Substituted tricyclic inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a substituted tricyclic inhibitor as well as a preparation method and application thereof. Specifically, the compound disclosed by the invention has a structure shown in a formula (I), and each substituent group is defined in the specification. The invention further discloses a preparation method of the compound and application of the compound as a KRAS mutation inhibitor. The compound has a very good inhibition effect on KRAS mutation and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a substituted tricyclic inhibitor, its preparation method, and its application. Background Technology

[0002] Approximately one-quarter of all human cancers are caused by RAS mutations, resulting in nearly one million deaths annually. Within 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 (primarily 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 activated, KRAS can activate multiple signaling pathways, promoting cell proliferation. The most common sites of KRAS protein gene mutation are codons 12, 13, and 61, with codon 12 mutations being the most frequent. The most prevalent KRAS G12 mutations are G12A, G12C, G12D, G12V, and G12S mutations, with G12C, G12D, and G12V mutations primarily occurring in NSCLC, CRC, and pancreatic cancer. To date, no drugs targeting multiple KRAS mutations have been approved for marketing.

[0004] Because the target protein of KRAS mutations is pathologically associated with a variety of diseases, especially lung cancer, pancreatic cancer, and colorectal cancer, there is a current need for novel KRAS mutation inhibitors for clinical treatment. Highly active KRAS mutation inhibitors can more effectively treat diseases such as cancers caused by KRAS mutations and have the potential to reduce off-target effects, thus meeting a more urgent clinical need. Summary of the Invention

[0005] The purpose of this invention is to provide a novel class of compounds that have inhibitory effects on KRAS mutations and / or better pharmacodynamic properties, and their use in the prevention and treatment of KRAS mutation-related diseases.

[0006] In a first aspect of the invention, a compound, or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, is provided, wherein the compound is shown in Formula I:

[0007]

[0008] In the formula,

[0009] V 1 V 2 V 3 Each is independently selected from the following group: CRv Or N; R v Selected from the following groups, substituted or unsubstituted: H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 member saturated or unsaturated heterocyclic groups, C2-C6 ester groups, amino groups (-NR'R"), C1-C 10 Alkyl carbonyl, C3-C 20 Cycloalkyl carbonyl, amide (-CONR'R"), sulfone or urea groups;

[0010] V 4 Each of them independently selected from the following group: CHR v NR v or CO;R v Selected from the following groups, substituted or unsubstituted: H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 member saturated or unsaturated heterocyclic groups, C2-C6 ester groups, amino groups (-NR'R"), C1-C 10 Alkyl carbonyl, C3-C 20 Cycloalkyl carbonyl, amide (-CONR'R"), sulfone or urea groups;

[0011] L 1 Selected from none, O, CO, NR L , or NR L CO;

[0012] L 2 Selected from the following groups: -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-CH2-, -CH2-N(R) L -CH2- or -CO-; where R L Self-substituted or unsubstituted subgroups: H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C20 Cycloalkyl groups, 4-20 saturated or unsaturated heterocyclic groups;

[0013] L 3 -CH-;

[0014] L 4 L 5 and L 6 Each is independently selected from the following group: -CH2- or -CH2-CH2-;

[0015] And L 3 L 4 L 5 and L 6 One or two of them can also be optionally passed through L p The connection forms a bridge ring or spiral ring structure; L p Selected from the following group: -CH2-, -CH2-CH2-, or -CH=CH-;

[0016] The above L 2 L 3 L 4 L 5 L 6 and L p In this context, "CH2" and "CH" can also be optionally replaced by one or more R... S Replaced;

[0017] R S Each is independently selected from the group consisting of: halogens, CN, or C1-C3 alkyl groups; or two Rs on the same or different carbon atoms (preferably the same or adjacent carbon atoms). S Together with the attached carbon atom, they form substituted or unsubstituted C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6 aryl, 4-6 membered heterocyclic, 4-6 membered heterocyclic alkenyl, 5-7 membered heteroaryl; wherein the substitution means being substituted by one or more substituents selected from the group consisting of halogen, CN, or C1-C3 alkyl.

[0018] U1 and U2 are each independently selected from the following group of substituent or unsubstituted groups: C4-C 14 Cycloalkyl, 4-14 membered heterocyclic, C6-C 14 Aryl, 5-14 heteroaryl, -OR a -NR a R b -CONR a R b -SO2NR a R b -NR a COR b -NR a SO2Rb or -NR a CONR a R b Each R a R b Whether identical or different, each is independently selected from the substituted or unsubstituted lower group: H, C1-C 10 Alkyl, C4-C 14 Cycloalkyl, 4-14 membered heterocyclic, and 4-14 membered heterocyclic alkyl, or R a and R b And the atoms connected to them form substituted or unsubstituted 4-14 membered heterocyclic groups; wherein, the substitution refers to being substituted by one or more R;

[0019] X is selected from: bond, O, NH, N (C1-C3 alkyl), -C≡C-;

[0020] Y is selected from: bonded, substituted or unsubstituted C1-C6 alkylene; wherein, the substitution refers to being substituted by one or more R;

[0021] 1) Z is

[0022] Wherein, W1 is selected from the following group: substituted or unsubstituted groups: C3-C 20 Cycloalkyl groups, 4-20 saturated or unsaturated heterocyclic groups;

[0023] R 4 Selected from the following groups, whether substituted or unsubstituted: H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, oxo (=O), C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 member saturated or unsaturated heterocyclic groups, C2-C6 ester groups, amino groups (-NR'R"), amide groups (-CONR'R"), C1-C 10 Alkylidene (e.g., methylidene, =CH2), halogenated C1-C 10 Alkylidene (e.g., halogenated methylidene, halogenated = CH2), sulfone, or urea;

[0024] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8, and the substitution refers to being replaced by one or more R;

[0025] or

[0026] 2) Z is -L4-Q2 or

[0027] Wherein, ring W2 is selected from the following group of substituted or unsubstituted groups: none, C3-C6 cycloalkyl subgroups, 4-6 membered saturated or unsaturated heterocyclic subgroups;

[0028] L4 is selected from the following groups, whether substituted or unsubstituted: bond, C1-C6 alkylene, deuterated C1-C6 alkylene;

[0029] Q2 is selected from the following group, either substituted or unsubstituted: C1-C 10 Alkoxy, C3-C 10 Cycloalkyl-O-, 4-10 membered heterocyclic-O-, C3-C 10 Cycloalkyl-(C1-C6 alkylene)-O-, 4-10 membered heterocyclic-(C1-C6 alkylene)-O-, C3-C 10 Cycloalkyl C1-C6 alkeneoxy, 4-10 membered heterocyclic C1-C6 alkeneoxy, C3-C 10 Cycloalkyl, phenyl, benzyl, naphthyl, 4-12 membered heterocyclic groups, NHR 9 or NR 9 R 10 ;R 9 and R 10 Each group is independently selected from the following group: substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C6 ... 10 Cycloalkyl, 4-10 membered heterocyclic groups, (C3-C 10 (cycloalkyl)-C1-C6 alkylene, (4-10 membered heterocyclic)-C1-C6 alkylene, or R 9 and R 10 The N atom attached to it forms a substituted or unsubstituted 4-10 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R atoms;

[0030] Unless otherwise specified, substitution refers to substitution by one or more R groups, each R being the same or different, and each independently selected from: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, amino, C1-C6 alkyl, methylene (=CH2), halogenated methylidene (e.g., =CHF, =CF2), deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C2-C6 alkenyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic groups, and hydroxyl-substituted C3-C 14 Cycloalkyl, hydroxyl-substituted 4-14 membered heterocyclic groups, and amino-substituted C3-C 14 Cycloalkyl, amino-substituted 4-14 membered heterocyclic groups, C6-C 10 Aryl, 5-10 membered heteroaryl, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-(C3-C6 cycloalkyl), -N(C1-C6 alkyl)(C3-C6 cycloalkyl), C3-C6 cycloalkyl-O-, 4-7 membered heterocyclic-O-, C3-C6 cycloalkyl-(C1-C6 alkylene))-, 4-6 membered heterocyclic-(C1-C6 alkylene))-, C3-C6 cycloalkyl-O-(C1-C6 alkylene))-, 4-6 membered heterocyclic-O-(C1-C6 alkylene))-, lkylene))-, (C1-C6 alkyl)-CH=C-, deuterated (C1-C6 alkyl)-CH=C-, halogenated (C1-C6 alkyl)-CH=C-, (C1-C6 alkyl)-C≡C-, (deuterated C1-C6 alkyl)-C≡C-, (halogenated C1-C6 alkyl)-C≡C-, (C3-C6 cycloalkyl)-C≡C-, (4-6 membered heterocyclic)-C≡C-, C1-C6 ester group, amino group (-NR'R"), amide group, sulfonamide group, sulfone group or urea group (preferably, the cycloalkyl group is saturated or partially saturated, and the heterocyclic group is saturated or partially saturated).

