

[0129] Or choose from:

[0130] Or choose from:

[0131]

[0132]

[0133] Or choose from:

[0134] Or choose from:

[0135]

[0136]

[0137]

[0138] Or choose from:

[0139]

[0140]

[0141]

[0142]

[0143] Or choose from:

[0144]

[0145] Or choose from:

[0146]

[0147]

[0148] Or choose from:

[0149] Or choose from:

[0150]

[0151]

[0152] Or choose from:

[0153]

[0154]

[0155] Or choose from:

[0156]

[0157]

[0158]

[0159]

[0160] In another preferred embodiment, the compound is preferably the compound prepared in the examples.

[0161] In a second aspect, the present invention provides a method for preparing a compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, characterized in that it comprises the steps of:

[0162]

[0163] (i) reacting a compound of formula XI with a compound of formula X-II in an inert solvent in the presence of a base, with or without a Pd catalyst, with or without a condensing agent to obtain a compound of formula X-III;

[0164] (ii) reacting a compound of formula X-III with a compound of formula X-IV in an inert solvent in the presence of a base and in the presence of Pd or other metal catalyst to obtain a compound of formula XV;

[0165] (iii) reacting a compound of formula XV with a compound of formula X-VI in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula I;

[0166] LG1, LG2, LG3, LG4, and LG5 are leaving groups, each independently selected from: H, OH, halogen, OTf, OTs, OMs, -B(OH)2, -B(KBF3), -Sn( n Bu)3. wait;

[0167] The Pd catalyst is selected from: Pd(OAc)2, Pd(dba)2, Pd2(dba)3, XPhos PdG2, RuPhos PdG2, XantPhos-Pd-G2, cataCXium A-Pd-G2, XPhos PdG3, RuPhos PdG3, PdG3, SPhos PdG3, tBuXPhos-Pd-G3, XantPhos-Pd-G4, BrettPhos PG4, SPhos PdG4, cataCXium A-Pd-G4, Rockphos PdG4, etc.;

[0168] R 1a , R 1b , R 1c, R 2 , R 3 , Ring A, Ring B, X, Y, Z, and m are as defined above.

[0169] The third aspect of the present invention provides a pharmaceutical composition comprising one or more compounds described in the first aspect, their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and a pharmaceutically acceptable carrier.

[0170] In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the following group: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomabtiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Oclatinib), PI3K inhibitors (such as Idelalisib, D uvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rocieletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib,Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), SOS1 inhibitors (such as BI1701963) or their combinations.

[0171] In a fourth aspect, the present invention provides a use of the compound as described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described in the third aspect, for preparing a drug for preventing and / or treating a disease associated with the activity or expression of KRAS mutations, preferably, the disease is a tumor or a disorder.

[0172] In another preferred embodiment, the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

[0173] In another preferred embodiment, the KRAS mutation is selected from the following group: G12D, G12V, G12R, G12S, G12A, G12C, or a combination thereof. Preferably, the KRAS mutation is selected from the following group: G12D, G12V, G12R, or a combination thereof. More preferably, the KRAS mutation is G12V.

[0174] In a fifth aspect, the present invention provides a non-diagnostic, non-therapeutic method for inhibiting KRAS mutation, comprising the steps of administering to a subject in need thereof an effective amount of the compound as described in the first aspect, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition as described in the third aspect.

[0175] In another preferred embodiment, the subject is a mammal, preferably a human.

[0176] In a sixth aspect, the present invention provides an in vitro method for inhibiting the activity of KRAS mutants, comprising the steps of contacting the compound as described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described in the third aspect with proteins or cells, thereby inhibiting the activity of KRAS mutants.

[0177] In another preferred embodiment, the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.

[0178] In another preferred embodiment, the cells are from rodents (such as mice and rats) or primates (such as humans).

[0179] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0180] After long-term and in-depth research, the inventor unexpectedly prepared a new type of compound with inhibitory effect on KRAS mutation and / or better pharmacodynamic performance. On this basis, the inventor completed the present invention.

[0181] the term

[0182] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0183] The term "alkyl" refers to a straight or branched alkane group or a cyclic hydrocarbon group (including hydrocarbon groups connected to other parts through carbon atoms on the ring or non-ring), preferably a straight or branched alkane group, containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms (C1-C10), more preferably 1-6 carbon atoms (C1-C6). Typical "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. In the present invention, alkyl also includes substituted alkyl. "Substituted alkyl" means that one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl3), nitrile, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R amay independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e It can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring can be optionally substituted.

[0184] The term "alkylene" refers to a group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, such as methylene (eg or -CH2-), ethylene (such as ), propylene (such as ), isopropylidene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as ), In addition, the term also includes a methylene group of an alkylene group (such as C1-C18 alkylene group) replaced by a cycloalkylene group (such as C3-C20 cycloalkylene group), for example, "C1-C18 alkylene group C3-C20 cycloalkylene group" or "C3-C20 cycloalkylene group C1-C18 alkylene group". In the present invention, alkylene group also includes substituted alkylene group, and the substituent group can be halogenated (such as -CHF- or -CF2-), hydroxyl, cyano, nitro, etc.

[0185] The term "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning and refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, such as etc. Preferably C1-C6 alkylene C3-C6 cycloalkylene. In the present invention, "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" also includes substituted "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene", and the substituent may be halogen, hydroxyl, cyano, nitro, etc.

[0186] In the present invention, the term "alkenyl" means a straight or branched hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. Alkenyl is preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl. In the present invention, alkenyl also includes substituted alkenyl, and the substituent can be halo, hydroxyl, cyano, nitro, etc.

[0187] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. Alkynyl is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. Alkynyl includes, but is not limited to, ethynyl, propynyl or similar groups. In the present invention, alkynyl also includes substituted alkynyl, and the substituent may be halo, hydroxyl, cyano, nitro, etc.

[0188] In the present invention, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms. 20 " refers to a cycloalkyl group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The cycloalkyl group is preferably C3-C 14 Cycloalkyl, more preferably C3-C 10 Cycloalkyl, more preferably C3-C6 monocyclic cycloalkyl, C7-C 10 Bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" means that one or more positions in the cycloalkyl are substituted, especially 1-4 substituents, which can be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl, and typical substitutions include but are not limited to one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl3), nitrile, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, OR a , SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e 、P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NRb R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R a R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl or heteroaryl. b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic radical, aryl or heteroaryl. The above typical substituents can be optionally substituted. Typical substitutions also include spirocyclic, pyrimidinyl and cyclocyclic or condensed ring substituents, especially spirocyclic alkyl, spirocyclic alkenyl, spirocyclic heterocyclic (excluding heteroaromatic ring), pyrimidinyl and cycloalkyl, pyrimidinyl and cycloalkenyl, pyrimidinyl and cyclocyclic heterocyclic (excluding heteroaromatic ring), condensed cycloalkyl, condensed cycloalkenyl, condensed ring heterocyclic radical or condensed ring aromatic ring radical, the above cycloalkyl, cycloalkenyl, heterocyclic radical and heteroaryl can be optionally substituted. The example of cycloalkyl includes but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl etc.

[0189] The term "C3-C20 cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: wait.

[0190] In the present invention, the term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic or 8-16 membered tricyclic or polycyclic system), wherein at least one heteroatom is present in the ring having at least one carbon atom. The term "4-20 membered heterocyclyl" refers to a heterocyclyl containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms. "Heterocyclyl" has the same meaning as "saturated or unsaturated heterocyclyl". "Heterocyclyl" is preferably a 4-14 membered heterocyclyl (including but not limited to a 4-6 membered monocyclic, 7-10 membered bicyclic or 8-14 membered tricyclic or polycyclic system), more preferably a 4-12 membered heterocyclyl, more preferably a 4-10 membered heterocyclyl, such as a 4-6 membered monocyclic heterocyclyl, a 7-11 membered bicyclic or tricyclic heterocyclyl, more preferably a 4-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl. Each heterocyclic ring containing heteroatoms may have 1, 2, 3 or 4 heteroatoms, each of which is independently selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen atom or the sulfur atom may be oxidized, and the nitrogen atom may also be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule, preferably to an N or C atom on the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl and tetrahydro-1,1-dioxythiophene, and the like. The polycyclic heterocyclic group includes spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0191] The term "4-20 membered heterocyclylene" refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as: wait.

[0192] In the present invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially a monocyclic and bicyclic group. 14 "Aryl" refers to an aromatic cyclic hydrocarbon compound radical containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Aryl is preferably C6-C 10 Aryl. Aryl includes phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl3), cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, OR a , SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e 、P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NRb C(=O)R a , or NR b P(=O)2R e , where R a may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aryl, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic radical or aryl. The above typical substituents can be optionally substituted. Typical substitutions also include condensed ring substituents, especially condensed ring alkyl, condensed ring alkenyl, condensed ring heterocyclic radical or condensed ring aromatic ring radical, and the above cycloalkyl, cycloalkenyl, heterocyclic radical and heterocyclic aryl can be optionally substituted.

[0193] The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1 to 4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Among them, "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms. The heteroaryl is preferably 5 to 10 rings, more preferably 5 or 6, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0194] In the present invention, the term "alkoxy" refers to a straight chain or branched alkoxy group, including alkyl-O-, alkyl-O-alkyl, wherein "C1-C 18 "Alkoxy" refers to a straight or branched chain alkoxy group having 1 to 18 carbon atoms, including C1-C 18 Alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably it is C1-C8 alkoxy, more preferably C1-C6 alkoxy.

[0195] In the present invention, the term "cycloalkyloxy" refers to cycloalkyl-O-, wherein "C3-C 20 "Cycloalkyloxy" refers to C3-C 20Cycloalkyl-O-, wherein C3-C 20 Cycloalkyl is as defined above.

[0196] In the present invention, the term "heterocyclyloxy" refers to heterocyclyl-O-, wherein "4-20 membered heterocyclyloxy" refers to 4-20 membered heterocyclyl-O-, wherein the 4-20 membered heterocyclyl is as defined above.

[0197] In the present invention, the term "C1-C 18 "Alkyleneoxy" refers to "C1-C 18 Alkoxy is a group obtained by removing a hydrogen atom.

[0198] In the present invention, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, and iodine.

[0199] In the present invention, the term "halogenated" means substituted with halogen.

[0200] In the present invention, the term "deuterated" means substituted with deuterium.

[0201] In the present invention, the term "hydroxyl" refers to a group having the structure OH.

[0202] In the present invention, the term "nitro" refers to a group having the structure NO2.

[0203] In the present invention, the term "cyano group" refers to a group having the structure CN.

[0204] In the present invention, the term "ester group" refers to a group with the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle. The ester group is preferably -COO C1-C6 alkyl.

[0205] The term "amine group" refers to a group with the structure -NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment. The amine group is preferably NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2.

[0206] The term "amido" refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment. The amide group is preferably CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl).

[0207] The term "sulfone group" refers to a group with the structure -SO2R, wherein R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclic or substituted heterocyclic, as defined above. The sulfone group is preferably -SO2C1-C6 alkyl.

[0208] The term "sulfonamide" refers to a group with the structure -SO2NRR', wherein R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, as defined above. Sulfonamide is preferably -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(C3-C6 cycloalkyl).

[0209] The term "urea group" refers to a group having the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, as defined above. R, R' and R" can be the same or different in the dialkylamine fragment. Urea groups are preferably -NHCONH2, -NHCONH(C1-C6 alkyl).

[0210] The term "alkylaminoalkyl" refers to a group with the structure -RNHR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, as defined above. R and R' can be the same or different. Alkylaminoalkyl is preferably -C1-C6 alkyleneNHC1-C6 alkyl.

[0211] The term "dialkylaminoalkyl" refers to a group with the structure -RNHR'R", wherein R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, as defined above. R, R' and R" can be the same or different in the dialkylamino fragment. The dialkylaminoalkyl is preferably -C1-C6 alkylene N(C1-C6 alkyl)2.

[0212] The term "heterocyclylalkyl" refers to a group with the structure -RR', wherein R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.

[0213] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 urea group, etc.

[0214] Unless otherwise stated, any heteroatom with unsatisfied valence is assumed to have sufficient hydrogen atoms to complete its valence.

[0215] When a substituent is a non-terminal substituent, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

[0216] In the present invention, a plurality refers to 2, 3, 4, or 5.

[0217] Active ingredients

[0218] As used herein, "compounds of the present invention" refers to compounds represented by formula I0, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of formula I0.

[0219] The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included in the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps in the preparation process. The compounds of the present invention may form salts, for example, Compound I reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution.

[0220] The compounds of the present invention contain basic fragments, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide

[0013] The invention also includes but is not limited to the following: esters, isothioates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonates, dodecanoates, and the like.

[0221] Some compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromides), etc.

[0222] Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention. The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease. The compounds of the present invention include solvates, such as hydrates.

[0223] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All these tautomers are part of the present invention.

[0224] All stereoisomers of the compounds (e.g., those due to asymmetric carbon atoms that may exist for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have two configurations, S or R, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereoisomers derived therefrom, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.

[0225] The compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.

[0226] All configurational isomers of the compounds of the present invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0227] Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

[0228] Specific functional groups and chemical term definitions are detailed below. For purposes of this invention, chemical elements are referred to as Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

[0229] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

[0230] According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by ordinary technicians in this profession, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

[0231] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number than the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2H, due to its good metabolic stability in certain therapies has advantages, such as increasing half-life or reducing dosage in vivo, therefore, in some cases, it can be preferred. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents using the schemes disclosed in the examples.

[0232] If a synthesis of a specific enantiomer of the compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.

[0233] As described herein, the compounds of the present invention can be replaced with any number of substituents or functional groups to expand its scope. Generally, the term "substituted" appears before or after the term "optional", and the general formula including substituents in the formulation of the present invention refers to the use of a specified structural substituent to replace the hydrogen free radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position. The term "substituted" used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence. In addition, the present invention is not intended to limit the allowed substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases. As used herein, the term "stable" refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0234] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0235] Preparation method

[0236] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any restriction to the present invention. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by those skilled in the art to which the present invention belongs.

[0237] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0238] Preferably, the compounds of the present invention are prepared by the following method:

[0239]

[0240] (i) reacting a compound of formula XI with a compound of formula X-II in an inert solvent in the presence of a base, with or without a Pd catalyst, with or without a condensing agent to obtain a compound of formula X-III;

[0241] (ii) reacting a compound of formula X-III with a compound of formula X-IV in an inert solvent in the presence of a base and in the presence of Pd or other metal catalyst to obtain a compound of formula XV;

[0242] (iii) reacting a compound of formula XV with a compound of formula X-VI in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula I;

[0243] LG1, LG2, LG3, LG4, and LG5 are leaving groups, each independently selected from: H, OH, halogen, OTf, OTs, OMs, -B(OH)2, -B(KBF3), -Sn( n Bu)3. wait;

[0244] The Pd catalyst is selected from: Pd(OAc)2, Pd(dba)2, Pd2(dba)3, XPhos PdG2, RuPhos PdG2, XantPhos-Pd-G2, cataCXium A-Pd-G2, XPhos PdG3, RuPhos PdG3, PdG3, SPhos PdG3, tBuXPhos-Pd-G3, XantPhos-Pd-G4, BrettPhos PG4, SPhos PdG4, cataCXium A-Pd-G4, Rockphos PdG4, etc.;

[0245] R 1a, R 1b , R 1c , R 2 , R 3 , Ring A, Ring B, X, Y, Z, and m are as defined above.

[0246] Pharmaceutical compositions and methods of administration

[0247] The pharmaceutical composition of the present invention is used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0248] The compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of them taken alone.

[0249] The drugs or active ingredients that can be used in combination with the compounds of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomabtiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Oclatinib), PI3K inhibitors (such as Idela lisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rocieletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib,Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040)), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof. The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.

[0250] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0251] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0252] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0253] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0254] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0255] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0256] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0257] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0258] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0259] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0260] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0261] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0262] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the general formula (IA) and formula (IB) of the present invention or their crystal forms, pharmaceutically acceptable salts, hydrates or solvates, thereby forming a pharmaceutical composition.

[0263] The present invention also provides a treatment method, which comprises the steps of administering the compound of general formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition described in the present invention to a subject in need of treatment, for inhibiting KRAS mutation.

[0264] Compared with the prior art, the present invention has the following main advantages:

[0265] (1) The compound has a good inhibitory effect on KRAS mutation;

[0266] (2) The compound has better pharmacodynamics, pharmacokinetic properties and lower toxic side effects.

[0267] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0268] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0269] The structure of the compound of the present invention is confirmed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0270] NMR was detected using a Bruker AVANCE-400 nuclear magnetic spectrometer. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), etc. Tetramethylsilane (TMS) was used as the internal standard, and the chemical shift was measured in parts per million (ppm).

[0271] Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer, and HPLC was determined using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0272] The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

[0273] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0274] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

[0275] Example

[0276] Intermediate 1-1 Preparation of 3-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine hydrochloride

[0277]

[0278] Step 1: Preparation of 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one

[0279] DIEA (117 g, 912 mmol, 159 mL, 5.00 eq) and 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methylamine (70.5 g, 273 mmol, 1.50 eq) were added to a solution of 1-(2-chloropyridin-3-yl)ethane-1-one (28.4 g, 182 mmol, 1.00 eq) in dioxane (300 mL). The mixture was reacted at 110°C for 16 h, diluted with ice water (100 mL) and extracted with EtOAC (250 mL*2). The combined organic phase was washed with saturated brine (250 mL*2), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (24.3 g, 61.3 mmol, 33.6% yield).

[0280] 1 H NMR (400MHz, DMSO-d6) δ8.27(dd,J=4.69,1.81Hz,1H),7.84(dd,J=7.57,1.81Hz,1H ),7.04(d,J=8.63Hz,4H),6.71-6.93(m,5H),4.42(s,4H),3.71(s,6H)2.42(s,3H).

[0281] Step 2: Preparation of (R)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)vinyl)-2-methylpropane-2-sulfenamide

[0282] Ti(OEt)4(58.9g, 258mmol, 53.5mL, 4.00eq) and (R)-2-methylpropane-2-sulfenamide(11.7g, 96.8mmol, 1.50eq) were added to a solution of 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one(24.3g, 64.6mmol, 1.00eq) in THF(300mL). The mixture was reacted at 180℃ for 16h, diluted with ice water(100mL) and extracted with EtOAC(250mL*2). The combined organic phase was washed with saturated brine(250mL*2), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product(11.0g, 19.2mmol, 30.8% yield).

[0283] 1 H NMR (400MHz, DMSO-d6) δ8.24(dd,J=4.58,1.53Hz,1H),7.63(dd,J=7.40,1.53Hz,1H),7.04(br d,J=8.44Hz,4H),6.94(dd,J=7.40,4.83Hz,1H),6.84(d,J=8.56Hz,4H),4.22 -4.48(m,4H),3.71(s,6H),2.51(dt,J=3.48,1.68Hz,3H),1.11-1.25(m,9H).