[0031] In another preferred embodiment, L 3 L 4 L 5 and L 6 Any one or two of them pass through L p The connection forms a bridge ring or spiral ring structure; L p Selected from the following group: -CH2-, -CH2-CH2-, or -CH=CH-;

[0032] In another preferred embodiment, L4 and L 5 Through L p The connection forms a bridge ring structure; L p Selected from the following group: -CH2-, -CH2-CH2-, or -CH=CH-.

[0033] In another preferred embodiment, the compound has the structure shown in formula (II):

[0034]

[0035] in,

[0036] V 1 V 2 V 3 R 1 R 2 L 1 L 2 L 3 L 6 As mentioned before, R is also mentioned.

[0037] In another preferred embodiment, the compound has the structure shown in formula (III):

[0038]

[0039] in,

[0040] V 1 V 2 V 3 R 1 R 2 L 1 L 2 L 3 L 6 As mentioned before, R is also mentioned.

[0041] In another preferred embodiment, R 1 and R 2 One of them is -XYZ or -U1, and the other is -U2.

[0042] In another preferred embodiment, R 1 For -XYZ or -U1, and / or R 2 It is -U2.

[0043] In another preferred embodiment, R 2 For -XYZ or -U1, and / or R 1 It is -U2.

[0044] In another preferred embodiment, X is a bond, O, NH or N (C1-C3 alkyl); more preferably, X is a bond or O.

[0045] In another preferred embodiment, Y is a bonded, substituted, or unsubstituted C1-C6 alkylene; more preferably, Y is a bonded, or C1-C6 alkylene.

[0046] In another preferred embodiment, Z is

[0047] In another preferred embodiment, The central ring W1 is selected from the following group: substituted or unsubstituted 4-7 membered monocyclic heterocyclic groups, substituted or unsubstituted C groups. 3-6 Cycloalkyl, substituted or unsubstituted 6-10 membered bicyclic (spirocyclic) heterocyclic groups, substituted or unsubstituted 6-9 membered bicyclic (fused-ring) heterocyclic groups, substituted or unsubstituted 6-9 membered bicyclic (bridged-ring) heterocyclic groups, substituted or unsubstituted 9-12 membered tricyclic heterocyclic groups, substituted or unsubstituted 11-14 membered tetracyclic heterocyclic groups, substituted or unsubstituted C7-C 10 Bridged cycloalkyl; wherein the substitution refers to substitution by one or more R; wherein the tricyclic and tetracyclic heterocyclic groups are spirocyclic and / or bridged and / or fused cyclocyclic.

[0048] In another preferred embodiment, The intermediate ring W1 is selected from substituted or unsubstituted 4-7 member monocyclic nitrogen-containing heterocyclic groups, substituted or unsubstituted 8-9 member bicyclic N-containing fused heterocyclic groups, substituted or unsubstituted 8-9 member bicyclic N-containing spirocyclic heterocyclic groups, or substituted or unsubstituted 10 member tricyclic nitrogen-containing heterocyclic groups, or substituted or unsubstituted 11 member tetracyclic nitrogen-containing heterocyclic groups, wherein the substitution refers to being substituted by one or more R, and the definition of R is as described above;

[0049] The monocyclic nitrogen-containing heterocyclic group, bicyclic N-bridged ring heterocyclic group, bicyclic N-spirocyclic heterocyclic group, bicyclic N-fused ring heterocyclic group, tricyclic nitrogen-containing heterocyclic group, and tetracyclic nitrogen-containing heterocyclic group may optionally contain 0-3 heteroatoms, each independently selected from the group consisting of N, S, or O; the tricyclic nitrogen-containing heterocyclic group and the tetracyclic nitrogen-containing heterocyclic group are spirocyclic and / or bridged ring and / or fused ring;

[0050] In another preferred embodiment, Selected from group A1, group A2, or group A3; among which,

[0051] Group A1 includes:

[0052]

[0053]

[0054] Group A2 includes:

[0055]

[0056] Group A3 includes:

[0057]

[0058] Where n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R 4 The definitions of R and n are as described above, and R and R are... 4 It can replace any one of the rings in a multi-ring system (such as a bridge ring or a spiral ring).

[0059] In another preferred embodiment, R 4 Selected from the following group: halogens, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C1-C 10 Alkylidene, halogenated C1-C 10 Alkylidene or amino group (preferably -NH (C1-C6 alkyl) or -N (C1-C6 alkyl)).

[0060] In another preferred embodiment, n is 0, 1, 2, 3 or 4; more preferably, it is 0, 1 or 2.

[0061] In another preferred embodiment, Selected from group A1a, group A2a, or group A3a:

[0062] Group A1a includes:

[0063]

[0064] Group A2a includes:

[0065]

[0066]

[0067] Group A3a includes:

[0068]

[0069] Where n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R 4 As defined above, R is located on any ring or alkylene chain of a polycyclic (such as a bridged ring or a spirocyclic) ring.

[0070] In another preferred embodiment, Selected from group A1, preferably selected from the following group: Among them, R 4 Selected from the following group: halogens, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C1-C10 Alkylidene, halogenated C1-C 10 Alkylidene, where n is 0, 1, or 2.

[0071] In another preferred embodiment, Selected from group A2 (preferably, selected from the following group) ); where R 4 Selected from the following group: halogens, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C1-C 10 Alkylidene, halogenated C1-C 10 Alkylidene, amino group, n is 0, 1 or 2.

[0072] In another preferred embodiment, Selected from group A3 (preferably, selected from the following group) ); where R 4 Selected from the following group: halogens, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C1-C 10 Alkylidene, halogenated C1-C 10 Alkylidene, amino group, n is 0, 1 or 2.

[0073] In another preferred embodiment, Z is

[0074] In another preferred embodiment, L4 is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkylene or deuterated C1-C6 alkylene; more preferably, L4 is selected from the group consisting of methylene or deuterated methylene.

[0075] In another preferred embodiment, for in,

[0076] Y is selected from bonded, substituted or unsubstituted C1-C6 alkylene groups;

[0077] The ring W2 is selected from the following group: substituted or unsubstituted: C3-C6 cycloalkyl subgroups, or 4-7 membered saturated or unsaturated heterocyclic subgroups;

[0078] L4 is selected from the following group of substituted or unsubstituted groups: bond, C1-C6 alkylene, or deuterated C1-C6 alkylene;

[0079] Q2 is selected from the following group, whether substituted or unsubstituted: C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclic-O-, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl(C1-C6 alkylene)-O-, 4-7 membered heterocyclic(C1-C6 alkylene)-O-, C3-C6 cycloalkylC1-C6 alkoxy, 4-7 membered heterocyclicC1-C6 alkoxy, C3-C7 cycloalkyl, 4-8 membered heterocyclic, phenyl, benzyl, NHR 9 NR 9 R 10 ;

[0080] R 9 and R 10 Each group is independently selected from the following group, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, (C3-C6 cycloalkyl)C1-C6 alkylene, (4-7 membered heterocyclic)C1-C6 alkylene, or R 9 and R 10 The N atom attached to it forms a substituted or unsubstituted 4-8 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R atoms.

[0081] In another preferred embodiment, Q2 is selected from the following group, whether substituted or unsubstituted: C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclic-O-, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl(C1-C6 alkylene))-O-, 4-7 membered heterocyclic(C1-C6 alkylene))-O-, C3-C7 cycloalkyl, 4-8 membered heterocyclic, NHR 9 NR 9 R 10 ; and / or

[0082] R 9 and R 10 Each group is independently selected from the following group, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, (C3-C6 cycloalkyl)C1-C6 alkylene, (4-7 membered heterocyclic)C1-C6 alkylene, or R 9 and R 10 The N atom attached to it forms a substituted or unsubstituted 4-8 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R atoms.

[0083] In another preferred embodiment, Selected from group B1, which includes:

[0084]

[0085]

[0086] In another preferred embodiment, U1 is selected from the group consisting of substituted or unsubstituted groups: -OR a -NR a R b Each R a R b Whether identical or different, each is independently selected from the substituted or unsubstituted lower group: H, C1-C 10 Alkyl, C4-C 14 Cycloalkyl, 4-14 membered heterocyclic, and 4-14 membered heterocyclic alkyl, or R a and R b And the atoms connected to them form substituted or unsubstituted 4-14 membered heterocyclic groups; wherein, the substitution refers to being substituted by one or more R.

[0087] In another preferred embodiment, U1 is selected from group B2, which includes:

[0088]

[0089] In another preferred embodiment, U2 is a substituted or unsubstituted 11-13 membered tricyclic heterocyclic group, or a substituted or unsubstituted 7-9 membered bicyclic heterocyclic group; wherein the substitution is by one or more groups selected from the group consisting of: deuterium, halogen, hydroxyl, cyano, oxo (=O), -NH2, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 6. Ester group, amino group (-NR'R”), amide group, sulfone group, urea group, sulfonamide group, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclic group-O-, -NH- (C1-C6 alkyl), -NH- (C3-C6 cycloalkyl), hydroxyl-substituted C3-C6 cycloalkyl, hydroxyl-substituted 4-6 membered heterocyclic group; wherein the heterocyclic group contains 1, 2, 3, 4 or 5 heteroatoms independently selected from the group consisting of S, N or O; and wherein the heterocyclic group is a spirocyclic and / or bridged ring and / or fused ring structure:

[0090] In another preferred embodiment, U2 is a group as shown in Formula A1:

[0091]

[0092] in,

[0093] X U 1 and X U 2Each independently constitutes CH and CR. U 、 or N;

[0094] X U 3 Select from the following group: O, S, NH, or NR U ;

[0095] X U 4 and X U 5 Each can be independently -CH2- or -CH2CH2-;

[0096] X U 6 and X U 7 Each is independently selected from the following groups: -CH2-, -CH2CH2-, -CH2O-, -C(=O), NH or NR. U ;

[0097] R U Selected from the group consisting of: cyano, -NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or C4-C6 heterocyclic groups;

[0098] n1 is 0, 1, 2, 3, 4, 5 or 6;

[0099] R is as defined above (preferably selected from the group consisting of: H, deuterium, halogen, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, and halogenated C1-C6 alkyl).

[0100] In another preferred example, X U 1 For CR U X U 2 For N or CR U .

[0101] In another preferred example, X U 1 For C(NH2), X U 2 It is N or C (CN).

[0102] In another preferred embodiment, U2 is selected from the following group C1, group C2, or group C3;

[0103] Group C1 includes:

[0104]

[0105]

[0106] Group C2 includes:

[0107]

[0108] Group C3 includes:

[0109]

[0110] More preferably, U2 is independently selected from the following group:

[0111]

[0112] In another preferred embodiment, the compound is selected from the group consisting of:

[0113]

[0114] Or select from:

[0115]

[0116] Or select from:

[0117]

[0118]

[0119] Or select from:

[0120]

[0121]

[0122] Or select from:

[0123]

[0124] Or select from:

[0125]

[0126] Or select from:

[0127]

[0128]

[0129] Or select from:

[0130]

[0131] Or select from:

[0132]

[0133]

[0134] In another preferred embodiment, the compound is the compound prepared in the examples.

[0135] In another preferred embodiment, each substituent is a corresponding group in the compound prepared in the examples.

[0136] In a second aspect of the invention, a pharmaceutical composition is provided comprising one or more compounds as described in the first aspect of the invention, or their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs; and a pharmaceutically acceptable carrier.

[0137] In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of: 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), 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, 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, oxacartinib), 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, Voronostat, 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.), SOS1 inhibitors (such as BI1701963), or combinations thereof.

[0138] In a third aspect of the invention, there is provided the use of a compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as described in the first aspect of the invention, or a pharmaceutical composition as described in the second aspect of the invention, for the preparation of a medicament for the prevention and / or treatment of diseases associated with the activity or expression level of KRAS mutations, preferably, said diseases being tumors or disorders.

[0139] In another preferred embodiment, the disease is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colon cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer, or combinations thereof.

[0140] In a fourth aspect of the invention, a method for inhibiting KRAS mutations is provided, comprising administering to a subject in need a therapeutically effective amount of the compound of the first aspect of the invention, or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition of the second aspect of the invention.

[0141] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0142] In another preferred embodiment, the method is performed in vitro.

[0143] In another preferred embodiment, the object is a mammal, preferably a human.

[0144] In another preferred embodiment, the object is a cell.

[0145] In a fifth aspect of the invention, a method for inhibiting KRAS mutant activity in vitro is provided, comprising the steps of contacting a compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as described in the first aspect, or a pharmaceutical composition as described in the third aspect, with a protein or cell to inhibit the activity of a KRAS mutant.

[0146] In another preferred embodiment, the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells and intestinal epithelial cells), or combinations thereof.

[0147] In another preferred embodiment, the cells are derived from rodents (such as mice or rats) or primates (such as humans).

[0148] It should be understood that, within the scope of this invention, any position of the compound described herein can be replaced by isotopes (such as...). 2 H, 13 Replaced by (C, etc.). Due to space limitations, they will not be listed one by one here.

[0149] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0150] none Detailed Implementation

[0151] Through long-term and in-depth research, the inventors unexpectedly prepared a novel class of compounds that inhibit KRAS mutations and / or exhibit better pharmacodynamic properties. Based on this, the inventors completed this invention.

[0152] the term

[0153] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0154] The term "alkyl" refers to a straight-chain or branched alkane group or a cyclic alkane group (including alkane groups connected to other parts via carbons on a ring or non-cyclic structures), preferably a straight-chain or branched alkane group, containing 1-20 carbon atoms, such as 1-18 carbon atoms, particularly 1-18 carbon atoms, and preferably containing 1-10 carbon atoms (C1-C2). 10 More preferably, it contains 1-6 carbon atoms (C1-C6). Typical "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. In this invention, alkyl also includes substituted alkyl groups. "Substituted alkyl" means that one or more positions in an alkyl group are substituted, particularly 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 (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), nitrile, nitro, oxygen (e.g., =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)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 R appears here aIt can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 ynyl, 5-14 membered heterocycles, or C6-C 14 Aromatic rings, R b R c and R d It can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 5-14 membered heterocycles, or C6-C 14 Aromatic rings, or R b and R c Together with N atoms, it can form heterocycles; R e It can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 ynyl, 5-14 membered heterocycles, or C6-C 14 Aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, may be optionally substituted.

[0155] As used herein, the term "alkylene" (also referred to herein as "alkylene chain") refers especially to those "alkylenes" located in the middle or not at the end of a molecule or group (such as "alkylenes" in Y, and L4) and as substituents (such as C3-C). 10 The "alkylene" in cycloalkyl-(C1-C6 alkylene)-O- refers to a linking group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, used to connect two different atoms, or a group formed by removing a hydrogen atom from the atom containing the unsaturated bond of an alkyl or substituted alkyl group, such as methylene or methylene (-CH2-), ethylene, etc. Propionide Isopropylidene Butylene (e.g.) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ), etc. Furthermore, the term also includes alkylene groups (such as C1-C...). 18 An alkylene group is formed by a methylene group (e.g., C3-C4) and a cycloalkyl group (e.g., C3-C4). 20 Replaced by (cycloalkylene), for example, "C1-C 18 Alkylene C3-C 20 "cyclohexene alkyl" or "C3-C" 20 Cycloalkyl C1-C 18 "alkylene". In this invention, alkylene also includes substituted alkylene, and the substituents can be halogenated (-CHF- or -CF2-), hydroxyl, cyano, nitro, etc.

[0156] As used herein, the term "alkylidene" (also referred to herein as "terminal alkylidene"), especially "alkylidene" as a terminal substituent (such as R...), refers to... 4 The term "alkylene" refers to a group formed by removing a hydrogen atom from the unsaturated bond of an alkyl or substituted alkyl group, thus connecting it to other parts of the molecule via a double bond. Examples include methylene (also called terminal methylene or methylidene). ), Ethylene (e.g.) ), propylidene (e.g.) ), isopropylidene (e.g.) ), butylene, pentylene, hexylene, heptylene, etc. Furthermore, the term also includes alkylene (e.g., C1-C18 alkylene) where one methylene group is replaced by a cycloalkylene (e.g., C3-C20 cycloalkylene), for example, "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkyl C1-C18 alkylene". In this invention, alkylene also includes substituted alkylene, where the substituent can be halogenated (e.g., alkylene). -CHF- or -CF2-), hydroxyl, cyano, nitro, etc.

[0157] The term "C1-C" 18 Alkylene C3-C 20 "Cycloalkylene" or "C3-C" 20 Cycloalkyl C1-C 18 "alkylene" has the same meaning, referring to the group formed by removing two hydrogen atoms from a cycloalkyl or alkylcycloalkyl group, such as... Etc. Preferably C1-C6 alkylene or C3-C6 cycloalkylene. In this invention, "C1-C..." 18 Alkylene C3-C 20 "Cycloalkylene" or "C3-C" 20 Cycloalkyl C1-C 18 "alkylene" also includes substitution of "C1-C" 18 Alkylene C3-C 20 "Cycloalkylene" or "C3-C" 20 Cycloalkyl C1-C 18 "alkylene" refers to a substituent that can be halogenated, hydroxylated, cyano, nitro, etc.