[0284] Step 3: Preparation of (R)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfenamide

[0285] Under nitrogen protection, NaBH4 (670 mg, 17.7 mmol, 2.50 eq) was added to a mixed solution of (R)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)vinyl)-2-methylpropane-2-sulfinamide (11.0 g, 21.5 mmol, 1.00 eq) in THF (100 mL) and H2O (16 mL) at 0°C. The mixture was reacted at 25°C for 5 h, then quenched with saturated aqueous ammonium chloride solution (50 mL) at 0°C, and then extracted with EtOAc (100 mL*2). The combined organic phase was washed with saturated brine (60 mL*2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (3.40 g, 7.06 mmol, 32.8% yield).

[0286] 1H NMR (400MHz, DMSO-d6) δ8.13-8.26(m,1H),7.75-7.96(m,1H),7.18(dd,J=11.62,8.68Hz,4H),7.04-7.12(m,1H),6.83(d,J =8.56Hz,4H),5.36-5.55(m,1H),4.90-5.14(m,1H),3.99-4.23(m,4H),3.70(s,6H),1.21-1.40(m,3H),0.99-1.13(m,9H).

[0287] Step 4: Preparation of 3-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine hydrochloride

[0288] HCl / EtOAc (4M, 5.29 mL, 3.00 eq) was added to a solution of (R)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (3.40 g, 7.06 mmol, 1.00 eq) in EtOAc (40 mL). The mixture was reacted at 0°C for 5 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (2.20 g, 5.83 mmol, 82.6% yield).

[0289] LC-MS: m / z 378 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.80(br d,J=2.32Hz,3H),8.20-8.44(m,2H),7.29(dd,J=7.64,4.95Hz,1H),7.15(d,J=8.68 Hz, 4H), 6.86 (d, J = 8.68Hz, 4H), 4.08-4.24 (m, 4H), 3.72 (s, 6H), 1.28-1.41 (m, 3H).

[0290] The following compounds were synthesized using the same synthetic method as intermediate 1-1 with different starting materials:

[0291] Intermediate 1-2N,N-bis(4-methoxybenzyl)-3-(1-(methylamino)ethyl)pyridin-2-amine hydrochloride

[0292]

[0293] LC-MS: m / z 392 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.17(dd,J=4.62,1.98Hz,1H),7.78(dd,J=7.59,1.87Hz,1H),7.17(d,J=8.58Hz,4H),7.05(dd,J=7.59 ,4.73Hz,1H),6.84(d,J=8.58Hz,4H),4.13-4.21(m,1H),4.05-4.12(m,4H),3.70(s,6H),1.96(s,3H),1.14(d,J=6.60Hz,3H).

[0294] Intermediate 1-2 was subjected to SFC chiral separation (chiral column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 um); mobile phase: CO2-EtOH (0.1% NH3H2O); B%: 30%-100%, 200 min) to obtain isomers 1-2A and 1-2B.

[0295] Intermediate 1-2A (S)-N,N-bis(4-methoxybenzyl)-3-(1-(methylamino)ethyl)pyridin-2-amine hydrochloride

[0296]

[0297] RT: 3.568min. LC-MS: m / z 392(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.17(dd,J=4.63,1.88Hz,1H),7.79(dd,J=7.63,1.75Hz,1H),7.17(d,J=8.63Hz,4H),7.0 5(dd,J=7.57,4.69Hz,1H),6.84(d,J=8.50Hz,4H),4.12(m,5H),3.70(s,6H),1.97(s,3H),1.14(d,J=6.38Hz,3H).

[0298] Intermediate 1-2B (R)-N,N-bis(4-methoxybenzyl)-3-(1-(methylamino)ethyl)pyridin-2-amine hydrochloride

[0299]

[0300] RT: 3.870min. LC-MS: m / z 392(M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.21(dd,J=4.63,1.88Hz,1H),7.83(dd,J=7.63,1.75Hz,1H),7.16(d,J=8.63Hz,4H),7.09(dd,J=7.6 3,4.75Hz,1H),6.84(d,J=8.63Hz,4H),4.25(q,J=6.46Hz,1H),4.10(m,4H),3.70(s,6H),1.99(s,3H),1.17(d,J=6.50Hz,3H).

[0301] Intermediate 1-3N,N-bis(4-methoxybenzyl)-5-(1-(methylamino)ethyl)pyrimidin-4-amine hydrochloride

[0302]

[0303] LC-MS: m / z 393 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=6.11Hz,2H),7.14(d,J=8.68Hz,4H),6.89(d,J=8.68Hz,4H )4.41-4.63(m,4H),3.77(d,J=6.48Hz,1H),3.73(s,6H),2.00(s,3H),1.28(d,J=6.60Hz,3H).

[0304] Intermediate 1-4 3-(1-(ethylamino)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine hydrochloride

[0305]

[0306] LC-MS: m / z 406 (M+H) + .

[0307] Intermediate 2-1 Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0308]

[0309] Step 1: Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-amine

[0310] At -40°C, 3-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (668 mg, 1.62 mmol, 1.02 eq, hydrochloride) and DIEA (614 mg, 4.75 mmol, 827 μL, 3.00 eq) were added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (400 mg, 1.58 mmol, 1.00 eq) in DCM (10 mL). The mixture was reacted at 25°C for 2 h, then quenched by adding H2O (50 mL) and extracted with EtOAc (100 mL*2). The combined organic phase was washed with saturated brine (60 mL*2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (0.750 g, 1.26 mmol, 79.7% yield).

[0311] 1 H NMR(400MHz,DMSO-d6)δ9.61(br d,J=6.97Hz,1H),9.34-9.47(m,1H),8.24(dd,J=4.77,1.71Hz,1H),7.82(dd,J=7.64,1.77Hz ,1H),7.25(d,J=8.68Hz,4H),7.08(dd,J=7.58,4.77Hz,1H),6.80(d,J=8.68Hz,4H),5.89(br t,J=6.79Hz,1H),4.21-4.42(m,4H),3.60-3.78(m,6H),1.45(d,J=6.85Hz,3H).

[0312] Step 2: Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0313] DIEA (489 mg, 3.79 mmol, 660 μL, 3.00 eq) was added to a solution of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-amine (0.750 g, 1.26 mmol, 1.00 eq) in CF3CH2OH (10 mL). The reaction solution was reacted at 70°C for 3 h, then concentrated under reduced pressure, and H2O (30 mL) was added to the residue, which was then extracted with EtOAc (25 mL*2). The combined organic phase was washed with saturated brine (25 mL*2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (0.770 g, 1.17 mmol, 92.7% yield).

[0314] LC-MS: m / z 657 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.37-9.55(m,2H),8.24(dd,J=4.71,1.77Hz,1H),7.86-7.97(m,1H),7.25(d,J=8.56Hz,3H),7.08(dd ,J=7.58,4.77Hz,1H),6.69-6.86(m,4H),4.89-5.10(m,2H),4.15-4.45(m,3H),3.62-3.76(m,6H),1.47(brd,J=6.72Hz,3H).

[0315] The following compounds were synthesized using the same synthetic method as intermediate 2-1 with different starting materials:

[0316] Intermediate 2-2 Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-8-fluoro-N-methyl-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0317]

[0318] LC-MS: m / z 671 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.48–8.34(m,1H),8.00(d,J=7.6Hz,1H),7.24(dd,J=7.6,4.8Hz,1H),6.95(d,J=8.3Hz,4H),6.60( t,J=9.1Hz,4H),6.44(d,J=6.9Hz,1H),5.26–4.98(m,2H),4.15–3.99(m,4H),3.66(s,6H),3.10(d,J=10.0Hz,3H),1.51(d,J=6.8Hz,3H).

[0319] Preparation of Intermediate 2-2A (S)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-8-fluoro-N-methyl-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0320]

[0321] LC-MS: m / z 671 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.81 (s, 1H), 8.41 (dd, J=

[0322] 4.7,1.6Hz,1H),8.00(dd,J=7.7,1.4Hz,1H),7.24(dd,J=7.7,4.7Hz,1H),6.95(d,J=8.4Hz,4H),6.58(d,J=8.6Hz, 4H),6.43(q,J=6.7Hz,1H),5.24–5.01(m,2H),4.13–3.98(m,4H),3.66(s,6H),3.08(s,3H),1.51(d,J=6.9Hz,3H).

[0323] Preparation of Intermediate 2-2B (R)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-8-fluoro-N-methyl-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0324]

[0325] LC-MS: m / z 671 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.81 (s, 1H), 8.41 (dd, J=

[0326] 4.7,1.7Hz,1H),8.00(dd,J=7.7,1.5Hz,1H),7.24(dd,J=7.7,4.7Hz,1H),6.95(d,J=8.5Hz,4H),6.58(d,J=8.6 Hz,4H),6.43(d,J=6.9Hz,1H),5.26–4.95(m,2H),4.06(s,4H),3.66(s,6H),3.08(s,3H),1.51(d,J=6.9Hz,3H).

[0327] Preparation of intermediate 2-3N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-N-ethyl-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0328]

[0329] LC-MS: m / z 685 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ8.79(s,1H),8.38-8.48(m,1H),8.01-8.13(m,1H),7.25(dd,J=7.63,4.75Hz,1H),6.75-6.93(m, 4H),6.47-6.65(m,5H),4.94-5.25(m,2H),3.83-4.15(m,5H),3.66(s,7H),3.52-3.61(m,2H),1.40-1.58(m,3H),0.51(br t,J=6.69Hz,3H).

[0330] Preparation of Intermediate 2-4N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)propyl)-7-chloro-8-fluoro--N-methyl 2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0331]

[0332] LC-MS: m / z 685 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.72-8.91(m,1H),8.76(s,1H),8.43(dd,J=4.51,1.43Hz,1H),7.91-8.04(m,1H),7.99(br d,J=6.60Hz,1H),7.21-7.30(m,1H),7.17-7.35(m,1H),7.26(dd,J=7.59,4. 73Hz,1H),6.87-7.04(m,4H),6.49-6.65(m,4H),6.15-6.39(m,1H),5.06(br d,J=3.52Hz,2H),4.02(q,J=14.38Hz,4H),3.60-3.68(m,6H),3.03-3.19(m,3H),1.99(s,2H),1.81-1.83(m,1H),0.42-0.75(m,3H).

[0333] Preparation of Intermediate 2-5N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-N-cyclopropyl-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0334]

[0335] LC-MS: m / z 697 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.47-8.35(m,1H),8.10(br d,J=7.5Hz,1H),7.31-7.18(m,1H),6.96(br d,J=8.6Hz,4H),6.58(d,J=8.6Hz,4H),6.28-6.12(m,1H),5.20-5.02(m,2H),4.17-3.97(m,4H),3.65(s,6H),2.69(brs,1H),1.61(br d,J=7.3Hz,3H),1.27-1.16(m,1H),0.97-0.86(m,1H),0.78-0.68(m,1H),0.38-0.27(m,1H).

[0336] Preparation of Intermediate 2-6N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-N-(2-fluoroethyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0337]

[0338] LC-MS: m / z 703 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ8.93(s,1H)8.56(br dd,J=4.69,1.69Hz,1H)7.82(br d,J=6.25Hz,1H)7.22(dd,J=7.75,4.75Hz,1H)6.67(m,8H)6.26(br d,J=6.88Hz,1H)4.85(q,J=8.42Hz,2H)4.25(m,1H)3.92(m,5H)3.78(m,6H)3.62(m,2H)1.51(br d,J=7.00Hz,3H).

[0339] Preparation of Intermediate 2-7N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-N-(2-fluoroethyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0340]

[0341] LC-MS: m / z 715 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.7-8.8(m,1H),8.4-8.5(m,1H),7.71(dd,1H,J=1.4,7.7Hz ),7.08(dd,1H,J=4.8,7.6Hz),6.7-6.8(m,4H),6.5-6.5(m,4H),6.3-6.4(m,1H),4. 7-4.9(m,2H),4.03(d,2H,J=13.3Hz),3.83(d,2H,J=13.4Hz),3.6-3.7(m,6H),3.4- 3.5(m,2H),3.0-3.1(m,3H),2.7-2.9(m,1H),2.3-2.4(m,1H),1.36(d,3H,J=6.8Hz).

[0342] Intermediate 3-1 Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4(3H)-one

[0343]

[0344] Step 1: Preparation of methyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0345] Under nitrogen protection, pinacol borane (304g, 1.20mol, 1.50eq), KOAc (235g, 2.39mol, 3.00eq) and Pd(dppf)Cl2 (40.8g, 55.8mmol, 0.07eq) were added to a solution of methyl 2-amino-4-bromo-3-fluorobenzoate (198g, 798mmol, 1.00eq) in dioxane (2000mL) at room temperature. The mixture was reacted at 90°C for 16h under nitrogen protection, then cooled to room temperature and filtered. The filter cake was washed with EtOAc (2L). The filtrates were combined and diluted with H2O (2L) and extracted with EtOAc (2x 1.5L). The combined organic phase was washed with saturated brine (2L), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (250 g, 762 mmol, 95.5% yield).

[0346] LC-MS: m / z 296 (M+H) + .

[0347] Step 2: Preparation of methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3-fluorobenzoate

[0348] Under nitrogen protection, 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (47.3 g, 105 mmol, 1.00 eq), Pd-118 (6.85 g, 10.5 mmol, 0.10 eq) and KF (18.3 g, 315 mmol, 3.00 eq) were added to a mixed solution of methyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (31.0 g, 105 mmol, 1.00 eq) in dioxane (400 mL) and water (40 mL) at room temperature. The mixture was reacted at 100°C for 1 h under nitrogen protection, then cooled to room temperature and filtered. The filtrate was diluted with H2O (500 mL) and extracted with EtOAc (3x500 mL). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (44.0 g, 75.4 mmol, 71.78% yield).

[0349] LC-MS: m / z 584 (M+H) + .

[0350] Step 3: Preparation of methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzoate

[0351] NCS (12.5 g, 94.2 mmol, 1.25 eq) was added to a solution of methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3-fluorobenzoate (44.0 g, 75.4 mmol, 1.00 eq) in NMP (500 mL). The mixture was reacted at 70°C for 3 h, then cooled to 0°C, diluted with H2O (500 mL), and extracted with EtOAc (3x200 mL). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (17.5 g, 28.3 mmol, 37.5% yield).

[0352] LC-MS: m / z 618 (M+H) + .

[0353] Step 4: Preparation of 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzoic acid

[0354] To a mixed solution of methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzoate (17.5 g, 28.3 mmol, 1.00 eq) in MeOH (180 mL), THF (60 mL) and H2O (60 mL) was added NaOH (16.9 g, 424 mmol, 15.0 eq). The mixture was reacted at 50°C for 3 h, then cooled to room temperature and concentrated under reduced pressure. H2O (300 mL) was added to the residue, which was diluted and extracted with EtOAc (3 x 200 mL). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was used directly in the next step without purification (20.0 g, crude product).

[0355] LC-MS: m / z 604 (M+H) + .

[0356] Step 5: Preparation of 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzamide

[0357] To a solution of 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzoic acid (9.00 14.9mmol, 1.00eq) in DMF (80mL) at 0°C were added NH4Cl (2.39g, 44.7mmol, 3.00eq), DIEA (5.78g, 44.7mmol, 7.79mL, 3.00eq) and HATU (11.3g, 29.8mmol, 2.00eq). The mixture was reacted at 25°C for 2h, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with H2O (300mL) at 0°C and extracted with EtOAc (3x 200mL). The combined organic phases were washed with saturated brine (200mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (9.00 g, 11.0 mmol, 74.1% yield).

[0358] LC-MS: m / z 603 (M+H) + .

[0359] Step 6: Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4(3H)-one

[0360] CSCl2 (3.43 g, 29.8 mmol, 2.29 mL, 2.00 eq) was added to a solution of 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzamide (9.00 g, 14.9 mmol, 1.00 eq) in dioxane (80 mL). The mixture was reacted at 100°C for 1 h, then cooled to room temperature and concentrated under reduced pressure. H2O (300 mL) was added to the residue and diluted, and the pH was adjusted to 7 with NaHCO3. The mixture was extracted with EtOAc (3 x 200 mL). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (4.60 g, 5.68 mmol, 38.0% yield).

[0361] LC-MS: m / z 647 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ13.34-13.92(m,1H),8.00(d,J=0.98Hz,1H),7.16(d,J=8.56Hz,4H),6.88(br d,J=8.31Hz,4H),6.84(s,1H),4.54-4.82(m,4H),3.73(s,6H),2.40(br d,J=1.10Hz,3H).

[0362] Intermediate 3-1 was subjected to SFC chiral separation (chiral column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) to obtain intermediate 3-1A and intermediate 3-1B.

[0363] Intermediate 3-1A (S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4(3H)-one

[0364]

[0365] RT: 0.891min. LC-MS: m / z 647(M+H) + . 1H NMR (400MHz, DMSO-d6) δ7.99 (s, 1H), 7.16 (d, J = 8.56Hz, 4H), 6.88 (br d, J = 8.31Hz, 4H), 6.84 (s, 1H), 4.58-4.82 (m, 4H), 3.73 (s, 6H), 2.40 (br d,J=1.10Hz,3H).

[0366] Intermediate 3-1B (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4(3H)-one

[0367]

[0368] RT: 1.168min. LC-MS: m / z 647(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.99 (s, 1H), 7.16 (d, J = 8.56Hz, 4H), 6.88 (br d, J = 8.31Hz, 4H), 6.84 (s, 1H), 4.58-4.82 (m, 4H), 3.73 (s, 6H), 2.40 (br d,J=1.10Hz,3H).

[0369] The following compounds were synthesized using the same synthetic method as intermediate 3-1 with different starting materials:

[0370] Intermediate 3-2 2,6-dichloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4(3H)-one

[0371]

[0372] LC-MS: m / z 557 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ14.08-13.58(m,1H),8.31-8.17(m,2H),7.94(s,1H),7.77-7.59(m,2H),7.51(br d,J=7.0Hz,1H),0.98-0.82(m,18H),0.71-0.61(m,3H).

[0373] Intermediate 3-3 (3-cyano-4-(2,6-dichloro-8-fluoro-4-oxo-3,4-dihydroquinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carboxylic acid tert-butyl ester

[0374]

[0375] LC-MS: m / z 523 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.86 (br s, 1H), 8.05 (d, 1H, J = 1.1Hz), 7.4-7.5 (m, 2H), 1.52 (s, 9H).

[0376] Intermediate 3-4 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-chloro-6,8-difluoroquinazolin-4(3H)-one

[0377]

[0378] LC-MS: m / z 631 (M+H) + .

[0379] Intermediate 3-4 was subjected to SFC chiral separation (chiral column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) to obtain intermediate 3-4A and intermediate 3-4B.