[0158] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. Alkenyl groups are preferably C2-C6 alkenyl groups, more preferably C2-C4 alkenyl groups. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In this invention, alkenyl groups include substituted alkenyl groups. In this invention, alkenyl groups also include substituted alkenyl groups, and the substituents can be halogenated, hydroxylated, cyano, nitro, etc.

[0159] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. The alkynyl group is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. The alkynyl group includes, but is not limited to, ethynyl, propynyl, or similar groups. In this invention, the alkynyl group also includes substituted alkynyl groups, which can be halogenated, hydroxyl, cyano, nitro, etc.

[0160] In this invention, the term "cycloalkyl" refers to a fully saturated or partially unsaturated (preferably fully saturated) cyclic hydrocarbon compound group comprising 1-4 rings, each ring containing 3-8 carbon atoms. The term "C3-C..." 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 groups, more preferably C3-C6 monocyclic cycloalkyl groups, C7-C 10 Bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" refers to a cycloalkyl group in which one or more positions are substituted, particularly 1-4 substituents, which can be substituted at any position. In this invention, "cycloalkyl" includes substituted cycloalkyl groups, and typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), nitrile, nitro, oxygen (e.g., =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)2NR b Rc 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 R appears here a It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, aryl, or heteroaryl, R b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c Together with N atoms, it can form heterocycles; R e The group can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, or heteroaryl. The typical substituents mentioned above can be optionally substituted. Typical substitutions also include spirocyclic, pyrimidine-fused, or fused-ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocyclic (excluding heteroaryl), pyrimidine-fused cycloalkyl, pyrimidine-fused cycloalkenyl, pyrimidine-fused cyclocyclic heterocyclic (excluding heteroaryl), fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aromatic cycloalkyl, wherein the cycloalkyl, cycloalkenyl, heterocyclic, and heteroaryl groups can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.

[0161] The term "C3-C" 20 "Cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as:

[0162] wait.

[0163] In this invention, the term "heterocyclic group" 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 systems), wherein at least one heteroatom is present in a ring with at least one carbon atom. The term "4-20 membered heterocyclic group" refers to a heterocyclic group containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. "Heterocyclic group" has the same meaning as "saturated or unsaturated heterocyclic group," for example, including benzo4-7 membered heterocyclic groups. The "heterocyclic group" is preferably a 4-14 membered heterocyclic group (including but not limited to 4-6 membered monocyclic, 7-10 membered bicyclic, or 8-14 membered tricyclic or polycyclic systems), more preferably a 4-12 membered heterocyclic group, even more preferably a 4-10 membered heterocyclic group, such as a 4-6 membered monocyclic heterocyclic group, a 7-11 membered bicyclic or tricyclic heterocyclic group, even more preferably a 4-8 membered heterocyclic group, and even more preferably a 4-6 membered heterocyclic group. Each heterocyclic group contains a heterocycle with 1, 2, 3, or 4 heteroatoms, each of which is independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of the ring or ring system molecule, preferably to an N or C atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, oxoheterocyclic butyl, pyrazolinyl, imidazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxaneyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the heterocyclic groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0164] The term "4-20 membered subheterocyclic group" refers to a group formed by removing two hydrogen atoms from a heterocyclic group, such as:

[0165] wait.

[0166] In this invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1-5 rings, particularly monocyclic and bicyclic groups. Specifically, "C6-C..." 14 "Aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. The aryl group is preferably C6-C. 10 Aryl. Aryl groups include phenyl, biphenyl, or naphthyl. Any aryl group containing two or more aromatic rings (bicyclic, etc.) can have these rings linked by single bonds (e.g., biphenyl) or fused (e.g., naphthalene, anthracene, etc.). "Substituted aryl" refers to an aryl group where one or more positions are substituted, particularly 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: hydrogen, deuterium, halogens (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, 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 cNR b C(=O)R a , or NR b P(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c Together with N atoms, it can form heterocycles; R e It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. The above-mentioned typical substituents can be optionally substituted. Typical substitutions also include fused-ring substituents, especially fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aryl groups, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted.

[0167] The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur. Specifically, "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms. Heteroaryl groups are preferably 5- to 10-membered rings, more preferably 5- or 6-membered, such as pyrroleyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. "Heteroaryl" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester.

[0168] In this invention, the term "alkoxy" refers to an alkoxy group having a straight or branched chain, including alkyl-O- and alkyl-O-alkyl groups, wherein "C1-C 18 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 18 carbon atoms, including C1-C2. 18 Alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is C1-C8 alkoxy, more preferably C1-C6 alkoxy.

[0169] In this invention, the term "cycloalkyloxy" refers to cycloalkyl-O-, wherein "C3-C 20 "Cycloalkyloxy" refers to C3-C20 cycloalkyl-O-, wherein, C3-C 20 The definition of cycloalkyl is as described above.

[0170] In this invention, the term "heterocyclic oxy group" refers to the heterocyclic group -O-, wherein "4-20 membered heterocyclic oxy group" refers to the 4-20 membered heterocyclic group -O-, and the definition of the 4-20 membered heterocyclic group is as described above.

[0171] In this invention, the term "C1-C" is used. 18 "Alkyloxy" refers to "C1-C 18 An alkoxy group is formed by removing one hydrogen atom.

[0172] In this invention, the term "halogen" or "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0173] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0174] In this invention, the term "deuterium substitution" refers to being replaced by deuterium.

[0175] In this invention, the term "hydroxyl group" refers to a group with the structure OH.

[0176] In this invention, the term "nitro" refers to a group containing the structure NO2.

[0177] In this invention, the term "cyano" refers to a group containing the structure CN.

[0178] In this invention, the term "ester group" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic. The ester group is preferably -COO C1-C6 alkyl.

[0179] The term "amine" refers to a group with the structure -NR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, or R' and R" together with the nitrogen atom connected thereto form a substituted or unsubstituted heterocyclic group, as defined above. In one embodiment, R' or R" is each independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or R' and R" together with the nitrogen atom connected thereto form a 4- to 7 membered heterocyclic group (preferably a saturated 4- to 7 membered heterocyclic group containing only one nitrogen heteroatom as a ring atom). In one embodiment, at least one of R' and R" is not H. R' and R" can be the same or different in the dialkylamine fragment. The amino group is preferably NH2, NHC1-C6 alkyl, or N(C1-C6 alkyl)2; more preferably NHC1-C6 alkyl or N(C1-C6 alkyl)2.

[0180] The term "amide group" refers to a group with the structure -CONR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, or R' and R" together with the nitrogen atom attached thereto form a substituted or unsubstituted heterocyclic group, as defined above. In one embodiment, R' or R" is each independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or R' and R" together with the nitrogen atom attached thereto form a 4- to 7 membered heterocyclic group (preferably a saturated 4- to 7 membered heterocyclic group containing only one nitrogen heteroatom as a ring atom). R' and R" can be the same or different in the dialkylamine segment. The amide group is preferably -CONH2, -CONH (C1-C6 alkyl), or -CONH (C3-C6 cycloalkyl).

[0181] The term "sulfone" refers to a group with the structure -SO2R', where R' can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic groups, as defined above. The sulfone group is preferably -SO2C1-C6 alkyl.

[0182] The term "sulfonamide group" refers to a group with the structure -SO2NR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, or R' and R" together with the nitrogen atom attached thereto form a substituted or unsubstituted heterocyclic group, as defined above. In one embodiment, R' or R" is each independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or R' and R" together with the nitrogen atom attached thereto form a 4- to 7 membered heterocyclic group (preferably a saturated 4- to 7 membered heterocyclic group containing only one nitrogen atom as a ring atom). The sulfonamide group is preferably -SO2NH2, -SO2NH (C1-C6 alkyl), or -SO2NH (C3-C6 cycloalkyl).

[0183] The term "ureido" refers to a group with the structure -NR'CONR"R"', where R', R"', and R"' can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic groups, as defined above. R', R"', and R"' can be the same or different in the dialkylamine segment. The ureido group is preferably -NHCONH2 or -NHCONH (C1-C6 alkyl).

[0184] The term "alkylaminoalkyl" refers to a group with the structure -R'NHR", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted (alkylene), substituted or unsubstituted (cycloalkylene), substituted or unsubstituted (cycloalkylene), substituted or unsubstituted (cycloalkenyl), substituted or unsubstituted (aryl), or substituted or unsubstituted (heterocyclic), as defined above. R' and R" can be the same or different. Alkylaminoalkyl is preferably -C1-C6 alkylene NHC1-C6 alkyl.