[0380] Intermediate 3-4A (R) -7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-chloro-6,8-difluoroquinazolin-4(3H)-one

[0381]

[0382] RT: 1.507min. LC-MS: m / z 631(M+H) + . 1 H NMR(400MHz, CDCl3)δ10.88(br d,J=11.00Hz,1H),7.81(dd,J=8.03,1.43Hz,1H),7.14(d,J=8.58Hz,4H),6.86(d,J=8 .58Hz, 4H), 6.42 (s, 1H), 4.66 (q, J = 16.07Hz, 4H), 3.81 (s, 6H), 2.42 (d, J = 1.76Hz, 3H).

[0383] Intermediate 3-4B (S) -7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-chloro-6,8-difluoroquinazolin-4(3H)-one

[0384]

[0385] RT: 1.784min. LC-MS: m / z 631(M+H) + . 1 H NMR(400MHz, CDCl3)δ10.22-10.79(m,1H)7.81(d,J=7.92Hz,1H)7.14(d,J=8.36Hz,4H) 6.86(d,J=8.36Hz,4H)6.42(s,1H)4.53-4.82(m,4H)3.81(s,6H)2.41(d,J=1.54Hz,3H).

[0386] Intermediate 4-1 Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,6-dichloro-8-fluoro-N-methylquinazolin-4-amine

[0387]

[0388] N,N-bis(4-methoxybenzyl)-3-(1-(methylamino)ethyl)pyridin-2-amine (72.5 mg, 185 μmol, 1.00 eq), DIEA (239 mg, 1.85 mmol, 322 μL, 10.0 eq) and Bop-Cl (188 mg, 741 μmol, 4.00 eq) were added to a solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4(3H)-one (120 mg, 185 μmol, 1.00 eq) in DCM (3 mL). The mixture was reacted at 25°C for 16 h, then quenched by the addition of water (30 mL) and extracted with DCM (30 mL*3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the target product (105 mg, 47.0% yield).

[0389] LC-MS: m / z 1020 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ8.29-8.39(m,1H)7.97-8.11(m,1H)7.84-7.95(m,1H)7.19(s,1H)7.13-7.18(m,4H)6.92(br s,4H)6.85-6.89(m,4H)6.60-6.67(m,4H)6.23-6.44(m,1H)4.52-4.86(m,4H)3 .99-4.12(m,4H)3.71-3.73(m,6H)3.58-3.67(m,6H)3.10-3.19(m,3H)2.39(br s,3H)1.43-1.57(m,1H)1.43-1.56(m,3H).

[0390] The following compounds were synthesized using the same synthetic method as intermediate 4-1 with different starting materials:

[0391] Intermediate 4-2 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,6-dichloro-8-fluoro-N-methylquinazolin-4-amine

[0392]

[0393] LC-MS: m / z 1020 (M+H) + .

[0394] Intermediate 4-2A (S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,6-dichloro-8-fluoro-N-methylquinazolin-4-amine

[0395]

[0396] LC-MS: m / z 1020 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ8.36-8.34(m,1H),8.03(s,1H),7.92-7.90(m,1H) ),7.20-7.15(m,5H),7.00-6.98(m,4H),6.89-6.83(m,5H),6.64-6.62(m ,4H),6.36-6.31(m,1H),4.81(s,2H),4.61(d,J=16Hz,2H),4.10(s,4H), 3.73(s,6H),3.61(s,6H),3.17(s,3H),2.40(s,3H),1.54(d,J=8Hz,3H).

[0397] Intermediate 4-2B (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,6-dichloro-8-fluoro-N-methylquinazolin-4-amine

[0398]

[0399] LC-MS: m / z 1020 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.36(dd,J=4.7,1.8Hz,1H),8.05(d,J=1.6Hz,1H),7.94(dd,J =7.7,1.8Hz,1H),7.21–7.12(m,5H),6.95(d,J=8.2Hz,4H),6.89–6.81(m,5H),6.68–6 .62(m,4H),6.42–6.34(m,1H),4.88–4.66(m,2H),4.63–4.50(m,2H),4.12–4.03(m,4H ),3.71(s,6H),3.66(s,6H),3.12(s,3H),2.40(d,J=2.0Hz,3H),1.47(d,J=6.9Hz,3H).

[0400] Intermediate 4-3 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,6-dichloro-N-ethyl-8-fluoroquinazolin-4-amine

[0401]

[0402] LC-MS: m / z 1034 (M+H)+ . 1 H NMR(400MHz, DMSO-d6)δ8.41(ddd,J=9.74,4.68,1.65Hz,1H)8.00-8.08(m,1H)7.93(br s,1H)7.20-7.26(m,1H)7.13-7.19(m,4H)6.74-6.91(m,9H)6.58-6.67(m,4H)6.39-6.51(m,1H)4.45-4.92(m ,4H)3.84-4.07(m,4H)3.77-3.84(m,1H)3.67-3.77(m,6H)3.65-3.67(m,2H)3.63(d,J=15.19Hz,6H)2.41(br d,J=2.20Hz,3H)1.44-1.56(m,3H)0.49-0.66(m,3H)

[0403] Intermediate 4-tert-Butyl 4-(4-(4-(((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)(methyl)amino)-2,6-dichloro-8-fluoroquinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carboxylate

[0404]

[0405] LC-MS: m / z 896 (M+H) + .

[0406] Intermediate 4-5 (4-(4-(((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)(ethyl)amino)-2,6-dichloro-8-fluoroquinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carboxylic acid tert-butyl ester

[0407]

[0408] LC-MS: m / z 910 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.89(br s,1H),8.4-8.5(m,1H),8.05(br d,1H,J=6.9Hz),7.92(s,1H),7.4-7.5(m,2H),6.96(br d,4H,J=8.4Hz),6.71(d,4H,J=8.6Hz),6.5-6.6(m,1H),6.52(br d,1H,J=6.6Hz),4.13(br d,2H,J=13.5Hz),3.9-3.9(m,2H),3.7-3.7(m,6H),3.5-3.6(m,3H),1.36(s, 9H), 1.20 (d, 1H, J = 6.8Hz), 1.2-1.2 (m, 3H), 0.8-0.9 (m, 1H), 0.8-0.9 (m, 3H).

[0409] Intermediate 4-6A (R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-chloro-6,8-difluoro-N-methylquinazolin-4-amine

[0410]

[0411] LC-MS: m / z 524 (M+H) + .

[0412] Intermediate 4-6B (S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-chloro-6,8-difluoro-N-methylquinazolin-4-amine

[0413]

[0414] LC-MS: m / z 524 (M+H) + .

[0415] Intermediate 5-1 Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile

[0416]

[0417] Step 1: Preparation of methyl 4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-2-(2-cyanoacetyl)-3-fluorobenzoate

[0418] Methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzoate (5.80 g, 9.38 mmol, 1.00 eq) and 2-cyanoacetic acid (1.60 g, 18.7 mmol, 2.00 eq) in DCM (50 mL) were added (3.60 g, 18.7 mmol, 2.00 eq). The resulting mixture was reacted at 25 °C for 16 h and then quenched by adding H2O (200 mL) at 0 °C and extracted with DCM (100 mL x 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (3.77 g, 5.50 mmol, 58.6% yield).

[0419] LC-MS: m / z 685 (M+H) + .

[0420] Step 2: Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2,4-dihydroquinoline-3-carbonitrile

[0421] MeONa / MeOH (1.49 g, 8.25 mmol, 30% wt, 1.50 eq) was added to a solution of methyl 4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-2-(2-cyanoacetyl)-3-fluorobenzoate (3.77 g, 5.50 mmol, 1.00 eq) in MeOH (40 mL). The reaction solution was reacted at 0°C for 1 h, and then HCl aqueous solution (10% wt) was added dropwise to adjust the pH to 2-3. The obtained mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the target product (3.20 g, 4.90 mmol, 89.0% yield). It was used directly in the next step without further purification.

[0422] LC-MS: m / z 653 (M+H) + .

[0423] Step 3: Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile

[0424] To a mixture of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2,4-dihydroquinoline-3-carbonitrile (2.00 g, 3.06 mmol, 1.00 eq) and POCl3 (1.41 g, 9.19 mmol, 856 μL, 3.00 eq) in Tol. (20 mL) at 0°C was added DIEA (1.98 g, 15.3 mmol, 2.67 mL, 5.00 eq). The resulting mixture was reacted at 110°C for 16 h and then concentrated under reduced pressure. The residue was poured into ice water and then extracted with DCM (100 mL x 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (0.52 g, 753 μmol, 24.6% yield).

[0425] LC-MS: m / z 689 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.18 (s, 1H), 7.15 (br d, J = 8.4Hz, 4H), 6.87 (br d,J=8.4Hz,4H),6.48(s,1H),4.81-4.68(m,2H),4.66-4.55(m,2H),3.82(s,6H),2.46(br s,3H).

[0426] Example A1 Preparation of 4-(4-((1-(2-aminopyridin-3-yl)ethyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0427]

[0428] Step 1: Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0429] Under nitrogen protection, N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine (630 mg, 958 μmol, 1.00 eq), 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropylsilane (589 mg, 1.15 mmol, 1.20 eq), Cs2CO3 (937 mg, 2.88 mmol, 3.00 eq) and CataxciAmPd A mixture of G2 (64.1 mg, 95.9 μmol, 0.100 eq) in dioxane (10 mL) and H2O (2 mL) was reacted at 100 °C for 3 h, then diluted with water (30 mL) and extracted with EtOAc (25 mL*2). The combined organic phase was washed with saturated brine (25 mL*2), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (0.66 g, 655 μmol, 68.3% yield).

[0430] LC-MS: m / z 1007 (M+H) + . 1 H NMR(400MHz, CDCl3)δ8.63-9.04(m,1H)8.29-8.56(m,1H)7.76-7.90(m,1H)7.64-7. 73(m,1H)7.47-7.59(m,1H)7.29-7.41(m,3H)6.98-7.20(m,4H)6.84(d,J=8.56Hz,1H )6.67(d,J=8.68Hz,3H)5.89-6.07(m,1H)5.23-5.44(m,2H)4.26-4.49(m,4H)3.65-3 .85(m,6H)1.41-1.56(m,3H)0.83-0.99(m,15H)0.71-0.82(m,5H)0.45-0.65(m,4H).

[0431] Step 2: Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridin[4,3-d]pyrimidin-4-amine

[0432] To ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (30 mg, 0.149 mmol) in toluene (1 mL) was added sodium hydride (12 mg, 60% wt, 0.297 mmol). The mixture was stirred at room temperature for 2 min, followed by the addition of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine (100 mg, 0.099 mmol). The resulting mixture was reacted at 110°C for 2 h, then diluted with water and extracted with EtOAc. The combined organic phase was washed with saturated brine (25 mL*2), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (35 mg, 21.2% yield).

[0433] LC-MS: m / z 1110 (M+H) + .

[0434] Step 3: Preparation of 4-(4-((1-(2-aminopyridin-3-yl)ethyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0435] A solution of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridin[4,3-d]pyrimidin-4-amine (35 mg, 0.03 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature for 16 h and then concentrated under reduced pressure (25 mg crude product). It was used directly in the next step without further purification.

[0436] LC-MS: m / z 826 (M+H) + .

[0437] Step 4: Preparation of 4-(4-((1-(2-aminopyridin-3-yl)ethyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0438] 4-(4-((1-(2-aminopyridin-3-yl)ethyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (25 mg) obtained in the previous step was dissolved in DMF (1 mL) and cesium fluoride (167 mg, 1.1 mmol) was added. The mixture was stirred at room temperature for 16 h, and then separated by preparative liquid phase to obtain the target product (3.2 mg, 16% yield for two steps).

[0439] LC-MS: m / z 670 (M+H) + .

[0440] The following examples were synthesized using different starting materials according to the method of Example A1:

[0441] Example A2 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0442]

[0443] LC-MS: m / z 693 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.21(s,1H),7.97(d,J=3.7Hz,1H),7.64(d,J=7.3Hz,1H),6.88(s,1H),6.66( dd,J=7.3,5.0Hz,1H),6.46(s,1H),6.34(s,2H),6.16(s,1H),5.81(s,2H),4.23(t,J=11.9Hz,2H),3.2 4(s,3H),3.14–3.06(m,1H),3.01(s,1H),2.72(d,J=11.8Hz,1H),2.54(s,1H),2.06(dd,J=20.5,16.4H z, 2H), 1.90 (d, J = 13.2Hz, 1H), 1.78 (d, J = 18.4Hz, 2H), 1.67–1.53 (m, 5H), 1.48 (dd, J = 8.6, 3.8Hz, 1H).

[0444] Example A2 was subjected to SFC chiral separation (equipment: SFC-150 (Waters); chiral column: OD 25*250mm, 10um (Daicel); column temperature: 35°C; mobile phase: CO2 / MEOH [0.2% NH3 (7M in MeOH) = 50 / 50) to obtain Examples A2-A and A2-B:

[0445] Example A2-A: 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-((R)-2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0446]

[0447] RT: 1.782min. LCMS:m / z 693(M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 7.99 (d, J = 8Hz, 1H), 7.67 (d, J = 8Hz, 1H), 6.90 (s, 1H), 6.69-6. 66(m,1H),6.47(s,1H),6.33(s,2H),6.20-6.15(m,1H),5.81(s,2H),4.31-4.20(m,2H),3.25(s,3H ),3.14-3.10(m,1H),3.05-3.01(m,1H),2.76(d,J=12Hz,1H),2.59-2.55(m,1H),2.12-2.07(m,1H) ,2.05-1.99(m,1H),1.94(d,J=16Hz,1H),1.84-1.75(m,2H),1.67-1.54(m,5H),1.52-1.45(m,1H).

[0448] Example A2-B: 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-((S)-2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0449]

[0450] RT: 2.303min. LCMS:m / z 693(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.99(d,J=8Hz,1H),7.67(d,J=8Hz,1H),6.90(s,1H),6.69- 6.66(m,1H),6.47(s,1H),6.33(s,2H),6.20-6.15(m,1H),5.81(s,2H),4.25(s,2H),3.25(s,3H), 3.14-3.10(m,1H),3.05-3.01(m,1H),2.76(d,J=12Hz,1H),2.59-2.55(m,1H),2.12-2.07(m,1H), 2.05-1.99(m,1H),1.94(d,J=16Hz,1H),1.84-1.75(m,2H),1.67-1.54(m,5H),1.52-1.45(m,1H).

[0451] Example A3 4-(4-((1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0452]

[0453] LCMS: m / z 688 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.96(s,1H),9.28(d,J=11.6Hz,1H),7.98(d,J=4.9Hz,1H),7.77(dd,J=9.1,6.0Hz,1H),7.66(d, J=7.4Hz,1H),7.35(dd,J=13.2,5.9Hz,2H),7.01(s,1H),6.19(s,1H),5.93(d,J=13.2Hz,1H),5.78(d,J=8.3Hz,1H),4.28 (d,J=11.6Hz,2H),3.28(d,J=2.0Hz,3H),3.12(s,1H),3.03(s,1H),2.75(s,1H),2.36(d,J=15.7Hz,1H),2.11(d,J=12.9H z, 2H), 2.02 (s, 1H), 1.92 (d, J = 13.0Hz, 1H), 1.79 (d, J = 24.4Hz, 2H), 1.61 (dd, J = 36.9, 33.8Hz, 6H), 0.75 (t, J = 6.8Hz, 3H).

[0454] Example A4 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0455]

[0456] LCMS: m / z 649 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.99(d,J=8Hz,1H),7.66(d,J=8Hz,1H),6 .89(m,1H),6.69-6.66(m,1H),6.47(s,1H),6.32(m,2H),6.19-6.14(m,1H),5.8 0(s,2H),5.38-5.25(m,1H),4.22-4.10(m,2H),3.26(s,3H),3.14(m,2H),3.06 (m,1H),2.87(m,1H),2.18-2.03(m,3H),1.89-1.81(m,3H),1.63(d,J=8Hz,3H).

[0457] Example A5 4-(4-((1-(2-2-aminopyridin-3-yl)ethyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0458]

[0459] LCMS: m / z 644 (M+H) + .

[0460] Example A6 4-(4-((1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0461]

[0462] LCMS: m / z 640 (M+H) + .

[0463] Example A7 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0464]

[0465] LCMS: m / z 619 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 7.98 (d, J = 4Hz, 1H), 7.65 (d, J = 8Hz, 1 H),6.88(s,1H),6.68-6.65(m,1H),6.46(s,1H),6.32(s,2H),6.18-6.13(m ,1H),5.79(s,2H),4.39(s,1H),4.21(s,1H),3.52-3.41(m,1H),3.25(s,3 H),3.16(s,1H),1.62(d,J=8Hz,3H),1.24-1.17(m,6H),0.72-0.55(m,4H).

[0466] Example A8 2-((1-(((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)methyl)cyclopropyl)methoxy)-7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0467]

[0468] LCMS: m / z 673 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.19 (s, 1H), 7.97 (d, J = 8Hz, 1H), 7.64 (d, J = 12Hz, 1H), 6.88 (s, 1H),6.67-6.64(m,1H),6.46(m,1H),6.31(s,2H),6.12(s,1H),5.77-5.75(m,2H),4.43 -4.18(m,3H),3.79-3.77(m,1H),3.48-3.46(m,2H),3.24(s,3H),2.86-2.84(m,1H),2. 69-2.56(m,2H),2.41-2.38(m,1H),1.67-1.51(m,5H),0.588(s,2H),0.49-0.40(m,2H).

[0469] Example A9 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-N-methyl-2-((1-methylpiperidin-4-yl)oxy)pyridin[4,3-d]pyrimidin-4-amine trifluoroacetate

[0470]

[0471] LCMS: m / z 605 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.83-9.73(m,1H),9.28(s,1H),8.05-7.97(m,2H),7.69-7.55(m,2H),6.90(s,2H),6.46-6.38(m,3H),6.04-6 .01(m,1H),5.39(s,1H),5.20(s,1H),3.38-3.18(m,4H),2.87-2.82(m,3H),2.34-2.03(m,4H),1.91-1.82(m,1H),1.68-1.66(m,3H).

[0472] Example A10 Example A11 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-4-amine

[0473]

[0474] LCMS: m / z 679 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H), 9.13(m,1H), 7.85(m,1H), 7.51(m,1H), 6.88(d,J=2.20Hz,1H), 6.55(m,1H), 6.46(d,J=2.2 4Hz,1H), 6.33(s,2H), 5.93(s,2H), 5.51(m,1H), 4.56(m,3H), 4.18(s,2H), 3.04(m,2H), 2.67(m,1H), 1.91(m,5H), 1.59(m,4H).