[0185] The term "dialkylaminoalkyl" refers to a group with the structure -R'NR”R"', where R', R”, and R"' can independently represent a substituted or unsubstituted ()alkylene), substituted or unsubstituted ()cycloalkylene), substituted or unsubstituted ()cycloalkenyl), substituted or unsubstituted ()aryl), or substituted or unsubstituted ()heterocyclic group, as defined above. R', R”, and R"' can be the same or different in the dialkylamine segment. The dialkylaminoalkyl is preferably -C1-C6 alkylene N(C1-C6 alkyl)2.

[0186] The term "heterocyclic alkyl" refers to a group with the structure -RR', where R can independently represent an alkyl or substituted alkyl, a cycloalkyl or substituted cycloalkyl, a cycloalkenyl or substituted cycloalkenyl, an aryl or substituted aryl; and R' represents a heterocyclic or substituted heterocyclic group.

[0187] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to, halogens, hydroxyl groups, cyano groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureyl groups, etc.

[0188] Unless otherwise stated, it is assumed that any heteroatom in a suboptimal valence state has enough hydrogen atoms to compensate for its valence state.

[0189] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0190] In this invention, "multiple" preferably refers to 2, 3, 4, and 5.

[0191] Active ingredients

[0192] As used herein, “compound of the invention” means a compound as described in the first aspect (e.g., a compound represented by formula I, II or III), and also includes stereoisomers or optical isomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of compounds of formula I.

[0193] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. Compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0194] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, 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 acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, etc.

[0195] Some compounds of this 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, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0196] The prodrugs and solvates of the compounds in this invention are also included within the scope of this invention. The term "prodrug" here refers to a compound that, in the course of treatment of a related disease, undergoes a chemical transformation through metabolism or a chemical process to produce the compounds, salts, or solvates of this invention. The compounds of this invention include solvates, such as hydrates.

[0197] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0198] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or 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 salting with an optically active acid.

[0199] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0200] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of compounds in this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0201] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0202] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0203] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0204] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have 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. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0205] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 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 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0206] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0207] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0208] The compounds involved in this application and their pharmaceutically acceptable salt metabolites, as well as prodrugs that can be converted in vivo into structures of the compounds involved in this application and their pharmaceutically acceptable salts, are also included in the claims of this application.

[0209] Preparation method

[0210] The preparation methods of the compounds of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0211] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0212] Preferably, the compounds of the present invention are prepared by the following method.

[0213]

[0214] (i) In an inert solvent, in the presence of a base, with or without a Pd catalyst, with or without a condensing agent, the compound of formula XI reacts with the compound of formula X-II to give the compound of formula X-III.

[0215] (ii) In an inert solvent, in the presence of a base, with or without a Pd catalyst, the compound of formula X-III reacts with the compound of formula X-IV to obtain the compound of formula XV.

[0216] (ii) Under acid, base, hydrogenation or oxidation conditions, the protecting group PG1 of compound XV is removed to obtain compound (I);

[0217] LG1, LG2, LG3, LG4, LG5, and LG6 are leaving groups, each independently selected from: H, OH, halogens, SMe, SOMe, SO2Me, OTf, OTs, OMs, -B(OH)2, -B(KBF3), -Sn( n Bu)3、 wait;

[0218] LG1 is a protecting group selected from: Boc, Bn, Cbz, PMB, DMB, TMS, TBS, TIPS, Trt, etc.

[0219] 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 Pd G4, cataCXium A-Pd-G4, Rockphos PdG4, etc.;

[0220] V 1 V 2 V 3 V 4 R 1 R 2 L 1 L 2 L 3 L 4 L 5 and L 6 The definition is as described above.

[0221] Pharmaceutical Compositions and Administration

[0222] The pharmaceutical compositions described in this invention are used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0223] The compound of formula (I) can be used in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula (I) is taken simultaneously or subsequently. When a compound of formula I is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and a compound of formula I is preferred. Drug combination also includes taking a compound of formula I with one or more other known drugs during overlapping time periods. When a compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula (I) or the known drug may be lower than the dose of either drug alone.

[0224] Drugs or active ingredients that can be used in combination with 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), 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, Ocalatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omip BTK inhibitors (such as alisib, Buparlisib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, 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). The pharmaceutical compositions of this invention include (but are not limited to) 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), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof. The dosage forms of the pharmaceutical compositions of this invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, controlled-release or sustained-release formulations, or nanoformulations.

[0225] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0226] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that 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 and with the compounds of the present invention without significantly reducing the efficacy of the compounds. 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0227] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0228] 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 components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0229] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0230] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0231] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0232] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0233] Compositions for parenteral injection may comprise 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.

[0234] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0235] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0236] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0237] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound or its crystal form represented by general formula (I)-(IV) of the present invention, a pharmaceutically acceptable salt, a hydrate or a solvate, thereby forming a pharmaceutical composition.

[0238] The present invention also provides a treatment method comprising the steps of: administering to a subject requiring treatment a compound of general formula (I) as described in the present invention, or a crystal form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, or administering a pharmaceutical composition as described in the present invention for inhibiting KRAS mutations.

[0239] Compared with the prior art, the main advantages of the present invention include:

[0240] (1) The compound has a good inhibitory effect on KRAS mutation;

[0241] (2) The compound has better pharmacodynamic and pharmacokinetic properties and lower toxic side effects.

[0242] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0243] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0244] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0245] NMR was performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the determination included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).

[0246] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC determinations were performed using an Agilent 1100 high-performance chromatograph (Microsorb 5micron C18 100x 3.0 mm column).

[0247] Thin-layer chromatography (TLC) uses Qingdao GF254 silica gel plates, with a thickness of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative TLC. Column chromatography typically uses Qingdao 200-300 mesh silica gel as the support.

[0248] The starting materials used in the embodiments of the present invention are all known and commercially available, or can be synthesized using or in accordance with literature reported in the field.

[0249] Unless otherwise specified, all reactions in this invention are carried out under the protection of a dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperature is [degrees Celsius].

[0250] Preparation of intermediate I-1: (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0251]

[0252] Step 1: Preparation of methyl (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate

[0253] A solution of methyl (S)-5-oxopyrrolino-2-carboxylate (40.0 g, 275 mmol, 1.00 eq) in dimethyl sulfate (52.5 g, 416 mmol, 39.5 mL, 1.50 eq) was reacted at 60 °C for 16 h, followed by the addition of MTBE solution (40.0 g) in TEA at 0 °C. The resulting mixture was diluted with 400 mL of saturated Na₂CO₃ aqueous solution and extracted with MTBE (200 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was used directly in the next reaction without purification (32.5 g, 206 mmol, yield: 74.0%).

[0254] 1 H NMR (400MHz, DMSO-d6) δ4.44(m,1H)3.75(s,3H)3.65(s,3H)2.50(m,2H)2.16(m,2H).

[0255] Step 2: Preparation of methyl (S)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolinoline-2-carboxylate

[0256] A mixture of ethyl 2-nitroacetate (76.4 g, 550 mmol, 63.7 mL, 3.00 eq) and methyl (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (30.0 g, 190 mmol, 1.00 eq) was reacted at 60 °C for 16 h, followed by concentration under reduced pressure. The residue was separated by silica gel column chromatography to give the target product (17.5 g, 67.5 mmol, yield: 35.50%).

[0257] 1 H NMR (400MHz, DMSO-d6) δ 4.58 (m, 1H) 4.23 (quin, J = 7.16Hz, 2H) 3.73 (d, J = 3.00Hz, 3H) 3.17 (m, 2H) 2.43 (m, 1H) 2.22 (m, 1H) 1.26 (td, J = 7.10, 3.44Hz, 3H).

[0258] Step 3: Preparation of (1R,2S,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester

[0259] Methyl (S)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolinoline-2-carboxylate (15.0 g, 58.3 mmol, 1.00 eq) and Pd / C (7.00 g, 6.58 mmol, 1.94 mL, 10% wt) in EtOH (200 mL) were reacted at room temperature for 60 h, followed by filtration. The filtrate was concentrated under reduced pressure to obtain the target product, which was used directly in the next reaction without purification (8.00 g, 47.9 mmol, yield: 41.3%).

[0260] LCMS: m / z 199(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ4.15(m,2H)3.69(m,3H)3.43(brd,J=6.00Hz,1H)2.24(m,1H)1.80(m,2H)1.23(m,3H).