[0475] Example A11 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine

[0476]

[0477] LCMS: m / z 635 (M+H) +. 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 9.19 (d, J = 6.84Hz, 1H), 7.85 (d, d, J = 1.80H) z, J=4.92Hz, 1H), 7.52 (m, 1H), 6.56 (d, d, J=4.88Hz, J=7.40Hz, 1H), 6.45 (s, 1H), 6.33(s,1H), 5.97(s,2H), 5.47(m,1H), 5.40(br,0.5H), 5.27(br,0.5H), 4.20(m, 3H), 3.48(m,1H), 3.42(m,1H), 2.94(m,1H), 2.03(m,1H), 1.56(d,J=6.84Hz,3H).

[0478] Example A12 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-pyridin[4,3-d]pyrimidin-4-amine

[0479]

[0480] LCMS: m / z 679 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 9.45 (s, 1H), 9.19 (m, 1H), 7.85 (m, 1H), 7.51 (m, 1H), 6.88 (d, J = 2.20Hz, 1H), 6.55 (m, 1H), 6.46 (m, 1H), 6.34(s,2H), 5.94(s,2H), 5.47(m,1H), 4.55(m,3H), 4.23(s,2H), 3.05(m,2H), 2.78(m,1H), 1.91(m,5H), 1.59(m,4H).

[0481] Example A13 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine

[0482]

[0483] LCMS: m / z 635 (M+H)+ . 1 H NMR (400MHz, DMSO-d6) δ 9.42 (s, 1H), 9.12 (d, J = 7.20Hz, 1H), 7.85 (m, 1H), 7.50 (m, 1H), 6.88 (m, 1H), 6.45 (m, 1H), 6.32 (s, 1H), 5.93 (s, 2H), 5.46 (m,1H), 5.29(br,0.5H), 5.16(br,0.5H), 4.56(m,2H), 4.07(s,2H), 3.0 6(m,2H), 2.80(m,1H), 1.95(m,2H), 1.77(m,3H), 1.56(d,J=6.84Hz,3H).

[0484] Example A14 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-N-methyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine

[0485]

[0486] LCMS: m / z 605 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 7.99 (d, J = 4Hz, 1H), 7.67 (d, J = 8Hz, 1H), 6.9 0(s,1H),6.70-6.67(m,1H),6.48(s,1H),6.33(s,2H),6.19-6.15(m,1H),5.76(d, J=12Hz,2H),4.43(s,1H),4.28(s,1H),3.24(s,3H),2.99(s,1H),2.68(s,1H),2. 40(s,3H),2.24(s,1H),2.01-1.96(m,1H),1.74-1.69(m,3H),1.63(d,J=4Hz,3H).

[0487] Example A15 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-N-methyl-2-((S)-1-methylpyrrolidin-2-yl)ethoxy)pyridin[4,3-d]pyrimidin-4-amine

[0488]

[0489] LCMS: m / z 619 (M+H)+ . 1 H NMR(400MHz,DMSO-d6)δ9.20(d,J=16Hz,1H),7.96(t,J=4Hz 1H),7.62(t,J=8Hz,1H),6.88(s,1H),6.68-6.63(m,1H),6.46(s,1H),6.31 (s,2H),6.16-6.05(m,1H),5.72(d,J=20Hz,2H),5.28(s,1H),3.25(d,J=16H z,3H),2.95(s,1H),2.63(s,1H),2.36(s,3H),2.17(s,1H),1.80-1.74(m,2H ),1.67(m,2H),1.61(d,J=4Hz,3H),1.29(d,J=4Hz,2H),1.21(d,J=4Hz,1H).

[0490] Example A16 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0491]

[0492] LCMS: m / z 605 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.22(m,1H),7.99(d,J=4Hz,1H),7.67(d,J=8Hz,1H),6.90 (s,1H),6.69-6.66(m,1H),6.48(s,1H),6.33(s,2H),6.18-6.15(m,1H),5.78(d,J =8Hz,2H),5.28-5.14(m,1H),4.51-4.33(m,2H),3.52-3.41(m,2H),3.24(s,3H),2 .99(s,1H),2.43(s,3H),2.22-2.10(m,1H),2.03-1.84(m,1H),1.63(d,J=4Hz,3H).

[0493] Example A17 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((3R,6S)-1,1-difluoro-5-methyl-5-azaspiro[2.4]heptane-6-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0494]

[0495] LCMS: m / z 667 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.22(d,J=4Hz,1H),7.99(d,J=4Hz,1H),7.67(d,J=8Hz,1H),6.90(s, 1H),6.69-6.66(m,1H),6.47(s,1H),6.34(s,2H),6.18-6.14(m,1H),5.75(d,J=8Hz,2H),4.5 1(s,1H),4.35(s,1H),3.24(s,3H),2.99(d,J=12Hz,1H),2.92-2.90(m,1H),2.47-2.45(m,1H ),2.39(s,3H),2.09-2.03(m,1H),1.96-1.89(m,1H),1.63(d,J=4Hz,3H),1.53-1.42(m,2H).

[0496] Example A18 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((3S,6S)-1,1-difluoro-5-methyl-5-azaspiro[2.4]heptane-6-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0497]

[0498] LCMS: m / z 667 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.23(d,J=4Hz,1H),7.99(d,J=4Hz,1H),7.67(d,J=8Hz,1H),6.90(s,1H ),6.69-6.66(m,1H),6.47(s,1H),6.34(s,2H),6.18-6.14(m,1H),5.79(d,J=16Hz,2H),4.50(s, 1H),4.42(s,1H),3.25(s,3H),2.93(d,J=8Hz,1H),2.84(m,1H),2.61-2.58(m,1H),2.39(s,3H), 2.27-2.22(m,1H),1.84-1.76(m,1H),1.63(d,J=4Hz,3H),1.58-1.55(m,1H),1.51-1.45(m,1H).

[0499] Example A19 2-((1-(((1S,4S)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)methyl)cyclopropyl)methoxy)-7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0500]

[0501] LCMS: m / z 605 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.19 (s, 1H), 7.97 (d, J = 8Hz, 1H), 7.64 (d, J = 12Hz, 1H), 6.88 (s, 1H),6.67-6.64(m,1H),6.46(m,1H),6.31(s,2H),6.12(s,1H),5.77-5.75(m,2H),4.43 -4.18(m,3H),3.79-3.77(m,1H),3.48-3.46(m,2H),3.24(s,3H),2.86-2.84(m,1H),2. 69-2.55(m,2H),2.40-2.38(m,1H),1.67-1.51(m,5H),0.58(s,2H),0.49-0.40(m,2H).

[0502] Example A20 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-N-methyl-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin[4,3-d]pyrimidin-4-amine trifluoroacetate

[0503]

[0504] LCMS: m / z 692 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.04-8.02 (m, 3H), 6.95 (t, J = 8Hz, 1H), 6.90 (s, 1H), 6.46 (s, 1H), 6.01-5.96 (m, 1H), 5. 20-5.15(m,1H),3.90-3.80(m,6H),3.54-3.42(m,5H),2.05-2.01(m,1H),1.80(s,1H),1.74-1.67(m,3H),1.63-1.54(m,1H).

[0505] Example A21 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-ethyl-8-fluoro-pyridin[4,3-d]pyrimidin-4-amine

[0506]

[0507] LCMS: m / z 707 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 8.01 (d, J = 5.0Hz, 1H), 7.74 (d, J = 7.5Hz, 1H), 6.91 (d, J = 2. 2Hz,1H),6.72(dd,J=7.6,5.0Hz,1H),6.49(d,J=2.4Hz,1H),6.39–6.23(m,2H),5.71(s,2H),4. 65–4.42(m,2H),3.92–3.66(m,2H),3.07–2.85(m,2H),2.43–2.26(m,1H),2.25–2.11(m,2H),2. 10–1.91(m,3H),1.89–1.70(m,3H),1.65(d,J=6.8Hz,3H),1.31–1.18(m,3H),1.05–0.94(m,2H).

[0508] Example A22 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl-N-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine

[0509]

[0510] LCMS: m / z 663 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.00(d,J=4.8Hz,1H),7.71(d,J=7.4Hz,1H ),6.96–6.85(m,1H),6.70(m,1H),6.50(d,J=9.7Hz,1H),6.31(m,3H),5.64(s,1H ),5.30(m,1H),4.25–3.96(m,3H),3.71(m,2H),3.18–2.95(m,3H),2.89–2.76(m ,1H),2.10(m,3H),1.81(m,2H),1.63(d,J=6.7Hz,3H),1.30(m,1H),1.02(m,3H).

[0511] Example A22 was subjected to SFC chiral separation to obtain Examples A22-A and A22-B:

[0512]

[0513] Example A22-A

[0514] LCMS: m / z 663 (M+H) + .

[0515] Example A22-B

[0516] LCMS: m / z 663 (M+H) + .

[0517] Example A23 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-(2-methoxyethyl)pyridin[4,3-d]pyrimidin-4-amine trifluoroacetate

[0518]

[0519] LCMS: m / z 737 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 9.28 (d, J = 8Hz, 1H), 8.17 (d, J = 8Hz, 1H) , 8.05 (d, J = 8Hz, 1H), 7.79 (s, 2H), 6.97-6.91 (m, 2H), 6.49-6.35 (m, 2H), 6.06 -6.05(m,1H),4.68-4.54(m,2H),4.13-4.01(m,3H),3.78-3.44(m,6H),3.18( s,1H),3.13(s,3H),2.34-2.17(m,3H),2.12-1.88(m,4H),1.71(d,J=8Hz,3H).

[0520] Example A24 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-N-cyclopropyl-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-4-amine trifluoroacetate

[0521]

[0522] LCMS: m / z 719 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),9.63(s,1H),8.27(m,1H),8.13-8.04(m,2H),,6.96 -6.91(m,2H),6.52(m,1H),6.36(s,1H),5.74(s,1H),4.65-4.63(m,1H),4.54-4.48(m,1H) ,3.78-3.65(m,3H),3.47-3.43(m,3H),3.15-3.09(m,1H),2.46-2.41(m,1H),2.28-2.15( m,3H),2.10-1.94(m,2H),1.91-1.85(m,5H),0.94-0.93(m,2H),0.64(m,1H),0.26(m,1H).

[0523] Example A25 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)propyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine trifluoroacetate

[0524]

[0525] LCMS: m / z 707 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ0.96(s,1H),9.46(s,1H),8.28-8.18(m,3H),8.10( d,J=8Hz,1H),6.99(t,J=8Hz,1H),6.92(m,1H),6.51-6.45(m,1H),5.99(s, 1H),4.74-4.61(m,2H),3.83-3.66(m,5H),3.49-3.43(m,4H),3.18-3.11(m ,1H),2.47-2.45(m,1H),2.34-2.17(m,4H),2.11-1.89(m,5H),0.98(s,3H).

[0526] Example A26 4-(4-((1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0527]

[0528] LCMS: m / z 684 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.60(s,1H),8.64(s,1H),8.29(s,1H),8.07–7.95(m,1H),7.65–7. 35(m,3H),7.21(d,J=3.3Hz,1H),4.56(m,3H),4.00(m,1H),2.22–1.74(m,8H),1.67(m,4H),1.25(s,3H).

[0529] Example A27 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl))-7-fluorophenylpropano[b]thiophene-3-carbonitrile

[0530]

[0531] LCMS: m / z 690 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.25 (s, 1H), 8.09 (s, 2H), 7.98 (d, J = 8Hz 1H), 7.66 (d, J = 8Hz 1H), 7.40-7.37 (m, 1H), 7.15 (t, J = 8Hz 1H),6.68-6.65(m,1H),6.19-6.14(m,1H),5.81(s,2H),4.31-4.20(m,2H),3.24(s,3H),3.14-3.04(m,2H),2.75-2.68(m ,1H),2.58-2.55(m,1H),2.13-2.00(m,2H),1.93-1.90(m,1H),1.81-1.76(m,1H),1.65-1.55(m,6H),1.51-1.45(m,1H).

[0532] Example A28 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-7-fluorophenylpropyl[b]thiophene-3-carbonitrile

[0533]

[0534] LCMS: m / z 605 (M+H) + .

[0535] Example A29 N-((R)-1-(2-aminopyridin-3-yl)ethyl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0536]

[0537] LCMS: m / z 624 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ9.36(d,J=7.2Hz,1H),8.43(d,J=4.7Hz,1H),8.31–8.17 (m,2H),7.96(m,1H),7.74–7.58(m,3H),7.37(m,1H),5.24(d,J=54.1Hz,1H),4. 08(m,3H),3.89–3.80(m,1H),3.05(m,2H),2.98(m,1H),2.86–2.75(m,1H),2.21 (d,J=11.9Hz,3H),2.02(m,3H),1.85–1.63(m,3H),1.33(dd,J=15.6,6.6Hz,3H).

[0538] Example A30 N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine

[0539]

[0540] LCMS: m / z 668 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.35(d,J=6.8Hz,1H),8.47–8.36(m,1H),8.23(m,2H),7.99–7.90(m,1H),7.77–7.57(m,3H),7.35(m,1H),4.16 (m,3H),3.82(m,1H),3.09–2.91(m,2H),2.68(d,J=11.5Hz,1H),2.19(d,J=10.7Hz,3H),2.04–1.88(m,2H),1.87–1.63(m,3H),1.49(m,m 3H),1.31(m,3H).

[0541] Example A31 4-(4-((1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate

[0542]

[0543] LCMS: m / z 654 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),10.83(s,1H),10.27(s,1H),9.61(d,J=8Hz,1H),9.12-8.93(m ,2H),8.65(m,1H),8.28(m,1H),8.04-8.01(m,1H),7.68(s,1H),7.51(t,J=8Hz,1H),7.44(m,1H),7.2 6-7.13(m,1H),5.58-5.45(m,1H),4.64-4.48(m,4H),4.00-3.84(m,5H),3.28(s,2H),2.90(s,1H),2 .75-2.68(m,1H),2.43(m,1H),2.26-2.13(m,4H),1.96(s,1H),1.69-1.60(m,3H),1.25-1.15(m,4H).

[0544] Example A32 N-(1-(2-aminopyridin-3-yl)ethyl)-N-ethyl-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine trifluoroacetate

[0545]

[0546] LCMS: m / z 638 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),10.83(s,1H),9.63(d,J=12Hz,1H),9.09(s,1H ),8.94(m,1H),8.65(m,1H),8.30-8.24(m,3H),7.74(t,J=4Hz,1H),7.69-7.63(m,3H ),5.58-5.45(m,1H),4.54-4.48(m,4H),4.09-4.02(m,2H),3.27(s,2H),2.88(s,1H) ,2.43(m,1H),2.28-2.15(m,4H),1.97(s,1H),1.69-1.60(m,3H),1.25-1.15(m,4H).

[0547] Example A32 was chirally separated by SFC to give Examples A32-A and A32-B: N-((R)1-(2-aminopyridin-3-yl)ethyl)-N-ethyl-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine and N-((S)1-(2-aminopyridin-3-yl)ethyl)-N-ethyl-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine

[0548]

[0549] Embodiment A32-A:

[0550] LCMS: m / z 638 (M+H) + .

[0551] Embodiment A32-B:

[0552] LCMS: m / z 638 (M+H) + .

[0553] Example A33 2-amino-4-(4-((1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-7-fluorophenylpropano[b]thiophene-3-carbonitrile trifluoroacetate

[0554]

[0555] LCMS: m / z 660 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.27(s,1H),8.10-8.15(m,3H),7.42-7. 39(m,1H),7.20-7.11(m,1H),6.94-6.91(m,1H),6.24-6.19(m,1H),5.66-5.53( m,1H),4.67-4.50(m,2H),4.05-3.99(m,1H),3.92-3.73(m,6H),3.35-3.29(m,2 H),2.36-2.33(m,1H),2.19-1.88(m,4H),1.69-1.61(m,3H),1.13-1.08(m,3H).

[0556] Example A33 was chiral separated by SFC to give Examples A33-A and A33-B: 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)- 7-Fluorophenylpropano[b]thiophene-3-carbonitrile and 2-amino-4-(4-(((S)-1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-7-fluorophenylpropano[b]thiophene-3-carbonitrile

[0557]

[0558] Embodiment A33-A:

[0559] LCMS: m / z 660 (M+H) + .

[0560] Embodiment A33-B:

[0561] LCMS: m / z 660 (M+H) + .

[0562] Example B1 Preparation of (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0563]

[0564] Step 1: Preparation of (S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0565] Sodium tert-butoxide (198 mg, 2.06 mmol) was added to a tetrahydrofuran solution (5 mL) of ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol. The mixture was reacted at room temperature for 10 minutes, and then (S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,6-dichloro-8-fluoro-N-methylquinazolin-4-amine (700 mg, 0.68 mmol) was added. The resulting mixture was reacted at room temperature for 5 hours, and then water was added to quench the mixture, followed by extraction with ethyl acetate. The combined organic phases were concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (650 mg, yield: 80%).

[0566] LCMS: m / z 1187 (M+H) + .

[0567] Step 2: Preparation of (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0568] (S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine (650 mg, 0.55 mmol) in trifluoroacetic acid (5 mL) was reacted at 55°C for 7 hours and then concentrated under reduced pressure. The residue was alkalized with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phase was concentrated under reduced pressure, and the residue was separated by preparative liquid phase to obtain the target product (203 mg, yield: 51%).

[0569] LCMS: m / z 707 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.00 (s, 1H), 7.96-7.94 (m, 1H), 7.63 (d, J = 8Hz, 1H), 6.85 (s, 2H), 6.66-6.63(m,1H),6.48(s,1H),6.01-5.98(m,3H),4.24-4.12(m,2H),3.18(s,3H),3.12- 3.07(m,1H),3.04-2.99(m,1H),2.73-2.67(m,1H),2.56-2.54(m,1H),2.37(s,3H),2.10- 1.97(m,2H),1.92-1.88(m,1H),1.83-1.73(m,2H),1.65-1.53(m,5H),1.50-1.44(m,1H).

[0570] The following examples were synthesized using different starting materials according to the method of Example B1:

[0571] Example B2: (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylquinazolin-4-amine

[0572]

[0573] LCMS: m / z 663 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.96-7.95(m,1H),7.63-7.61(s,1H),6.84 (s,2H),6.66-6.63(m,1H),6.49(s,1H),6.07-5.97(m,3H),5.36-5.22(m,1H),4 .08(s,2H),3.18(s,3H),3.15-3.11(m,2H),3.04(s,1H),2.85(s,1H),2.37(m,3 H),2.20-2.14(m,1H),2.07-2.03(m,2H),1.87-1.80(m,3H),1.61-1.59(m,3H).

[0574] Example B3: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0575]

[0576] LCMS: m / z 707 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=1.5Hz,1H),7.97(dd,J=4.9,1.7Hz,1H),7.63(dd,J=7.6,1.7Hz,1 H),6.87(s,2H),6.66(dd,J=7.5,4.9Hz,1H),6.50(s,1H),6.03–5.95(m,1H),5.80(s,2H),4.19(q,J= 10.5Hz,2H),3.15(s,3H),3.13–3.07(m,1H),3.06–2.99(m,1H),2.76–2.70(m,1H),2.38(d,J=2.2Hz ,3H),2.13–2.06(m,1H),2.05–1.97(m,1H),1.95–1.88(m,1H),1.86–1.71(m,2H),1.68–1.44(m,6H).

[0577] Example B4: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylquinazolin-4-amine

[0578]

[0579] LCMS: m / z 663 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.00(d,J=1.6Hz,1H),7.96(dd,J=4.9,1.7Hz,1H),7.62(dd,J= 7.7,1.8Hz,1H),6.85(s,2H),6.65(dd,J=7.5,4.9Hz,1H),6.49(s,1H),6.02–5.93(m,1H ),5.77(s,2H),5.36–5.22(m,1H),4.19–3.97(m,2H),3.19–3.01(m,7H),2.90–2.79(m, 1H),2.37(d,J=2.2Hz,3H),2.23–1.97(m,3H),1.91–1.75(m,3H),1.61(d,J=6.7Hz,3H).

[0580] Example B5: 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-ethyl-8-fluoroquinazolin-4-amine

[0581]

[0582] LCMS: m / z 721 (M+H) + .

[0583] Example B5 was separated by preparative liquid phase to obtain Examples B5-A and B5-B:

[0584] Embodiment B5-A:

[0585] LCMS: m / z 721 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.16–10.68(m,1H),8.19(d,J=7.4Hz,1H),8.13–7.96(m,3H ),7.03–6.79(m,3H),6.56–6.52(m,1H),6.00–5.89(m,1H),4.68–4.61(m,2H),4.56– 4.48(m,2H),3.89–3.84(m,2H),3.82–3.74(m,1H),3.71–3.63(m,1H),3.48–3.40(m, 1H),3.18–3.07(m,1H),2.47–1.87(m,13H),1.70–1.64(m,3H),1.09(t,J=6.9Hz,3H).

[0586] Embodiment B5-B:

[0587] LCMS: m / z 721 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.16–10.79(m,1H),8.21–8.03(m,4H),7.03–6.80(m,3H),6.52(s,1H),5.99–5.91(m,1H),4.67–4.53(m,3H),4 .03–3.95(m,1H),3.81–3.65(m,3H),3.49–3.43(m,1H),3.18–3.09(m,1H),2.49–1.87(m,12H),1.67(d,J=6.8Hz,3H),1.17–1.05(m,3H).

[0588] Example B6: 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(1-(2-aminopyridin-3-yl)ethyl)-6-chloro-N-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-amine

[0589]

[0590] LCMS: m / z 677 (M+H) + .

[0591] Example B6 was separated by preparative liquid phase to obtain Examples B6-A and B6-B:

[0592] Example B6-A:

[0593] LCMS: m / z 677 (M+H)+ . 1 H NMR (400MHz, DMSO-d6) δ11.16–10.72(m,2H),8.68–8.55(m,1H),8.21–8.15(m,1H),8.13–7.97(m,3H),7.02–6.77(m,3H),6.56–6.49(m,1H) ,5.98–5.87(m,1H),5.69–5.51(m,1H),4.64–4.37(m,3H),3.92–3.82 (m,3H),2.44–2.00(m,11H),1.66(d,J=6.7Hz,3H),1.12–1.04(m,3H).

[0594] Example B6-B:

[0595] LCMS: m / z 677 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.13(m,1H),8.07–7.82(m,3H),7.02–6.78(m,3H),6.53–6.49(m,1H),5.99–5.87(m, 1H),5.93–5.54(m,1H),4.67–4.37(m,3H),3.97–3.78(m,4H),2.40–2.05(m,12H),1.66(d,J=6.7Hz,3H),1.12–1.03(m,3H).

[0596] Example B7: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methylquinazolin-4-amine

[0597]

[0598] LCMS: m / z 691 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ7.95 (dd, J=4.9, 1.7Hz, 1H), 7.81 (dd, J=11.1, 1.7Hz, 1H), 7.63 (dd, J=7.5, 1.8Hz,1H),6.87(s,2H),6.65(dd,J=7.5,4.9Hz,1H),6.51(s,1H),6.06–5.95(m,1H),5.79(s,2H), 4.27–4.10(m,2H),3.18–3.02(m,5H),2.73(d,J=11.9Hz,1H),2.60–2.52(m,1H),2.37(d,J=2.3Hz, 3H),2.13–2.05(m,1H),2.04–1.97(m,1H),1.94–1.87(m,1H),1.85–1.72(m,2H),1.62–1.45(m,5H).

[0599] Example B8: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylquinazolin-4-amine

[0600]

[0601] LCMS: m / z 647 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.97(dd,J=4.9,1.7Hz,1H),7.83(dd,J=11.2Hz,1.7Hz,1H),7.64(dd ,J=7.5Hz,1.7Hz,1H),6.89(s,2H),6.67(dd,J=7.5,4.9Hz,1H),6.52(s,1H),6.05–5.97(m,1H ),5.79(s,2H),5.38(s,0.5H),5.25(s,0.5H),4.21–4.02(m,2H),3.22–3.02(m,6H),2.93–2. 82(m,1H),2.38(d,J=2.2Hz,3H),2.25–2.01(m,3H),1.93–1.75(m,3H),1.62(d,J=6.8Hz,3H).

[0602] Example B9: (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methylquinazolin-4-amine

[0603]

[0604] LCMS: m / z 691 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.95 (dd, J=4.9, 1.7Hz, 1H), 7.82 (dd, J=11.1, 1.7Hz, 1H), 7.63 (dd ,J=7.5,1.8Hz,1H),6.87(s,2H),6.65(dd,J=7.5,4.9Hz,1H),6.50(s,1H),6.06–5.93(m,3H ),4.28–4.08(m,2H),3.21–3.06(m,5H),2.74(d,J=11.9Hz,1H),2.60–2.52(m,1H),2.37(d ,J=2.2Hz,3H),2.13–1.97(m,2H),1.95–1.88(m,1H),1.85–1.74(m,2H),1.63–1.46(m,6H).

[0605] Example B10: (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylquinazolin-4-amine

[0606]

[0607] LCMS: m / z 647 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ7.97 (dd, J=5.0, 1.7Hz, 1H), 7.83 (dd, J=11.2Hz, 1.7Hz, 1H), 7.6 4(dd,J=7.6,1.7Hz,1H),6.89(s,2H),6.66(dd,J=7.5,4.9Hz,1H),6.52(s,1H),6.07–5. 93(m,3H),5.38(s,0.5H),5.25(s,0.5H),4.10(s,2H),3.22–3.02(m,6H),2.93–2.82(m, 1H),2.38(d,J=2.4Hz,3H),2.25–2.01(m,3H),1.95–1.77(m,3H),1.61(d,J=6.7Hz,3H).

[0608] Example B11A: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((S)-1-(2-amino-5-fluoropyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0609]

[0610] LCMS: m / z 725 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ8.02(s,1H),7.95–7.94(d,J=2.8Hz,1H),7.61–7.58(dd,J=9.7,2.9Hz,1H),6.87(s,2H),6.50(s,1H),6.02–5.84( m,3H),4.28–4.07(m,2H),3.23(s,3H),3.18–3.00(m,2H),2.81–2.67(m,1H),2.38(d,J=2.2Hz,3H),2.13–1.73(m,5H),1.71–1.46(m,6H).

[0611] Example B11B: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-amino-5-fluoropyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0612]

[0613] LCMS: m / z 725 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ8.02(d,J=1.5Hz,1H),7.95–7.94(d,J=2.8Hz,1H),7.63–7.60(dd,J=9.5,2.9Hz,1H),6.88(s,2H),6.50(s,1H),5.98–5 .88(m,1H),5.75(s,2H),4.30–4.08(m,2H),3.25–2.92(m,5H),2.83–2. 68(m,1H),2.38(d,J=2.2Hz,3H),2.15–1.72(m,5H),1.70–1.44(m,6H).

[0614] Example B12A: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(3-amino-pyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0615]

[0616] LCMS: m / z 708 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.10–8.04(m,1H),7.95(d,J=2.7Hz,1H),7.79(d, J=2.5Hz,1H),6.88(s,2H),6.50(s,1H),6.46(s,2H),6.07–5.99(m,1H),4 .27–4.06(m,2H),3.35(s,3H),3.19–2.99(m,2H),2.83–2.67(m,1H),2.62 –2.53(m,1H),2.38(d,J=2.3Hz,3H),2.13–1.72(m,5H),1.68–1.46(m,6H).

[0617] Example B12B: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((S)-1-(3-amino-pyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0618]

[0619] LCMS: m / z 708 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ8.08(s,1H),7.95(d,J=2.7Hz,1H),7.79(d,J=2.7Hz,1H),6.89(s,2H),6.61(s,2H),6.50(s,1H),6.05–5.97(m,1H),4.39 –4.05(m,2H),3.41(s,3H),3.26–3.02(m,2H),2.89–2.71(m,1H),2.69–2 .55(m,1H),2.38(d,J=2.2Hz,3H),2.19–1.74(m,5H),1.70–1.45(m,6H).

[0620] Example B13A and Example B13B: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b ]thiophene-3-carbonitrile and (S)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0621]

[0622] Example B13A

[0623] LCMS: m / z 723 (M+H) + . 11H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 2H), 8.03 (s, 1H), 7.97 - 7.95 (m, 1H), 7.64 - 7.61 (m, 1H), 7.24 - 7.21 (m, 1H), 7.17 - 7.12 (m, 1H), 6.67 - 6.64 (m, 1H), 6.01 - 5.96 (m, 1H), 5.83 (s, 2H), 4.25 - 4.14 (m, 2H), 3.17 (s, 3H), 3.12 - 3.08 (m, 1H), 3.04 - 2.99 (m, 1H), 2.74 - 2.66 (m, 1H), 2.56 - 2.52 (m, 1H), 2.11 - 2.06 (m, 1H), 1.03 - 1.98 (m, 1H), 1.92 - 1.88 (m, 1H), 1.83 - 1.72 (m, 2H), 1.64 (d, J = 8 Hz, 3H), 1.60 - 1.54 (m, 2H), 1.50 - 1.43 (m, 1H).

[0624] Example B13B

[0625] LCMS: m / z 723 (M + H) + 。 1 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 3H), 7.97 - 7.95 (m, 1H), 7.65 - 7.63 (m, 1H), 7.25 - 7.22 (m, 1H), 7.17 - 7.13 (m, 1H), 6.67 - 6.64 (m, 1H), 6.11 - 6.06 (m, 1H), 5.93 (s, 2H), 4.24 - 4.14 (m, 2H), 3.17 (s, 3H), 3.13 - 3.09 (m, 1H), 3.03 - 3.01 (m, 1H), 2.74 - 2.67 (m, 1H), 2.56 - 2.52 (m, 1H), 2.12 - 2.07 (m, 1H), 2.04 - 1.98 (m, 1H), 1.92 - 1.89 (m, 1H), 1.83 - 1.72 (m, 2H), 1.66 - 1.54 (m, 5H), 1.49 - 1.43 (m, 1H).

[0626] Example B14A and Example B14B: (R)-7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl Quinazolin-4-amine and (S)-7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0627]

[0628] Example B14A

[0629] LCMS: m / z 726 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 7.97 (d, J = 4Hz, 1H), 7.64 (d, J = 8Hz, 1H), 6.90 (s, 1H), 6.68-6.65(m,1H),6.36-6.33(m,3H),6.04-5.99(m,1H),5.85(s,2H),4.24-4.15(m,2H),3. 17(s,3H),3.14-3.08(m,1H),3.06-3.00(m,1H),2.75-2.68(m,1H),2.57-2.55(m,1H),2.1 1-2.06(m,1H),2.04-1.98(m,1H),1.93-1.89(m,1H),1.84-1.72(m,2H),1.66-1.44(m,6H).

[0630] Example B14B

[0631] LCMS: m / z 726 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 7.97 (d, J = 4Hz, 1H), 7.64 (d, J = 8Hz, 1H), 6.90 (s, 1H), 6.68-6.65(m,1H),6.36-6.33(m,3H),6.05-6.00(m,1H),5.92(s,2H),4.25-4.13(m,2H),3. 19(s,3H),3.13-3.08(m,1H),3.05-3.00(m,1H),2.74-2.68(m,1H),2.57-2.55(m,1H),2.1 0-2.06(m,1H),2.04-1.98(m,1H),1.93-1.89(m,1H),1.85-1.72(m,2H),1.66-1.45(m,6H).

[0632] Example B15A and Example B15B: (R)-7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl Quinazolin-4-amine and (S)-7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0633]

[0634] Example B15A

[0635] LCMS: m / z 724 (M+H) + . 11H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.97 (d, J = 4 Hz, 1H), 7.64 (d, J = 8 Hz, 1H), 6.86 - 6.83 (m, 1H), 6.68 - 6.65 (m, 1H), 6.07 - 6.02 (m, 3H), 5.89 (s, 2H), 4.25 - 4.15 (m, 2H), 3.19 (s, 3H), 3.14 - 3.09 (m, 1H), 3.06 - 3.00 (m, 1H), 2.75 - 2.68 (m, 1H), 2.57 - 2.55 (m, 1H), 2.37 - 2.34 (m, 3H), 2.11 - 2.06 (m, 1H), 2.04 - 1.98 (m, 1H), 1.93 - 1.89 (m, 1H), 1.85 - 1.73 (m, 2H), 1.66 - 1.54 (m, 5H), 1.51 - 1.45 (m, 1H).

[0636] Example B15B

[0637] LCMS: m / z 724 (M + H) + 。 1 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.98 (d, J = 4 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 6.86 - 6.84 (m, 1H), 6.68 - 6.65 (m, 1H), 6.05 - 6.00 (m, 3H), 5.86 (s, 2H), 4.27 - 4.16 (m, 2H), 3.20 (s, 3H), 3.14 - 3.04 (m, 2H), 2.77 - 2.69 (m, 1H), 2.59 - 2.56 (m, 1H), 2.37 - 2.33 (m, 3H), 2.12 - 2.00 (m, 2H), 1.94 - 1.90 (m, 1H), 1.83 - 1.74 (m, 2H), 1.67 - 1.55 (m, 5H), 1.52 - 1.46 (m, 1H).

[0638] Example B16A and Example B16B: 7-((R)-3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl Quinazolin-4-amine and 7-((S)-3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[0639]

[0640] Example B16A

[0641] LCMS: m / z 718 (M+H) + .

[0642] Example B16B

[0643] LCMS: m / z 718 (M+H) + .

[0644] Example B17A and Example B17B: 7-((R)-3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methyl Quinazolin-4-amine and 7-((S)-3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methylquinazolin-4-amine

[0645]

[0646] Example B17A

[0647] LCMS: m / z 702 (M+H) + .

[0648] Example B17B

[0649] LCMS: m / z 702 (M+H) + .

[0650] Example B18A and Example B18B: (S)-7-(6-amino-4-(prop-1-yn-1-yl)-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methyl Quinazolin-4-amine and (R)-7-(6-amino-4-(prop-1-yn-1-yl)-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methylquinazolin-4-amine

[0651]

[0652] Example B18A

[0653] LCMS: m / z 731 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ8.02(s,1H),7.97(d,J=8Hz,1H),7.64(d,J=8Hz,1H),7.07(s,2H), 6.67-6.65(m,2H),6.00-5.96(m,1H),5.80(s,2H),4.23-4.16(m,2H),3.15(s,3H),3.10(m, 1H),3.03(m,1H),2.74-2.68(m,1H),2.57-2.55(m,1H),2.12(s,3H),2.10-2.07(m,1H),2. 04-1.98(m,1H),1.93-1.89(m,1H),1.84-1.70(m,2H)1.63-1.54(m,5H),1.51-1.45(m,1H).

[0654] Example B18B

[0655] LCMS: m / z 731 (M+H) + . 1 H NMR (400 MHz, DMSO-d6)δ 1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.97(d,J=8Hz,1H),7.64(d,J=8Hz,1H),7.0 7(s,2H),6.67-6.64(m,2H),6.02-5.97(m,3H),4.27-4.14(m,2H),3.19(s,3H),3. 12-3.02(m,1H),2.78-2.68(m,1H),2.59-2.55(m,1H),2.12(s,3H),2.10-2.07(m ,1H),2.05-1.99(m,1H),1.94-1.91(m,1H),1.87-1.75(m,2H),1.68-1.46(m,7H).

[0656] Example B19A and Example B19B: (S)-7-(3-amino-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methyl Quinazolin-4-amine and (R)-7-(3-amino-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methylquinazolin-4-amine

[0657]

[0658] Example B19A

[0659] LCMS: m / z 748 (M+H) + .

[0660] Example B19B

[0661] LCMS: m / z 748 (M+H) + .

[0662] Example B20A and Example B20B: (R)-7-(5-amino-4-fluoro-3-(prop-1-yn-1-yl)-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methyl Quinazolin-4-amine and (S)-7-(5-amino-4-fluoro-3-(prop-1-yn-1-yl)-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methylquinazolin-4-amine

[0663]

[0664] Example B20A

[0665] LCMS: m / z 748 (M+H) + .

[0666] Example B20B

[0667] LCMS: m / z 748 (M+H) + .

[0668] Example B21A and Example B21B: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl-N-((S)-1-(2-(methylamino)pyridin-3-yl)ethyl )quinazolin-4-amine and (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl-N-((R)-1-(2-(methylamino)pyridin-3-yl)ethyl)quinazolin-4-amine

[0669]

[0670] Example B21A

[0671] LCMS: m / z 721 (M+H) + .1 H NMR (400MHz, DMSO-d6) δ8.05(d,J=4Hz,1H),8.02(s,1H),7.61(d,J=8Hz,1H),6.85(s,2H),6.67-6.6 4(m,1H),6.62-6.59(m,1H),6.49(s,1H),6.00-5.95(m,1H),4.25-4.23(m,1H),4.13-4.11(m,1H),3. 19(s,3H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.83(d,J=4Hz,3H),2.74-2.67(m,1H),2.57-2.55(m ,1H),2.37-2.33(m,3H),2.11-1.99(m,2H),1.92-1.88(m,1H),1.83-1.71(m,2H),1.65-1.44(m,6H).

[0672] Example B21B

[0673] LCMS: m / z 721 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.05(d,J=4Hz,1H),8.01(s,1H),7.63(d,J=8Hz,1H),6.99-6.96(m,1H) ,6.85(s,2H),6.62-6.59(m,1H),6.49(s,1H),5.96-5.91(m,1H),4.25-4.14(m,2H),3.22(s,3H) ,3.14-3.03(m,2H),2.85(d,J=4Hz,3H),2.75-2.67(m,1H),2.58-2.54(m,1H),2.37-2.33(m,3H) ,2.14-2.10(m,1H),2.04-1.99(m,1H),1.94-1.91(m,1H),1.83-1.76(m,2H),1.61-1.47(m,6H).