[0261] Step 4: Preparation of 8-tert-butyl-2-ethyl(1R,2S,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate

[0262] (1R,2S,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (6.50 g, 32.8 mmol, 1.00 eq) was reacted with Boc₂O (7.87 g, 36.1 mmol, 8.29 mL, 1.10 eq) and TEA (9.95 g, 98.4 mmol, 13.7 mL, 3.00 eq) in DCM (50 mL). The resulting mixture was reacted at 25 °C for 16 h, then quenched with H₂O (40 mL) at 0 °C and extracted with DCM (50 mL * 2). The combined organic phases were 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 give the target product (2.00 g, 6.70 mmol, yield: 20.4%).

[0263] LCMS: m / z 299(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.71 (s, 1H) 4.59 (m, 1H) 4.15 (m, 3H) 2.18 (m, 1H) 1.89 (m, 3H) 1.36 (s, 9H) 1.24 (br t, J = 7.03Hz, 3H).

[0264] Step 5: Preparation of (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0265] Under nitrogen protection, BH3-Me2S (10M, 2.51mL, 5.00eq) was added dropwise to a THF solution of 8-tert-butyl-2-ethyl(1R,2S,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (1.50 g, 5.03 mmol, 1.00 eq) in 10 mL of THF at 0 °C. The resulting mixture was reacted at 25 °C for 16 h, and then MeOH (20 mL) was added. The resulting mixture was reacted at 50 °C for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the target product (510 mg, 1.99 mmol, yield: 39.6%).

[0266] LCMS: m / z 243(M+H) + . 1 H NMR (400MHz, DMSO-d6) δppm 4.01 (m, 2H) 3.34 (m, 4H) 2.86 (br d, J = 11.00Hz, 1H) 2.39 (dd, J = 11.98, 1.96Hz, 1H) 1.77 (m, 4H) 1.39 (s, 9H).

[0267] Intermediate II-1: (6aS,7R,10S)-4-chloro-2-(methylthio)-6a,7,8,9,10,11-hexahydro-6H-7,10-bridged imine pyrimidine [4',5':5,6][1,4]oxazine [4,3-a]aza Preparation of tert-butyl 1,3-carboxylate

[0268]

[0269] Step 1: Preparation of (1R,2S,5S)-3-(5,6-dichloro-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0270] A solution of 4,5,6-trichloro-2-(methylthio)pyrimidine (500 mg, 2.17 mmol), (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500 mg, 2.06 mmol), and DIPEA (0.56 mL, 3.26 mmol) in EtOH (10 mL) was reacted at 75 °C for 1.5 hr, followed by concentration under reduced pressure. The residue was diluted with DCM (10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the target product (233 mg). No further purification was required; it was used directly in the next reaction.

[0271] LCMS: m / z 435(M+H) + .

[0272] Step 2: (6aS,7R,10S)-4-chloro-2-(methylthio)-6a,7,8,9,10,11-hexahydro-6H-7,10-bridged imine pyrimidine [4',5':5,6][1,4]oxazine [4,3-a]aza Preparation of tert-butyl 1,3-carboxylate

[0273] (1R,2S,5S)-3-(5,6-dichloro-2-(methylthio)pyrimidin-4-yl)-2-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (233 mg, 0.536 mmol) was added to anhydrous THF (25 mL) solution with NaH (60% wt, 21 mg, 0.536 mmol). The resulting mixture was reacted completely at 60 °C, then transferred to ice water and extracted with DCM. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography to obtain the target product (45 mg, two-step yield: 5.5%).

[0274] LCMS: m / z 399(M+H) + .

[0275] Example A1: 2'-amino-1-((6aS,7R,10S)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-pyrrolidine]-7a'(5'H)-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine[4',5':5,6][1,4]oxazine[4,3-a]aza Preparation of -4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0276]

[0277] Step 1: (6aS,7R,10S)-4-chloro-2-(methanesulfonyl)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine [4',5':5,6][1,4]oxazine [4,3-a]aza Preparation of tert-butyl 1,3-carboxylate

[0278] (6aS,7R,10S)-4-chloro-2-(methylthio)-6a,7,8,9,10,11-hexahydro-6H-7,10-bridged imine pyrimidine [4',5':5,6][1,4]oxazine [4,3-a]aza Oxone (516 mg, 0.84 mmol) was added to a mixture of tetrahydrofuran (3 mL) and water (3 mL) containing tert-butyl 1,3-carboxylate (167 mg, 0.42 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with dichloromethane. The combined organic phases were washed successively 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 silica gel column chromatography to give the target product (124 mg, yield: 70.5%).

[0279] LCMS:m / z 431(M+H) + .

[0280] Step 2: (6aS,7R,10S)-4-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bispyrrolidine]-7a'(5'H)-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine[4',5':5,6][1,4]oxazine[4,3-a]aza Preparation of tert-butyl 1,3-carboxylate

[0281] (6aS,7R,10S)-4-chloro-2-(methanesulfonyl)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine[4',5':5,6][1,4]oxazine[4,3-a]aza A solution of tert-butyl 1,3-carboxylate (124 mg, 0.288 mmol) and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis(pyrrolididine)-7a'(5'H)-yl)methanol (120 mg, 0.58 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 hr, then quenched with water and extracted with dichloromethane. The combined organic phases were washed successively 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 silica gel column chromatography to give the target product (98 mg, yield: 61.4%). LCMS: m / z 554 (M+H) + .

[0282] Step 3: (6aS,7R,10S)-4-(2'-amino-3'-cyano-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopropane[b]thiophene]-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bispyrrolidine]-7a'(5'H)-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine[4',5':5,6][1,4]oxazine[4,3-a]aza Preparation of tert-butyl 1,3-carboxylate

[0283] (6aS,7R,10S)-4-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bispyrrolidine]-7a'(5'H)-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine[4',5':5,6][1,4]oxazine[4,3-a]aza 1,4-Dioxane (3 mL) of tert-butyl 1,3-carboxylate (98 mg, 0.177 mmol), 2'-amino-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-carboxynitrile (47.6 mg, 0.23 mmol), and DIPEA (78.8 mg, 0.61 mmol) was stirred at 90 °C for 2 hr, followed by direct separation by silica gel column chromatography to obtain the target product (62 mg, yield: 48.9%). LCMS: m / z 723 (M+H) + .

[0284] Step 4: 2'-amino-1-((6aS,7R,10S)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-pyrrolidine]-7a'(5'H)-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine[4',5':5,6][1,4]oxazine[4,3-a]aza Preparation of -4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0285] (6aS,7R,10S)-4-(2'-amino-3'-cyano-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopropane[b]thiophene]-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bispyrrolidine]-7a'(5'H)-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine[4',5':5,6][1,4]oxazine[4,3-a]aza A solution of tert-butyl 1,3-carboxylate (62 mg, 0.086 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for 10 min, then concentrated under reduced pressure. The residue was separated by preparative liquid chromatography to give the target product (15 mg, yield: 28%). LCMS: m / z 623 (M+H) + .

[0286] The following compounds were synthesized using different starting materials in the same manner as in Example A1:

[0287] Example A2: 2'-amino-1-((6aS,7R,10S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis(5H)-pyrrolidone-7a(5H)-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine [4',5':5,6][1,4]oxazine [4,3-a]aza -4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0288]

[0289] LCMS: m / z 579(M+H) + .

[0290] Example A3: 2'-amino-1-((6aS,7R,10S)-2-(((S)-2-(difluoromethylene)tetrahydro-1H-bis(5H)-pyrrolidone-7a(5H)-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine [4',5':5,6][1,4]oxazine [4,3-a]aza -4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0291]

[0292] LCMS:m / z 609(M+H) + .

[0293] Example A4: 2'-amino-1-((6aS,7R,10S)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine [4',5':5,6][1,4]oxazine [4,3-a]aza -4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0294]

[0295] LCMS: m / z 549(M+H) + .

[0296] Example A5: 2'-amino-1-((6aS,7R,10S)-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine[4',5':5,6][1,4]oxazine[4,3-a]aza -4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0297]

[0298] LCMS: m / z 619(M+H) + .

[0299] Examples A6A and A6B: 2'-amino-1-((6aS,7R,10S)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged imine pyrimidine [4',5':5,6][1,4]oxazine [4,3-a]aza -4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile and 2'-amino-1-((6aS,7R,10S)-2-(((S,Z)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-6a,7,8,9,10,11-hexahydro-6H-[7,10]bridged iminepyrimidine[4',5':5,6][1,4]oxazine[4,3-a]aza -4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0300]

[0301] Example A6A

[0302] LCMS: m / z 593(M+H) + .

[0303] Example A6B

[0304] LCMS: m / z 593(M+H) + .

[0305] Example B1: 2'-amino-1-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-pyrrolidone]-7a'(5'H)-yl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridged imine aziridine [1,2-d]pyrimidine[5,4-b][1,4]oxazetane-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0306]

[0307] LCMS: m / z 637(M+H) + .