[0674] Example B22 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazoline-6-carbonitrile

[0675]

[0676] LCMS: m / z 698 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.53–8.46(m,1H),8.00–7.93(m,1H),7.67–7.60(m,1H),6.94(s ,2H),6.69–6.62(m,1H),6.53(s,1H),6.13–5.99(m,1H),5.89(s,1H),5.75(s,1H),4.29– 4.09(m,2H),3.25–3.16(m,3H),3.13–2.96(m,2H),2.77–2.69(m,1H),2.54(dd,J=8.9,6. 2Hz,1H),2.39(q,J=2.1Hz,3H),2.11–1.94(m,2H),1.92–1.70(m,3H),1.66–1.42(m,6H).

[0677] Examples B23A and B23B: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-trimethylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (S)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-trimethylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0678]

[0679] Example B23A

[0680] LCMS: m / z 634 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.11 (s, 2H), 7.95 (d, J=

[0681] 4.5Hz,2H),7.60(d,J=7.3Hz,1H),7.21(dd,J=8.3,5.4Hz,1H),7.14(t,J=8.9Hz,1H),6.64(dd,J=7.3,5.0H z,1H),6.04(m,3H),3.94(m,2H),3.79(m,2H),3.11(s,3H),2.21(s,6H),1.60(d,J=6.7Hz,3H),1.32(s,3H).

[0682] Example B23B

[0683] LCMS: m / z 634 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.11 (s, 2H), 7.94 (dd, J=

[0684] 4.8,1.4Hz,1H),7.89(s,1H),7.59(d,J=7.3Hz,1H),7.26–7.06(m,2H),6.64(dd,J=7.4,5.0Hz,1H),5.96(d, J=10.3Hz,3H),3.92(m,2H),3.76(m,2H),3.12(s,3H),2.17(s,6H),1.61(d,J=6.8Hz,3H),1.38–1.26(m,3H).

[0685] Examples B24A, B24B, B24C and B24D: (R)-2-amino-4-(4-(((S)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl )-7-fluorobenzo[b]thiophene-3-carbonitrile, (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzene benzo[b]thiophene-3-carbonitrile, (S)-2-amino-4-(4-(((S)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene -3-carbonitrile, and (S)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0686]

[0687] Example B24A

[0688] LCMS: m / z 724 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.12 (s, 2H), 8.08 (s, 1H), 7.94 (d, J = 4Hz, 1H), 7.77 (d, J = 4Hz, 1H),7.24-7.21(m,1H),7.17-7.13(m,1H),6.49(s,2H),6.02-5.97(m,1H),4.17-4.08( m,2H),3.40(s,3H),3.13-3.00(m,2H),2.73-2.68(m,1H),2.58-2.55(m,1H),2.09-2. 04(m,1H),1.99-1.95(m,1H),1.91-1.87(m,1H),1.81-1.72(m,2H),1.65-1.42(m,6H).

[0689] Example B24B

[0690] LCMS: m / z 724 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.15 (s, 1H), 8.12 (s, 2H), 7.93 (d, J = 4Hz, 1H), 7.77 ( d,J=4Hz,1H),7.27-7.23(m,1H),7.18-7.13(m,1H),6.57(s,2H),6.05-6.00( m,1H),4.18-4.06(m,2H),3.40(s,3H),3.06-3.03(m,2H),2.73-2.67(m,1H) ,2.58-2.53(m,1H),2.08-1.95(m,2H),1.90-1.75(m,3H),1.65-1.45(m,6H).

[0691] Example B24C

[0692] LCMS: m / z 724 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.12(s,2H),8.08(s,1H),7.94(d,J=4Hz,1H),7.78(d,J= 4Hz,1H),7.24-7.21(m,1H),7.17-7.13(m,1H),6.51(s,2H),6.04-5.99(m,1H),4. 21-4.05(m,2H),3.39(s,3H),3.11-3.00(m,2H),2.73-2.67(m,1H),2.57-2.54(m ,1H),2.08-1.95(m,2H),1.89-1.86(m,1H),1.80-1.74(m,2H),1.65-1.42(m,6H).

[0693] Example B24D

[0694] LCMS: m / z 724 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),8.12(s,2H),7.93(d,J=4Hz,1H),7.77(d,J=4Hz,1H),7.27-7.23(m,1H),7.18-7.13(m,1H),6.53(s,2H),6. 04-5.99(m,1H),4.16-4.06(m,2H),3.41(s,3H),3.12-3.00(m,2H),2.7 3-2.67(m,1H),2.56-2.53(m,1H),2.07-1.72(m,5H),1.65-1.44(m,6H).

[0695] Examples B25A and B25B: (R)-7-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinol Quinazoline-4-amine and (S)-7-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazoline-4-amine

[0696]

[0697] Example B25A

[0698] LCMS: m / z 724 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.06 (s, 1H), 7.98-7.97 (m, 1H), 7.65 (d, J = 8Hz, 1H), 6.69-6.66 (m ,1H),6.44(d,J=8Hz,1H),6.10(s,2H),6.05-6.00(m,1H),5.88(s,2H),4.26-4.16(m,2H), 3.18(s,3H),3.16-3.04(m,2H),2.76-2.70(m,1H),2.59-2.57(m,1H),2.36(s,3H),2.12-1 .99(m,2H),1.94(d,J=12Hz,1H),1.85-1.75(m,2H),1.64-1.62(m,3H),1.59-1.48(m,3H).

[0699] Example B25B

[0700] LCMS: m / z 724 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.03 (s, 1H), 7.96 (d, J = 4Hz, 1H), 7.63 (d, J = 8Hz, 1H), 6.66-6. 63(m,1H),6.41(d,J=8Hz,1H),6.08(s,2H),6.03-5.98(m,1H),5.93(s,2H),4.23-4.1 2(m,2H),3.18(s,3H),3.12-3.00(m,2H),2.74-2.67(m,1H),2.56-2.54(m,1H),2.33( s,3H),2.10-1.97(m,2H),1.92(d,J=12Hz,1H),1.81-1.71(m,2H),1.65-1.45(m,6H).

[0701] Example B26: Preparation of (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(4-methylpiperazin-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0702]

[0703] LCMS: m / z 620 (M+H)+ . 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.22–7.86(m,7H),7.17(m,2H),7.01–6.87(m,1H),5.91–5. 79(m,1H),4.75(m,2H),3.48(m,2H),3.31(m,5H),3.04(m,2H),2.82(s,3H),1.66(d,J=6.7Hz,3H).

[0704] Example B27: Preparation of (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0705]

[0706] LCMS: m / z 635 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.10(m,7H),7.25–7.16(m,1H),7.00– 6.94(m,1H),5.89(m,1H),4.75(m,1H),4.48(m,1H),3.83(m,1H),3.62(m,1 H),3.38(s,3H),3.15(m,1H),2.97(s,3H),2.80(m,1H),2.27(m,1H),2.07( d,J=13.8Hz,1H),1.93(m,2H),1.70(d,J=6.8Hz,3H),1.51(d,J=6.6Hz,1H).

[0707] Example B28: Preparation of (R)-2-amino-4-(4-(((R)-1-(2-2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-fluorobenzo[b]thiophene-3-carbonitrile

[0708]

[0709] LCMS: m / z 649 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.15(s,2H),8.04(s,1H),7.96(d,J=4.1Hz,1H),7.62(d,J=7.0Hz,1H),7.27–7.09(m,2H),6.66(dd,J=7.3,4.9Hz,1H),5.9 8(d,J=6.5Hz,1H),5.84(s,2H),4.33(d,J=11.4Hz,1H),4.21(d,J=11.4Hz ,1H),3.18(s,3H),1.63(d,J=6.6Hz,3H),1.40–1.05(m,5H),0.80(m,4H).

[0710] Example B29: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-azetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0711]

[0712] LCMS: m / z 620 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.14 (s, 2H), 7.95 (dd, J=

[0713] 4.9,1.4Hz,1H),7.91(d,J=1.1Hz,1H),7.61(d,J=6.6Hz,1H),7.24–7.06(m,2H),6.65(dd,J=7.4,5.0Hz,1H ),6.11–5.90(m,3H),4.23–4.10(m,2H),4.07–3.89(m,2H),3.12(s,3H),2.30(s,6H),1.61(d,J=6.8Hz,3H).

[0714] Example B30: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-pyrrolidine-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0715]

[0716] LCMS: m / z 634 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.02(m,7H),7.37(s,1H),7.23–7.11(m,1H),6.94(m,1H),5.88–5.75(m,1H),3.95(m,2 H),3.77–3.63(m,2H),3.34(s,3H),2.84(s,6H),2.38(s,1H),2.25–2.08(m,1H),1.67(d,J=6.7Hz,3H),1.52(t,J=8.7Hz,1H).

[0717] Example B31: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-piperidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0718]

[0719] LCMS: m / z 620 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.00–7.94(m,1H),7.87–7.83(m,1H),7.60(dd,J=12.6, 7.4Hz,1H),7.26–7.11(m,2H),6.73–6.64(m,1H),5.98–5.88(m,1H),5.69(s,2H),4.89–4.71 (m,1H),4.57–4.40(m,1H),3.11(d,J=12.2Hz,3H),2.70–2.55(m,2H),2.08–1.96(m,2H),1.8 8–1.74(m,1H),1.63(d,J=6.7Hz,3H),1.55–1.38(m,2H),1.25(s,6H),0.87(t,J=6.6Hz,1H).

[0720] Example B32: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(4-(dimethylamino)-piperidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0721]

[0722] LCMS: m / z 620 (M+H) + .1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),8.39–7.89(m,6H),7.29–7.08(m,2H),6.95(t,J=6.8Hz,1H),5.78(q,J=6.7Hz,1H),4.85(d,J=12.5Hz ,2H),3.48(m,1H),3.34(s,3H),2.88(m,2H),2.81–2.60(m,6H),2.09–1.91(m,2H),1.67(d,J=6.8Hz,3H),1.52(m,1H),1.43–1.23(m,1H).

[0723] Example B33: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(6-methyl-1,6-diazaspiro[3.3]hept-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0724]

[0725] LCMS: m / z 632 (M+H) + .

[0726] Example B34: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(1-methyl-1,6-diazaspiro[3.3]hept-6-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0727]

[0728] LCMS: m / z 632 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.32–7.94(m,7H),7.24–7.10(m,2H),7.05–6.94(m,1H),5.80(d,J=6 .6Hz,1H),4.53(m,4H),4.29(m,2H),3.28(s,3H),2.92(s,3H),2.75(t,J=8.3Hz,2H),1.69(d,J=6.7Hz,3H).

[0729] Example B35: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-methylazetidin-3-yl)oxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0730]

[0731] LCMS: m / z 607 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.26–8.05(m,5H),7.81(s,2H),7.20(m,2H),7.05–6.94(m,1H),5.85( s,1H),5.43(m,1H),4.68(s,1H),4.41(s,2H),4.20(s,1H),3.26(s,3H),2.94(s,3H),1.69(d,J=6.6Hz,3H).

[0732] Example B36: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-methylazetidin-3-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0733]

[0734] LCMS: m / z 621 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.39–7.91(m,7H),7.29–7.09(m,2H),6.97(t,J=6.7Hz,1H),5.91(d,J=6.6Hz,1H),4 .52(m,2H),4.31(m,1H),4.18(m,1H),4.05(m,1H),3.92(m,1H),3.26(m,4H),2.86(d,J=9.3Hz,3H),1.69(d,J=6.6Hz,3H).

[0735] Example B37: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoro-N-methylquinazolin-4-amine

[0736]

[0737] LCMS: m / z 618 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.94 (dd, J=4.8, 1.4Hz,

[0738] 1H),7.86(s,1H),7.58(d,J=7.2Hz,1H),6.84(s,2H),6.63(dd,J=7.4,4.9Hz,1H),6.47(s,1H),6.01–5.83(m,3 H),3.97–3.78(m,2H),3.72(m,2H),3.09(s,3H),2.36(s,3H),2.12(s,6H),1.58(d,J=6.8Hz,3H),1.25(s,3H).

[0739] Example B38: (4R)-4-(4-((1-(1H-pyrazol-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0740]

[0741] LCMS: m / z 697 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.33–8.10(m,3H),7.76–7.70(m,1H),7.32(s,1H),7. 30–7.23(m,1H),7.22–7.14(m,2H),7.06(s,1H),6.42–6.34(m,1H),6.11–5.99(m,1H),4.67– 4.64(m,1H),3.81–3.75(m,1H),3.71–3.64(m,1H),3.48–3.43(m,1H),3.21–3.07(m,4H),2. 31–2.12(m,3H),2.09–2.02(m,1H),1.99–1.93(m,1H),1.91–1.82(m,2H),1.69–1.60(m,3H).

[0742] Example B39A and 39B: (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-fluoro-8-(prop-1-yn-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiol phene-3-carbonitrile and (S)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-fluoro-8-(prop-1-yn-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0743]

[0744] Example B39A

[0745] LCMS: m / z 728 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.06 (s, 2H), 7.94 (d, J = 4Hz, 1H), 7.90 (d, J = 12Hz, 1H), 7 .79(d,J=4Hz,1H),7.25-7.22(m,1H),7.14(t,J=8Hz,1H),6.50(s,2H),6.03-5.9 9(m,1H),4.29-4.14(m,2H),3.11-3.04(m,3H),2.74-2.68(m,1H),2.57-2.55(m, 1H),2.12-2.07(m,1H),2.04-1.98(m,1H),1.91-1.75(m,7H),1.65-1.45(m,7H).

[0746] Embodiment B39B:

[0747] LCMS: m / z 728 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.06 (s, 2H), 7.97 (d, J = 8Hz, 1H), 7.93 (d, J = 4Hz, 1H), 7. 78(d,J=4Hz,1H),7.29-7.25(m,1H),7.14(t,J=8Hz,1H),6.60(s,2H),6.05-5.99 (m,1H),4.24-4.14(m,2H),3.12-3.02(m,3H),2.74-2.68(m,1H),2.57-2.55(m, 1H),2.09-2.04(m,1H),2.00-1.96(m,1H),1.90-1.73(m,7H),1.65-1.45(m,7H).

[0748] Examples B40A and B40B: (S)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-7-fluorobenzo[b]thiol Thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0749]

[0750] Embodiment B40A:

[0751] LCMS: m / z 708 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.17 (s, 2H), 7.95 (d, J = 4Hz, 1H), 7.90 (d, J = 12Hz, 1H), 7.79 (d, J = 4Hz, 1H),7.35-7.31(m,1H),7.17(t,J=8Hz,1H),6.53(s,2H),6.08-6.03(m,1H),4.21-4.06(m,2H) ,3.38(s,3H),3.12-3.02(m,2H),2.73-2.70(m,1H),2.57-2.55(m,1H),2.09-2.04(m,1H),2.0 2-1.96(m,1H),1.91(d,J=12Hz,1H),1.83-1.71(m,2H),1.66(d,J=8Hz,3H),1.60-1.45(m,3H).

[0752] Embodiment B40B:

[0753] LCMS: m / z 708 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.17 (s, 2H), 7.95-7.92 (m, 2H), 7.79 (d, J = 4Hz, 1H) 7.36-7.33 (m ,1H),7.17(t,J=8Hz,1H),6.59(s,2H),6.09-6.04(m,1H),4.19-4.04(m,2H),3.39(s,3H ),3.12-3.02(m,2H),2.72-2.69(m,1H),2.57-2.55(m,1H),2.08-2.03(m,1H),2.00-1.9 4(m,1H),1.89(d,J=12Hz,1H),1.83-1.71(m,2H),1.65(d,J=8Hz,3H),1.60-1.45(m,3H).

[0754] Example B41: 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0755]

[0756] LCMS: m / z 689 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.89 (s, 1H), 8.12-8.09 (m, 3H), 7.95-7.93 (m, 1H), 7.79 (t, J = 4Hz, 1H), 7.27-7.23 (m, 2H), 7.17-7.12 (m,1H),6.66(s,1H),6.55(s,1H),6.13-6.06(m,1H),4.37(s,3H),3.45(d,J=20Hz,4H),2.22-1.89(m,6H),1.67-1.65(m,5H).

[0757] Example B42: (R)-2-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0758]

[0759] LCMS: m / z 632 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.10 (s, 2H), 7.93 (dd, J=

[0760] 23.4,8.5Hz,2H),7.73(d,J=1.9Hz,1H),7.20(dd,J=8.4,5.4Hz,1H),7.13(t,J=8.9Hz,1H),6.54(d,J =20.0Hz,2H),5.89(s,1H),3.99–3.56(m,4H),2.11(s,6H),1.61(d,J=6.8Hz,3H),1.33–1.18(m,6H).

[0761] Examples B43A and B43B: (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(prop-1-yn-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((S)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(prop-1-yn-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0762]

[0763] Example B43A

[0764] LCMS: m / z 639 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.02 (s, 2H), 7.90 (d, J = 4

[0765] Hz,1H),7.75-7.73(m,2H),7.22-7.19(m,1H),7.12(t,J=12Hz,1H),6.55(s,2H),5.93-5.87(m,1H),3. 86(s,1H),3.71-3.62(m,3H),3.31(s,3H),2.11(s,6H),1.82(s,3H),1.62(d,J=8Hz,3H),1.25(s,3H).

[0766] Embodiment B43B:

[0767] LCMS: m / z 639 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.02 (s, 2H), 7.89 (d, J = 4

[0768] Hz,1H),7.73-7.72(m,1H),7.26-7.23(m,1H),7.13(t,J=12Hz,2H),6.64(s,2H),5.87(s,1H),3.85-3. 80(m,1H),3.68-3.56(m,3H),3.38(s,3H),2.10(s,6H),1.83(s,3H),1.61(d,J=8Hz,3H),1.23(s,3H).

[0769] Example B44: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-3-yl)oxy)quinazolin-7-yl)-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0770]

[0771] LCMS: m / z 621 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.11(m,5H),7.78(m,1H),7.31–7.08(m,2H),7.01–6.92(m,1H),5.87(d,J=6.6Hz,1H ),5.65(m,1H),3.25(m,4H),3.20–3.10(m,2H),2.89(s,3H),2.68(m,1H),2.28(m,2H),1.70(d,J=6.6Hz,3H),1.47(m,1H).

[0772] Example B45: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((R)-1-methylpyrrolidin-3-yl)oxy)quinazolin-7-yl)-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0773]

[0774] LCMS: m / z 621 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.12(m,7H),7.29–7.12(m,3H),6.98(t,J=6.7Hz,1H),5.8 9(s,1H),5.64(s,1H),3.30(m,5H),3.17(m,1H),2.90(m,4H),2.25(m,2H),1.70(d,J=6.6Hz,3H).

[0775] Example B46: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((trans)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0776]

[0777] LCMS: m / z 651 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.15(s,2H),8.02(s,1H),7.98(d,J=4.9Hz,1H),7.62(d,J=7.7Hz,1H),7.24(d d,J=8.5,5.2Hz,1H),7.16(t,J=8.9Hz,1H),6.68(dd,J=7.6,4.8Hz,1H),5.96–5.89(m,1H),5.72(s,2H ),5.45–5.39(m,1H),4.11(dd,J=10.5,5.4Hz,1H),4.02(dd,J=9.4,6.7Hz,1H),3.85(dd,J=10.6,2.5H z,1H),3.62(dd,J=9.4,6.2Hz,1H),3.19(s,3H),3.12–3.04(m,1H),2.25(s,6H),1.64(d,J=5.9Hz,3H).

[0778] Example B47: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((cis)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0779]

[0780] LCMS: m / z 651 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.15(s,2H),8.02(s,1H),7.98(dd,J=4.9,1.8Hz,1H),7.61(dd,J=7.7,1.7Hz,1H), 7.24(dd,J=8.4,5.3Hz,1H),7.16(t,J=8.9Hz,1H),6.67(dd,J=7.5,4.8Hz,1H),5.96–5.89(m,1H),5.72(s,2 H),5.40(dd,J=5.4,2.7Hz,1H),4.10(dd,J=10.7,5.5Hz,1H),4.01(dd,J=9.2,6.6Hz,1H),3.85(dd,J=10.4, 2.5Hz,1H),3.61(dd,J=9.2,6.2Hz,1H),3.19(s,3H),3.07–3.01(m,1H),2.23(s,6H),1.63(d,J=6.5Hz,3H).

[0781] Example B48: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0782]

[0783] LCMS: m / z 635 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.14(m,3H),8.05(m,3H),7.30(m,1H),7.26–7.11(m,3H),7.05(m,1H),6.92(m ,1H),5.89(m,1H),5.34(m,1H),3.33(m,3H),3.19(m,4H),2.84(m,3H),2.34~2.20(m,4H),1.88(m,1H),1.69(s,3H).

[0784] Example B49: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-(methoxyethyl)piperidin-4-yl)oxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0785]

[0786] LCMS: m / z 679 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.24–7.85(m,6H),7.19(m,2H),6.92(m,1H),5.88(m ,1H),5.23(m,1H),3.68(m,3H),3.33(m,7H),3.15(m,3H),2.39–1.83(m,6H),1.68(s,3H).

[0787] Example B50: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0788]

[0789] LCMS: m / z 653 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ8.11(s,2H),7.96(d,J=4.0Hz,1H),7.89(s,1H),7.61(d,J=7.1Hz,1H),7.26–7.03(m,2H),6.65(dd,J=7.4,5.0Hz,1H), 5.96(s,3H),4.16–3.90(m,4H),3.71(s,1H),3.11(s,3H),2.78(s,2H), 2.56(m,2H),2.31(s,3H),2.11(t,J=6.9Hz,2H),1.61(d,J=6.8Hz,3H).

[0790] Example B51: (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0791]

[0792] LCMS: m / z 654 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.51(d,J=7.4Hz,2H),8.28(s,1H),8.15(s,2H),7.27(dd,J=8 .3,5.3Hz,1H),7.17(t,J=8.9Hz,1H),5.14(d,J=57.1Hz,1H),4.34(dd,J=11.1,4.3Hz, 1H),4.26(dd,J=11.0,5.5Hz,1H),4.17(s,1H),3.51–3.42(m,2H),2.86(m,1H),2.45( m,1H),2.43–2.23(m,7H),2.17–1.97(m,1H),1.95–1.75(m,1H),1.41(t,J=7.9Hz,3H).

[0793] Example B52: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0794]

[0795] LCMS: m / z 649 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.14 (s, 2H), 7.98 (d, J=

[0796] 6.0Hz,2H),7.63(d,J=6.5Hz,1H),7.24(dd,J=8.4,5.3Hz,1H),7.15(t,J=8.9Hz,1H),6.68(dd,J=7.4,4.9Hz,1H),5.91(q,J=6.5Hz,1H),5.71( s,2H),5.25(dd,J=12.1,6.1Hz,1H),3.15(s,3H),2.98(s,1H),2.68(s, 1H), 2.40 (s, 3H), 2.23 (s, 1H), 1.87–1.57 (m, 7H), 1.29 (d, J = 6.3Hz, 3H).

[0797] Example B53: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((S)-1-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0798]

[0799] LCMS: m / z 667 (M+H) + .

[0800] Example B54: (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0801]

[0802] LCMS: m / z 649 (M+H) + .

[0803] Example B55: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0804]

[0805] LCMS: m / z 671 (M+H) + .

[0806] Example B56: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((S)-4-(difluoromethylene)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0807]

[0808] LCMS: m / z 683 (M+H) + .

[0809] Example B57: (4R)-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((S)-4-(difluoromethyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0810]

[0811] LCMS: m / z 685 (M+H) + .

[0812] Example B58: (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((2S)-6,6-difluoro-3-methyl-3-azabicyclo[3.1.0]ethane-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0813]

[0814] LCMS: m / z 683 (M+H) + .

[0815] Example B59: (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((6S)-1,1-difluoro-5-methyl-5-azaspiro[2.4]heptane-6-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0816]

[0817] LCMS: m / z 697 (M+H) + .

[0818] Embodiment B60A and B60B:

[0819] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1-methylpiperidin-3-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0820] and (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4R)-4-(difluoromethyl)-1-methylpiperidin-3-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0821]

[0822] Example B60A

[0823] LCMS: m / z 699 (M+H) + .

[0824] Example B60B

[0825] LCMS: m / z 699 (M+H) + .

[0826] Embodiment B61A and B61B:

[0827] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0828] and (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4R)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0829]

[0830] Example B61A

[0831] LCMS: m / z 713 (M+H) + .

[0832] Example B61B

[0833] LCMS: m / z 713 (M+H) + .

[0834] Embodiment B62A and B62B:

[0835] (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0836] and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4R)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0837]

[0838] Example B62A

[0839] LCMS: m / z 714 (M+H) + .

[0840] Example B62B

[0841] LCMS: m / z 714 (M+H) + .

[0842] Embodiments B63A, B63B, B63C and B63D:

[0843] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4S)-1,1-difluoro-6-methyl-6-azaspiro[2.5]octan-4-yl))methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0844] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4R)-1,1-difluoro-6-methyl-6-azaspiro[2.5]octan-4-yl))methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0845] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4S)-1,1-difluoro-6-methyl-6-azaspiro[2.5]octan-4-yl))methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0846] and (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4R)-1,1-difluoro-6-methyl-6-azaspiro[2.5]octan-4-yl))methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0847]

[0848] Example B63A

[0849] LCMS: m / z 711 (M+H) + .

[0850] Example B63B

[0851] LCMS: m / z 711 (M+H) + .

[0852] Example B63C

[0853] LCMS: m / z 711 (M+H) + .

[0854] Example B63D

[0855] LCMS: m / z 711 (M+H) + .

[0856] Embodiments B64A, B64B, B64C and B64D:

[0857] (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4S)-1,1-difluoro-6-methyl-6-azaspiro[2.5]octan-4-yl))methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0858] (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4R)-1,1-difluoro-6-methyl-6-azaspiro[2.5]octan-4-yl))methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0859] (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4S)-1,1-difluoro-6-methyl-6-azaspiro[2.5]octan-4-yl))methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0860] and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4R)-1,1-difluoro-6-methyl-6-azaspiro[2.5]octan-4-yl))methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0861]

[0862] Example B64A

[0863] LCMS: m / z 712 (M+H) + .

[0864] Example B64B

[0865] LCMS: m / z 712 (M+H) + .

[0866] Example B64C

[0867] LCMS: m / z 712 (M+H) + .

[0868] Example B64D

[0869] LCMS: m / z 712 (M+H) + .

[0870] Embodiments B65A, B65B, B65C and B65D:

[0871] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((3S,6S,8aS)-3-methylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0872] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((3S,6S,8aR)-3-methylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0873] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((3S,6R,8aS)-3-methylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0874] and (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((3S,6R,8aR)-3-methylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0875]

[0876] Example B65A

[0877] LCMS: m / z 691 (M+H) + .

[0878] Example B65B

[0879] LCMS: m / z 691 (M+H) + .

[0880] Example B65C

[0881] LCMS: m / z 691 (M+H)+ .

[0882] Example B65D

[0883] LCMS: m / z 691 (M+H) + .

[0884] Embodiments B66A, B66B, B66C and B66D:

[0885] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((3R,6S,8aS)-3-methylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0886] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((3R,6S,8aR)-3-methylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0887] (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((3R,6R,8aS)-3-methylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0888] and (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((3R,6R,8aR)-3-methylhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0889]

[0890] Example B66A

[0891] LCMS: m / z 691 (M+H) + .

[0892] Example B66B

[0893] LCMS: m / z 691 (M+H) + .

[0894] Example B66C

[0895] LCMS: m / z 691 (M+H) + .

[0896] Example B66D

[0897] LCMS: m / z 691 (M+H) + .

[0898] Example B67: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0899]

[0900] LCMS: m / z 632 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),8.28–7.85(m,7H),7.23–7.10(m,2H),7.03–6.93(m,1H),5.81(d,J=6 .8Hz,1H),4.42(m,2H),4.27(m,4H),4.15(m,2H),3.26(s,3H),2.83(d,J=2.9Hz,3H),1.68(d,J=6.8Hz,3H).

[0901] Example B68: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0902]

[0903] LCMS: m / z 646 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.11 (s, 2H), 7.96 (d, J=

[0904] 4.0Hz,1H),7.89(s,1H),7.61(d,J=7.1Hz,1H),7.26–7.03(m,2H),6.65(dd,J=7.4,5.0Hz,1H),5.96(s,3H),4.16–3.90 (m,4H),3.71(s,1H),3.11(s,3H),2.78(s,2H),2.56(m,2H),2.31(s,3H),2.11(t,J=6.9Hz,2H),1.61(d,J=6.8Hz,3H).

[0905] Example B69: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate

[0906]

[0907] LCMS: m / z 646 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.03(m,7H),7.24–7.09(m,2H),6.97(s,1H),5.85(s,1H),4.34– 3.92(m,6H),3.47–3.35(m,2H),3.27(s,3H),2.88(d,J=4.4Hz,3H),2.25(s,2H),1.68(d,J=5.9Hz,3H).

[0908] Example B70: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0909]

[0910] LCMS: m / z 719 (M+H) + .

[0911] Example B71: (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0912]

[0913] LCMS: m / z 720 (M+H) + .

[0914] Example B72: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0915]

[0916] LCMS: m / z 737 (M+H) + .

[0917] Example B73: (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0918]

[0919] LCMS: m / z 738 (M+H) + .

[0920] Example B74: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(difluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0921]

[0922] LCMS: m / z 739 (M+H) + .

[0923] Example B75: (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(difluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0924]

[0925] LCMS: m / z 740 (M+H) + .

[0926] Example B76: (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0927]

[0928] LCMS: m / z 705 (M+H) + .

[0929] Example B77: (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0930]

[0931] LCMS: m / z 723 (M+H) + .

[0932] Example B78: (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((1,1-difluoro-5-azaspiro[2.4]heptane-5-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0933]

[0934] LCMS: m / z 737 (M+H) + .

[0935] Example B79: (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0936]

[0937] LCMS: m / z 685 (M+H) + .

[0938] Example B80: (4R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0939]

[0940] LCMS: m / z 686 (M+H) + .

[0941] Example B81: (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-((S)-2-(dimethylamino)propyl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0942]

[0943] LCMS: m / z 623 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.49–7.94(m,7H),7.35–7.10(m,2H),6.96(t,J=6.8Hz,1H),5.90(d,J=6.7Hz ,1H),4.64(m,1H),4.52(m,1H),3.85(m,1H),3.36(s,3H),2.82(s,6H),1.70(d,J=6.6Hz,3H),1.35(d,J=6.8Hz,3H).

[0944] Example B82: (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-((S)-1-(dimethylamino-2-yl)propyl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0945]

[0946] LCMS: m / z 623 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.13(s,2H),8.00(d,J=1.6Hz,1H),7.96(dd,J=4.9,1.7Hz,1H),7. 61(dd,J=7.6,1.8Hz,1H),7.22(dd,J=8.4,5.3Hz,1H),7.15(t,J=8.9Hz,1H),6.66(dd,J=7 .5,4.8Hz,1H),5.98–5.88(m,1H),5.73(s,2H),5.44–5.33(m,1H),3.78–3.63(m,2H),3.17 (s,3H),2.39–2.25(m,5H),1.62(d,J=6.8Hz,3H),1.51–1.42(m,1H),1.33(d,J=6.2Hz,3H).

[0947] Example B83: N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-N-methylquinazolin-4-amine

[0948]

[0949] LCMS: m / z 681 (M+H) + .

[0950] Example B84: N-((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-N-methylquinazolin-4-amine

[0951]

[0952] LCMS: m / z 682 (M+H) + .

[0953] Example B85: 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile

[0954]

[0955] LCMS: m / z 741 (M+H) + .

[0956] Example B86: 2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile

[0957]

[0958] LCMS: m / z 742 (M+H) + .

[0959] Example B87: 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile

[0960]

[0961] LCMS: m / z 652 (M+H) + .

[0962] Example B88: 2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile

[0963]

[0964] LCMS: m / z 653 (M+H) + .

[0965] Embodiments B89A, B89B, B89C and B89D:

[0966] (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((S)-1-((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0967] (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((S)-1-((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0968] (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((R)-1-((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile,

[0969] and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((R)-1-((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0970]

[0971] Example B89A

[0972] LCMS: m / z 681 (M+H) + .

[0973] Example B89B

[0974] LCMS: m / z 681 (M+H) + .

[0975] Example B89C

[0976] LCMS: m / z 681 (M+H) + .

[0977] Example B89D

[0978] LCMS: m / z 681 (M+H) + .

[0979] Example B90 (4R)-2-amino-4-(6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1-(imidazole[1,2-a]pyrazin-5-yl)ethyl)(methyl)amino)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0980]

[0981] LCMS: m / z 748 (M+H) + .

[0982] Example B91 (4R)-2-amino-4-(6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoro-4-((1-(imidazole[1,2-a]pyrazin-5-yl)ethyl)(methyl)amino)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0983]

[0984] LCMS: m / z 659 (M+H) + .

[0985] Example B92 (4R)-2-amino-4-(4-((1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0986]

[0987] LCMS: m / z 635 (M+H) + .

[0988] Example B93 (4R)-2-amino-4-(4-((1-(5-amino-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0989]

[0990] LCMS: m / z 637 (M+H) + .

[0991] Example B94 (4R)-2-amino-4-(4-((1-(3-amino-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0992]

[0993] LCMS: m / z 637 (M+H) + .

[0994] Example B95 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((7-methyl-7-azaspiro[3.5]nonan-2-yl)oxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0995]

[0996] LCMS: m / z 675 (M+H) + .

[0997] Example B96 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(3-methoxy-3-methylazetidin-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0998]

[0999] LCMS: m / z 621 (M+H) + .

[1000] Example B97 (R)-4-(2-([1,3'-diazetidine]-1'-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[1001]

[1002] LCMS: m / z 632 (M+H) + .

[1003] Example BD1: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy-d2)-8-fluoro-N-methylquinazolin-4-amine

[1004]

[1005] LCMS: m / z 711 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.97(d,J=3.7Hz,1H),7.64(d,J=7.2Hz,1H),6.86(s,2H),6.67(dd,J=7.4,4. 9Hz,1H),6.50(s,1H),6.00(m,1H),5.81(s,2H),3.16(s,3H),3.09(m,2H),2.38(s,3H),1.96(m,5H),1.63(m,6H).

[1006] Example BD2: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-(methyl-d3)quinazolin-4-amine

[1007]

[1008] LCMS: m / z 710 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ8.01(s,1H),7.95(dd,J=4.8,1.7Hz,1H),7.62(dd,J =7.5,1.7Hz,1H),6.82(s,2H),6.65(dd,J=7.5,4.9Hz,1H),6.49(s,1H),6.0 4–5.89(m,3H),4.26(s,2H),3.05–3.13(m,2H),2.85(m,1H),2.63(m,1H),2. 37(d,J=2.2Hz,3H),2.18–2.13(m,1H),2.08–1.92(m,3H),1.70–1.53(m,6H).

[1009] Example BD3: (7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(1-(2-aminopyridin-3-yl)ethyl-1,2,2,2-d4)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[1010]

[1011] LCMS: m / z 711 (M+H) + .

[1012] Example BD3 was subjected to chiral separation to give the isomers Example BD3A and Example BD3B: (7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl-1,2,2,2-d4)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy) -8-fluoro-N-methylquinazolin-4-amine and (7R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((S)-1-(2-aminopyridin-3-yl)ethyl-1,2,2,2-d4)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine

[1013]

[1014] Example BD3A

[1015] LCMS: m / z 711 (M+H) + .

[1016] Example BD3B

[1017] LCMS: m / z 711 (M+H) + .

[1018] Example C1: N-((R)-1-(2-aminopyridin-3-yl)ethyl)-7-(8-chloronaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine trifluoroacetate

[1019]

[1020] Step 1: Preparation of 7-(8-chloronaphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate

[1021] 7-(8-Chloronaphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H-pyran[4,3-d]pyrimidin-4-ol (200 mg, 0.56 mmol) and DIPEA (145 mg, 1.12 mmol) were dissolved in dichloromethane (5 mL), and trifluoromethanesulfonic anhydride (285 mg, 1.01 mmol) was added dropwise under ice-water bath. The reaction solution was stirred in ice-water bath for 1 h, then diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target product (150 mg).

[1022] Step 2: Preparation of N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-(8-chloronaphth-1-yl)-N-methyl-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

[1023] Under argon protection, 7-(8-chloronaphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (150 mg, 0.31 mmol) and (R)-N,N-bis(4-methoxybenzyl)-3-(1-(methylamino)ethyl)pyridin-2-amine (242 mg, 0.62 mmol) were dissolved in DMSO (2 mL), and DIPEA (120 mg, 0.93 mmol) was added. The reaction solution was stirred at 80°C for 1 h, then diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target product (106 mg).

[1024] Step 3: Preparation of N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-(8-chloronaphthalen-1-yl)-N-methyl-2-(methylsulfoxide)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

[1025] At 0°C, N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-(8-chloronaphthalen-1-yl)-N-methyl-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (106 mg, 0.15) was dissolved in ethyl acetate (2 mL), followed by dropwise addition of a solution of m-chloroperbenzoic acid (63 mg, 0.36) in ethyl acetate (2 mL). The reaction mixture was stirred at 0°C for 10 min, then quenched with a saturated sodium hyposulfite solution (30 mL), diluted with water (30 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target product (95 mg).