[0308] Example B2: 2'-amino-1-(2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridged imine azirconium [1,2-d]pyrimidine[5,4-b][1,4]oxazetane-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0309]

[0310] LCMS: m / z 593(M+H) + .

[0311] Example B3: 2'-amino-1-(2-(((S)-2-(difluoromethylene)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridged imine azirconium [1,2-d]pyrimidine[5,4-b][1,4]oxazetane-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0312]

[0313] LCMS:m / z 623(M+H) + .

[0314] Example B4: 2'-amino-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridged imine azirconium [1,2-d]pyrimidine[5,4-b][1,4]oxazetane-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0315]

[0316] LCMS: m / z 563(M+H) + .

[0317] Example B5: 2'--amino-1-(2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridged imine azirconium [1,2-d]pyrimidine[5,4-b][1,4]oxazetane-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0318]

[0319] LCMS:m / z 633(M+H) + .

[0320] Examples B6A and B6B: 2'-amino-1-(2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridged imine azirconium [1,2-d]pyrimidine[5,4-b][1,4]oxazyrazine-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile and 2'-amino-1-(2-(((S,Z)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridgedimine-aza [1,2-d]pyrimidine[5,4-b][1,4]oxazetane-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0321]

[0322] Example B6A

[0323] LCMS:m / z 607(M+H) + .

[0324] Example B6B

[0325] LCMS:m / z 607(M+H) + .

[0326] Examples B7A and B7B: 2'-amino-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-yl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridged imine azirconium [1,2-d]pyrimidine[5,4-b][1,4]oxazetane-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile and 2'-amino-1-(2-(((3R,4R)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-yl)methoxy)-6,7,7a,8,9,10,11,12-octahydro-[8,11]bridgedimineaza [1,2-d]pyrimidine[5,4-b][1,4]oxazetane-4-yl)-5',6'-dihydrospiro[azacyclobutane-3,4'-cyclopentane[b]thiophene]-3'-formonitrile

[0327]

[0328] Example B7A

[0329] LCMS: m / z 627(M+H) + .

[0330] Example B7B

[0331] LCMS: m / z 627(M+H) + .

[0332] Formulation Examples: Pharmaceutical Compositions

[0333] Oral tablets:

[0334] The compound prepared in Example A1 was added to the excipients microcrystalline cellulose (101) and lactose monohydrate, the internal disintegrant sodium croscarmellose, the binder hydroxypropyl methylcellulose (E15), the external disintegrant sodium croscarmellose, and the lubricant magnesium stearate to prepare 50 mg oral tablets.

[0335] Injectable:

[0336] The compound prepared in Example A1 was added to sodium sulfobutyl betacyclodextrin, sodium chloride, water for injection, etc., to prepare an injectable formulation.

[0337] Biological test cases

[0338] Biological testing evaluation

[0339] The following biological test examples further illustrate the invention, but these examples are not intended to limit the scope of the invention.

[0340] 1. Cell proliferation detection

[0341]

[0342] Positive reference: MRTX1133

[0343]

[0344] 2. Experimental Procedure

[0345] The diluted test compound was added to a 384-well cell culture plate using a nanoliter pipetting system, with replicates. An equal volume of culture medium was added to the positive control group; an equal volume of DMSO was added to the negative control group. The plates were centrifuged at 1000 rpm for 1 min at room temperature.

[0346] Cells were seeded into a) 384 culture plates. An equal volume of cells was added to the negative control group, while an equal volume of culture medium was added to the positive control group. The plates were centrifuged at 1000 rpm for 1 min at room temperature. The final concentration of the compound, DMSO, was 0.5%. The plates were then incubated at 37°C in a 5% CO2 incubator for 7 days.

[0347] Add 20 μL / well Place the cells in a 3D to a 384-well cell culture plate, shake at 320 rpm for 20 min in the dark, and incubate at room temperature in the dark for 2 hours.

[0348] The luminescence value was read using an Envision multi-functional microplate reader.

[0349] 3. Data Analysis

[0350] The inhibition rate (IR) of the detected compound is calculated using the following formula: IR (%) = (1 - (RLU) / (RLU) 化合物 -RLU 空白对照 ) / (RLU 溶媒对照 -RLU 空白对照 *100%. The inhibition rates of different compound concentrations were calculated in Excel, and then inhibition curves were plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC50, were calculated using GraphPad Prism software. 50 .

[0351] The results show that the compounds in the embodiments of the present invention exhibit good inhibitory activity against KRAS mutations.

[0352] I. Pharmacokinetic Testing and Evaluation

[0353] Male ICR mice, weighing approximately 18-25g, were fasted overnight and then orally administered a solution of 100mg / kg of the compound of the present invention or the control compound [using 10% DMSO / 60% polyethylene glycol 400 / 30% aqueous solution as a carrier]. Blood samples were collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, and 24 hours 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.

[0354] The test results show that the compound of this invention has good pharmacokinetic characteristics.

[0355] II. Pharmacokinetic Testing and Evaluation

[0356] Male SD rats, weighing approximately 220g, were fasted overnight and then orally administered a solution of the compound of the present invention or the control compound [using 10% DMSO / 60% polyethylene glycol 400 / 30% aqueous solution as a carrier]. Blood samples were collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, and 24 hours 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.

[0357] The test results show that the compound of this invention has good pharmacokinetic characteristics.

[0358] III. Evaluation of antitumor activity pharmacodynamics (AsPC-1CDX tumor model)

[0359] 100uL containing 5x10 6 AsPC-1 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. The health of the mice was monitored daily, and measurements were taken when the tumor grew to a palpable size. Tumor volume was calculated using the formula: 0.5 x L x W. 2 Where L and W represent the length and width of the tumor, respectively. The tumor is approximately 200 mm long. 3 Mice were randomly assigned to groups. Mice were administered the appropriate dose of the compound daily via gavage, while their general condition was monitored. Tumors were measured three times a week, and body weight was measured twice a week.

[0360] The test results show that the compound of the present invention has good anti-tumor effects.