[1026] Step 4: Preparation of N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-(8-chloronaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

[1027] ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (79 mg, 0.39 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium tert-butoxide (79 mg, 0.39 mmol) was added. After the mixture was stirred for 1 min, a solution of N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-(8-chloronaphthalen-1-yl)-N-methyl-2-(methylsulfoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (95 mg, 0.13 mmol) in tetrahydrofuran (1 mL) was added. After the addition was complete, the reaction solution was stirred at room temperature for 1 h, and then water was added to quench, and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was separated by column chromatography to obtain the target product (60 mg).

[1028] Step 5: Preparation of N-((R)-1-(2-aminopyridin-3-yl)ethyl)-7-(8-chloronaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine trifluoroacetate

[1029] N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-(8-chloronaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (60 mg, 0.07 mmol) was dissolved in trifluoroacetic acid (2 mL). The resulting mixture was stirred at 60° C. for 2 h, then concentrated under reduced pressure, and the residue was separated by preparative liquid phase to obtain the target product (10 mg).

[1030] LCMS: m / z 647 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.69–8.40(m,1H),8.12–7.77(m,6H),7.76–7.69(m,1H),7.6 9–7.60(m,1H),7.56–7.47(m,1H),6.99–6.90(m,1H),6.35–6.26(m,1H),5.78–5.65(m,1H),5.28–4 .99(m,2H),4.52–4.27(m,2H),3.76–3.60(m,2H),3.48–3.28(m,2H),3.17–3.05(m,1H),2.99(s,1. 5H),2.89(s,1.5H),2.81–2.66(m,1H),2.46–2.29(m,1H),2.26–1.82(m,7H),1.58(t,J=6.6Hz,3H).

[1031] The following compounds were synthesized using the same method as Example C1 with different starting materials.

[1032] Example C2: 7-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

[1033]

[1034] LCMS: m / z 670 (M+H) + .

[1035] Example C3: 7-(3-amino-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

[1036]

[1037] LCMS: m / z 702 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ7.95–7.88(m,1H),7.59–7.44(m,1H),7.17(s,2H),6.88(d,J=8.4Hz,1H),6.67–6.55(m,1H),6.21 -6.05(m,2H),5.77–5.54(m,1H),5.38–5.29(m,1H),5.04–4.94(m,1H),4.94–4.70(m,2H),4.12–3.95(m,2H),3.12–2.97( m,3H),2.81–2.74(m,2H),2.71–2.61(m,3H),2.06–2.00(m,4H),1.88–1.83(m,1H),1.80–1.69(m,2H),1.56–1.44(m,7H).

[1038] Example D1: N-((R)-1-(2-aminopyridin-3-yl)ethyl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-amine

[1039]

[1040] LCMS: m / z 664 (M+H) + .

[1041] Example D2: 7-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-amine

[1042]

[1043] LCMS: m / z 669 (M+H) + .

[1044] Example D3: 7-(3-amino-2-fluoro-5-(prop-1-ynyl)-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-methyl-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-amine

[1045]

[1046] LCMS: m / z 701 (M+H) + .

[1047] Example F1: 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinoline-3-carbonitrile

[1048]

[1049] Step 1: Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-(bis(-4-methoxybenzyl)amino)pyridin-3-yl)ethyl)(methyl)amino)-2,6-dichloro-8-fluoroquinoline-3-carbonitrile trifluoroacetate

[1050] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile (250 mg, 0.36 mmol) was dissolved in N,N-dimethylacetamide (3 mL), and N,N-diisopropylethylamine (140 mg, 1.09 mmol) and (R)-N,N-bis(4-methoxybenzyl)-3-(1-(methylamino)ethyl)pyridin-2-amine (156 mg, 0.40 mmol) were added. The resulting mixture was reacted at 100° C. for 2 hours and then cooled to room temperature, and then directly purified by medium pressure column chromatography to obtain the target product (0.25 g, yield: 60%).

[1051] LCMS: m / z 1044 (M+H) + .

[1052] Step 2: Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-(bis(4-methoxyphenyl)amino)pyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinoline-3-carbonitrile

[1053] ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (46 mg, 0.23 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of sodium tert-butoxide (33 mg, 0.34 mmol). The resulting mixture was reacted for 10 minutes, followed by the addition of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-(bis(-4-methoxybenzyl)amino)pyridin-3-yl)ethyl)(methyl)amino)-2,6-dichloro-8-fluoroquinoline-3-carbonitrile trifluoroacetate (130 mg, 0.11 mmol). The resulting mixture was reacted at room temperature for 1 hour, followed by the addition of water and extraction with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the residue was separated by silica gel column chromatography to obtain the target product (90 mg, yield: 67%).

[1054] LCMS: m / z 1212 (M+H) + .

[1055] Step 3: Preparation of 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinoline-3-carbonitrile

[1056] A solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-(bis(4-methoxyphenyl)amino)pyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinoline-3-carbonitrile (90 mg, 0.074 mmol) in trifluoroacetic acid (3 mL) was reacted at 50° C. for 2 hours and then concentrated under reduced pressure. The residue was separated by preparative liquid phase to give the target product (11 mg, yield: 20%).

[1057] LCMS: m / z 731 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.27(s,1H),7.85(s,1H),7.22(d,J=8Hz,2H),6.86(d,J=8Hz,2H),6.58(s,1H),4.42-4.30(m,2H),4.23( s,2H),3.71(s,3H),3.36-3.35(m,3H),3.18-3.06(m,2H),2.70(s,1H) ,2.36(s,3H),2.10-2.01(m,2H),1.91-1.81(m,3H),1.64-1.43(m,4H).

[1058] Example F1 was subjected to chiral separation to give the isomers Example F1A and Example F1B: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methyl (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinoline-3-carbonitrile

[1059]

[1060] Example F1A

[1061] LCMS: m / z 731 (M+H) + .

[1062] Example F1B

[1063] LCMS: m / z 731 (M+H) + .

[1064] The following compounds were synthesized using different starting materials in the same manner as in Example F1:

[1065] Example F2: 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinoline-3-carbonitrile

[1066]

[1067] LCMS: m / z 642 (M+H) + .

[1068] Example F2 was chirally separated to give the isomers Example F2A and Example F2B: (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinoline-3-carbonitrile and (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinoline-3-carbonitrile

[1069]

[1070] Example F2A

[1071] LCMS: m / z 642 (M+H) + .

[1072] Example F2B

[1073] LCMS: m / z 642 (M+H) + .

[1074] Example Pharmaceutical Composition

[1075] Oral tablet:

[1076] Example A2 or A3 is added with auxiliary fillers microcrystalline cellulose (101) and lactose monohydrate, an internal disintegrant croscarmellose sodium, a binder hydroxypropyl methylcellulose (E15), an external disintegrant croscarmellose sodium, and a lubricant magnesium stearate to prepare a 10 mg oral tablet.

[1077] Injection:

[1078] Example A2 or A3 is prepared into an injection preparation by adding sodium sulfobutyl beta-cyclodextrin, sodium chloride, water for injection, etc.

[1079] Biological test cases

[1080] Biological test evaluation

[1081] The following biological test examples further describe and explain the present invention, but these examples are not intended to limit the scope of the present invention.

[1082] 1. Cell Proliferation Assay

[1083]

[1084] Positive reference: MRTX1133

[1085]

[1086] Experimental procedures

[1087] Use a nanoliter pipetting system to add the diluted test compound to a 384-well cell culture plate and set up duplicate wells. Add an equal volume of culture medium to the positive control group; add an equal volume of DMSO to the negative control group, and centrifuge at 1000 rpm for 1 min at room temperature.

[1088] The cells were inoculated into a) 384 culture plate, and the negative control group was added with an equal volume of cells, and the positive control group was added with an equal volume of culture medium only. Centrifuged at 1000 rpm for 1 min at room temperature, and the final DMSO concentration of the compound was 0.5%, and incubated in a 37°C, 5% CO2 constant temperature incubator for 7 days.

[1089] Add 20 μL / well of CellTiter- 3D to b) in a 384-well cell culture plate, shake at 320 rpm for 20 min in the dark, and incubate at room temperature for 2 hrs in the dark.

[1090] The luminescence value was read using Envision multi-function microplate reader.

[1091] 3. Data Analysis

[1092] The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1 – (RLU化合物 –RLU 空白对照 ) / (RLU 溶媒对照 –RLU 空白对照 ))*100%. The inhibition rates of compounds at different concentrations were calculated in Excel, and then the inhibition curves were plotted and related parameters were calculated using GraphPad Prism software, including the minimum inhibition rate, maximum inhibition rate, and IC 50 .

[1093] The results showed that the compounds of the examples of the present invention showed good inhibitory activity against KRAS mutations.

[1094] Table 1 Anti-cell proliferation activity of compounds

[1095]

[1096]

[1097]

[1098]

[1099] Pharmacokinetic testing evaluation

[1100] Male ICR mice, weighing about 18-25 g, were fasted overnight and orally administered with a 100 mg / kg solution of the compound of the present invention or a control compound [10% DMSO / 60% polyethylene glycol 400 / 30% aqueous solution as a vehicle]. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0 and 24 h after administration of the compound of the present invention, and the concentration of the compound of the present invention or the control compound in plasma was determined by LC / MS / MS.

[1101] Table 2 Main pharmacokinetic parameters in plasma

[1102]

[1103] It can be seen from the test results that the compound of the present invention has good oral pharmacokinetic properties.

[1104] Pharmacokinetic testing evaluation

[1105] Male SD rats, weighing about 220 g, were fasted overnight and orally administered with a 100 mg / kg solution of the compound of the present invention or a control compound [10% DMSO / 60% polyethylene glycol 400 / 30% aqueous solution as a vehicle]. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0 and 24 h after administration of the compound of the present invention, and the concentration of the compound of the present invention or the control compound in plasma was determined by LC / MS / MS.

[1106] Table 3 Main pharmacokinetic parameters in plasma

[1107]

[1108] Table 4 Main pharmacokinetic parameters in plasma

[1109]

[1110] It can be seen from the test results that the compound of the present invention has good oral pharmacokinetic properties.

[1111] Pharmacodynamic evaluation of antitumor activity (NCI-H727 CDX tumor model)

[1112] 100uL containing 5x10 6 NCI-H727 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. The health of the mice was monitored daily, and the measurement was started when the tumor grew to a palpable size. The tumor volume was calculated using the formula: 0.5xLxW 2 , where L and W represent the length and width of the tumor, respectively. The tumor grows to 200 mm 3 The mice were randomly divided into groups. The corresponding dose of compound was given by gavage every day, and their general condition was monitored. Tumors were measured 3 times a week, and body weight was measured twice a week.

[1113] It can be seen from the test results that the compound of the present invention has a good anti-tumor effect.

[1114] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula (I0), its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug: In the formula, Select from the following group: in, Select from the following group: Ring B is selected from the following substituted or unsubstituted groups: C6-C 14 Aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more R; R 1a are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C 10 Alkyl, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclic C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; R 1b are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C1-C 10 Alkoxy C1-C6 alkylene, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclic C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; R 1c Independently selected from the following substituted or unsubstituted groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group, C1-C 10 Alkoxy C1-C6 alkylene, C3-C 20 Cycloalkyl C1-C6 alkylene, 4-20 membered saturated or unsaturated heterocyclic C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; or R 1a and R 1c Connected to form 4-7 membered rings; R 2 Selected from the following substituted or unsubstituted groups: C6-C 14 Aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more R; R 3 Each is independently selected from the following substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R; m is an integer of 0, 1, 2, 3, 4, 5 or 6; X is selected from: bond, O, NH, N(C1-C3 alkyl), C≡C; Y is selected from: a bond, a substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; 1) Z is selected from: Wherein, ring W1 is selected from the following substituted or unsubstituted groups: C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R; R 4 Selected from: H, deuterium, alkenyl, fluoroalkenyl, ethynyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, (C3-C6 cycloalkyl)C1-C6 alkyl, (4-6 membered heterocyclyl)C1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C3-C6 cycloalkyloxy)C1-C6 alkyl, (4-6 membered heterocyclyloxy)C1-C6 alkyl, (C1-C6 alkyl)vinyl, deuterated (C1-C6 alkyl) )vinyl, halogenated (C1-C6 alkyl)vinyl, (C1-C6 alkyl)ethynyl, deuterated (C1-C6 alkyl)ethynyl, halogenated (C1-C6 alkyl)ethynyl, (C3-C6 cycloalkyl)ethynyl, (4-6 membered heterocyclyl)ethynyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, halogen, nitro, hydroxy, oxo (═O), cyano, ester, amine, amide, sulfone or urea; n is an integer selected from: 0, 1, 2, 3, 4, 5 or 6; or 2) Z is selected from: -L4-Q2 or Wherein, ring W2 is selected from the following group of substituted or unsubstituted groups: C3-C6 cycloalkylene, 4-6 membered saturated or unsaturated heterocyclylene; wherein, the substitution refers to substitution by one or more R; Each L4 is independently selected from the group consisting of a substituted or unsubstituted bond, a C1-C6 alkylene group, and a deuterated C1-C6 alkylene group; wherein the substitution refers to substitution by one or more R; Each Q2 is independently selected from the following groups: substituted or unsubstituted: C1-C6 alkoxy, C3-C 10 Cycloalkyloxy, 4-10 membered heterocyclyloxy, C3-C 10 Cycloalkyl C1-C6 alkyleneoxy, 4-10 membered heterocyclic C1-C6 alkyleneoxy, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, NHR 9 NR 9 R 10 ; R 9 and R 10 Each is independently selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, (C3-C 10 cycloalkyl)C1-C6 alkylene, (4-10 membered heterocyclic)C1-C6 alkylene, or R 9 and R 10 The N atom connected thereto together forms a substituted or unsubstituted 4-10 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; Each R is the same or different and is independently selected from the group consisting of H, deuterium, alkenyl, fluoroalkenyl, ethynyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylene, halogenated C1-C6 alkylene, (C3-C6 cycloalkyl)C1-C6 alkyl, (4-6 membered heterocyclyl)C1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C3-C6 cycloalkyloxy)C1-C6 alkyl, (4-6 membered heterocyclyloxy)C1-C6 alkyl, (C1-C6 alkoxy) alkyl)ethynyl, deuterated (C1-C6 alkyl)ethynyl, halogenated (C1-C6 alkyl)ethynyl, (C1-C6 alkyl)ethynyl, deuterated (C1-C6 alkyl)ethynyl, halogenated (C1-C6 alkyl)ethynyl, (C3-C6 cycloalkyl)ethynyl, (4-6 membered heterocyclyl)ethynyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 aryl, 5-10 membered heteroaryl, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amine, amide, sulfone or urea.

2. The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has the structure shown in formula (I): In the formula, B.R 1a , R 1b , R 1c , R 2 , R 3 , X, Y, Z and m are as defined in claim 1.

3. The compound according to claim 2, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure shown in formula (II-A) or formula (II-B): In the formula, Ring B, R 1a , R 1b , R 1c , R 2 , R 3 , X, Y, Z and m are as defined in claim 1.

4. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 3, characterized in that: It has a structure shown by formula (III-A1), formula (III-A2) or formula (III-B1), formula (III-B2): In the formula, ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , X, Y, W1, W2, L4, Q2, m and n are defined as in claim 1; Preferably, it has a structure represented by formula (III-A1) or formula (III-B1).

5. The compound according to any one of claims 1 to 4, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure shown by formula (IV-A1), formula (IV-A2) or formula (IV-B1), formula (IV-B2): In the formula, Ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , Y, W1, W2, L4, Q2, m and n are defined as in claim 1.

6. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 5, characterized in that: It has a structure shown by formula (V-A1), formula (V-A2) or formula (V-B1), formula (V-B2): In the formula, ring B, R 2 , R 3 , R 4 , Y, W1, W2, L4, Q2, m and n are defined as in claim 1.

7. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 6, characterized in that: It has a structure shown in formula (VI-A1) or formula (VI-B1): In the formula, ring B, R 2 , R 3 , m and n are as defined in claim 1; each R 5 The same or different, each independently selected from hydrogen or deuterium.

8. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure shown in formula (VII-A1) or formula (VII-B1): In the formula, P 1 , P 2 , P 3 Each independently selected from CH, CF, C-Cl, C-CN, C-CF 3 , or N; Ring B, R 1a , R 1b , R 1c , R 3 , R 4 , X, Y, W1, W2, L4, Q2, m and n are defined as in claim 1.

9. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 8, characterized in that: W1 is selected from: substituted or unsubstituted 4-7 membered monocyclic heterocyclic group, substituted or unsubstituted C3-C7 monocyclic cycloalkyl group, substituted or unsubstituted 6-10 membered bicyclic heterocyclic group, substituted or unsubstituted C6-C 10 bicyclic cycloalkyl, substituted or unsubstituted 7-12 membered tricyclic heterocyclic group, substituted or unsubstituted C7-C 12 tricyclic cycloalkyl, preferably, W1 is a substituted or unsubstituted 8-12 membered N-containing heterocyclic group, wherein the substitution refers to substitution by one or more R, and R is defined as described in claim 1; Preferably, Selected from: wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R 4 and n are as defined in claim 1, R, R 4 It can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring); More preferably, Selected from: wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, R 4 and n are as defined in claim 1, and R may be substituted on any one of the polycyclic (eg bridged or spiro) rings.

10. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: for Preferably, Selected from: Or choose from:

11. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 10, characterized in that: R 2 is selected from the following substituted or unsubstituted groups: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyridyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following groups: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, ester, amine, amide, sulfone, urea, sulfonamide, C3-C6 cycloalkyl O-, 4-6 membered heterocyclyl O-, C3-C6 cycloalkyl OH, 4-6 membered heterocyclyl OH; preferably, R 2 Selected from: Or choose from: Or choose from: Or choose from:

12. The compound according to any one of claims 1 to 11, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: Ring B is selected from the following substituted or unsubstituted groups: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, ester, amine, amide, sulfone, urea, sulfonamide, C3-C6 cycloalkyl O-, 4-6 membered heterocyclyl O-, C3-C6 cycloalkyl OH, 4-6 membered heterocyclyl OH; preferably, ring B is selected from: Or choose from: More preferably, Ring B is selected from: Or choose from:

13. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 12, characterized in that: The compound is selected from the group consisting of: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from:

14. A pharmaceutical composition, characterized in that Comprising one or more compounds according to any one of claims 1 to 13, their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and a pharmaceutically acceptable carrier.

15. A use of the compound according to any one of claims 1 to 13, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the pharmaceutical composition according to claim 14, characterized in that: Used for preparing a drug for preventing and / or treating a disease associated with the activity or expression of KRAS mutations, preferably, the disease is a tumor or a disorder.

Images