[0361] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound, or its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compound is shown in Formula I: In the formula, V 1 V 2 V 3 Each is independently selected from the following group: CR v Or N; R v Selected from the following groups, substituted or unsubstituted: H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 member saturated or unsaturated heterocyclic groups, C2-C6 ester groups, amino groups (-NR'R"), C1-C 10 Alkyl carbonyl, C3-C 20 Cycloalkyl carbonyl, amide (-CONR'R"), sulfone or urea groups; V 4 Each of them independently selected from the following group: CHR v NR v or CO;R v Selected from the following groups, substituted or unsubstituted: H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 member saturated or unsaturated heterocyclic groups, C2-C6 ester groups, amino groups (-NR'R"), C1-C 10 Alkyl carbonyl, C3-C 20 Cycloalkyl carbonyl, amide (-CONR'R"), sulfone or urea groups; L 1 Selected from: None, O, CO, NR L , or NR L CO; L 2 Selected from the following groups: -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-CH2-, -CH2-N(R) L -CH2- or -CO-; where R L Self-substituted or unsubstituted subgroups: H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl groups, 4-20 saturated or unsaturated heterocyclic groups; L 3 -CH-; L 4 L 5 and L 6 Each is independently selected from the following group: -CH2- or -CH2-CH2-; And L 3 L 4 L 5 and L 6 One or two of them can also be optionally passed through L p The connection forms a bridge ring or spiral ring structure; L p Selected from the following group: -CH2-, -CH2-CH2-, or -CH=CH-; The above L 2 L 3 L 4 L 5 L 6 and L p In the text, "CH2" and "CH" can also be optionally replaced by one or more R... S Replaced; R S Each is independently selected from the group consisting of: halogens, CN, or C1-C3 alkyl groups; or two Rs on the same or different carbon atoms (preferably the same or adjacent carbon atoms). S Together with the attached carbon atom, they form substituted or unsubstituted C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6 aryl, 4-6 membered heterocyclic, 4-6 membered heterocyclic alkenyl, 5-7 membered heteroaryl; wherein the substitution means being substituted by one or more substituents selected from the group consisting of halogen, CN, or C1-C3 alkyl. U1 and U2 are each independently selected from the following group of substituent or unsubstituted groups: C4-C 14 Cycloalkyl, 4-14 membered heterocyclic, C6-C 14 Aryl, 5-14 heteroaryl, -OR a -NR a R b -CONR a R b -SO2NR a R b -NR a COR b -NR a SO2R b or -NR a CONR a R b Each R a R b Whether identical or different, each is independently selected from the substituted or unsubstituted lower group: H, C1-C 10 Alkyl, C4-C 14 Cycloalkyl, 4-14 membered heterocyclic, and 4-14 membered heterocyclic alkyl, or R a and R b And the atoms connected to them form substituted or unsubstituted 4-14 membered heterocyclic groups; wherein, the substitution refers to being substituted by one or more R; X is selected from: bond, O, NH, N (C1-C3 alkyl), -C≡C-; Y is selected from: bonded, substituted or unsubstituted C1-C6 alkylene; wherein, the substitution refers to being substituted by one or more R; 1) Z is Wherein, W1 is selected from the following group: substituted or unsubstituted groups: C3-C 20 Cycloalkyl groups, 4-20 saturated or unsaturated heterocyclic groups; R 4 Selected from the following groups, whether substituted or unsubstituted: H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, oxo (=O), C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 member saturated or unsaturated heterocyclic groups, C2-C6 ester groups, amino groups (-NR'R"), amide groups (-CONR'R"), C1-C 10 Alkylidene (e.g., methylidene, =CH2), halogenated C1-C 10 Alkylidene (e.g., halogenated methylidene, halogenated = CH2), sulfone, or urea; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8, and the substitution refers to being replaced by one or more R; or 2) Z is -L4-Q2 or Wherein, ring W2 is selected from the following group of substituted or unsubstituted groups: none, C3-C6 cycloalkyl subgroups, 4-6 membered saturated or unsaturated heterocyclic subgroups; L4 is selected from the following groups, whether substituted or unsubstituted: bond, C1-C6 alkylene, deuterated C1-C6 alkylene; Q2 is selected from the following group, either substituted or unsubstituted: C1-C 10 Alkoxy, C3-C 10 Cycloalkyl-O-, 4-10 membered heterocyclic-O-, C3-C 10 Cycloalkyl-(C1-C6 alkylene)-O-, 4-10 membered heterocyclic-(C1-C6 alkylene)-O-, C3-C 10 Cycloalkyl C1-C6 alkeneoxy, 4-10 membered heterocyclic C1-C6 alkeneoxy, C3-C 10 Cycloalkyl, phenyl, benzyl, naphthyl, 4-12 membered heterocyclic groups, NHR 9 or NR 9 R 10 ;R 9 and R 10 Each group is independently selected from the following group: substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C6 ... 10 Cycloalkyl, 4-10 membered heterocyclic groups, (C3-C 10 (cycloalkyl)-C1-C6 alkylene, (4-10 membered heterocyclic)-C1-C6 alkylene, or R 9 and R 10 The N atom attached to it forms a substituted or unsubstituted 4-10 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R atoms; Unless otherwise specified, substitution refers to substitution by one or more R groups, each R being the same or different, and each independently selected from: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, amino, C1-C6 alkyl, methylene (=CH2), halogenated methylidene (e.g., =CHF, =CF2), deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C2-C6 alkenyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C 14 Cycloalkyl, 4-14 membered heterocyclic groups, and hydroxyl-substituted C3-C 14 Cycloalkyl, hydroxyl-substituted 4-14 membered heterocyclic groups, and amino-substituted C3-C 14 Cycloalkyl, amino-substituted 4-14 membered heterocyclic groups, C6-C 10 Aryl, 5-10 membered heteroaryl, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-(C3-C6 cycloalkyl), -N(C1-C6 alkyl)(C3-C6 cycloalkyl), C3-C6 cycloalkyl-O-, 4-7 membered heterocyclic-O-, C3-C6 cycloalkyl-(C1-C6 alkylene))-, 4-6 membered heterocyclic-(C1-C6 alkylene))-, C3-C6 cycloalkyl-O-(C1-C6 alkylene))-, 4- 6-membered heterocyclic group -O-(C1-C6 alkylene)-, (C1-C6 alkyl)-CH=C-, deuterated (C1-C6 alkyl)-CH=C-, halogenated (C1-C6 alkyl)-CH=C-, (C1-C6 alkyl)-C≡C-, (deuterated C1-C6 alkyl)-C≡C-, (halogenated C1-C6 alkyl)-C≡C-, (C3-C6 cycloalkyl)-C≡C-, (4-6-membered heterocyclic group)-C≡C-, C1-C6 ester group, amino group (-NR'R”), amide group, sulfonamide group, sulfone group or urea group.

2. The compound according to claim 1, characterized in that, The compound has the structure shown in formula (II): in, V 1 V 2 V 3 R 1 R 2 L 1 L 2 L 3 L 6 And R as described in claim 1.

3. The compound according to claim 1, characterized in that, The compound has the structure shown in formula (III): in, V 1 V 2 V 3 R 1 R 2 L 1 L 2 L 3 L 6 And R as described in claim 1.

4. The compound according to claim 1, characterized in that, The central ring W1 is selected from the following group: substituted or unsubstituted 4-7 membered monocyclic heterocyclic groups, substituted or unsubstituted C groups. 3-6 Cycloalkyl, substituted or unsubstituted 6-10 membered bicyclic (spirocyclic) heterocyclic groups, substituted or unsubstituted 6-9 membered bicyclic (fused-ring) heterocyclic groups, substituted or unsubstituted 6-9 membered bicyclic (bridged-ring) heterocyclic groups, substituted or unsubstituted 9-12 membered tricyclic heterocyclic groups, substituted or unsubstituted 11-14 membered tetracyclic heterocyclic groups, substituted or unsubstituted C7-C 10 Bridged cycloalkyl; wherein the substitution refers to substitution by one or more R; wherein the tricyclic and tetracyclic heterocyclic groups are spirocyclic and / or bridged and / or fused cyclocyclic; Better place, The central ring W1 is selected from substituted or unsubstituted 4-7 member monocyclic nitrogen-containing heterocyclic groups, substituted or unsubstituted 8-9 member bicyclic N-containing fused heterocyclic groups, substituted or unsubstituted 8-9 member bicyclic N-containing spirocyclic heterocyclic groups, or substituted or unsubstituted 10 member tricyclic nitrogen-containing heterocyclic groups, or substituted or unsubstituted 11 member tetracyclic nitrogen-containing heterocyclic groups, wherein the substitution refers to being substituted by one or more R, and the definition of R is as described in claim 1; The monocyclic nitrogen-containing heterocyclic group, bicyclic N-bridged ring heterocyclic group, bicyclic N-spirocyclic heterocyclic group, bicyclic N-fused ring heterocyclic group, tricyclic nitrogen-containing heterocyclic group, and tetracyclic nitrogen-containing heterocyclic group may optionally contain 0-3 heteroatoms, each independently selected from the group consisting of N, S, or O; the tricyclic nitrogen-containing heterocyclic group and the tetracyclic nitrogen-containing heterocyclic group are spirocyclic and / or bridged ring and / or fused ring; Better, Selected from group A1, group A2, or group A3; among which, Group A1 includes: Group A2 includes: Group A3 includes: Where n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R 4 The definitions of R and n are as described in claim 1, R, R 4 It can replace any one of the rings in a multi-ring system (such as a bridge ring or a spiral ring); More preferably, Selected from group A1a, group A2a, or group A3a: Group A1a includes: Group A2a includes: Group A3a includes: Where n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R 4 The definition of n is as described in claim 1, where R is located on any one of the rings or alkylene chains of a polycyclic (such as a bridged ring or a spirocyclic) chain.

5. The compound according to claim 1, characterized in that, for in, Y is selected from bonded, substituted or unsubstituted C1-C6 alkylene groups; The ring W2 is selected from the following group: substituted or unsubstituted: C3-C6 cycloalkyl subgroups, or 4-7 membered saturated or unsaturated heterocyclic subgroups; L4 is selected from the following group of substituted or unsubstituted groups: bond, C1-C6 alkylene, or deuterated C1-C6 alkylene; Q2 is selected from the following group, whether substituted or unsubstituted: C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclic-O-, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl(C1-C6 alkylene)-O-, 4-7 membered heterocyclic(C1-C6 alkylene)-O-, C3-C6 cycloalkylC1-C6 alkoxy, 4-7 membered heterocyclicC1-C6 alkoxy, C3-C7 cycloalkyl, 4-8 membered heterocyclic, phenyl, benzyl, NHR 9 NR 9 R 10 ; R 9 and R 10 Each group is independently selected from the following group, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, (C3-C6 cycloalkyl)C1-C6 alkylene, (4-7 membered heterocyclic)C1-C6 alkylene, or R 9 and R 10 The N atom attached to it forms a substituted or unsubstituted 4-8 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R atoms; Preferably, Q2 is selected from the following group, whether substituted or unsubstituted: C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclic-O-, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl(C1-C6 alkylene))-O-, 4-7 membered heterocyclic(C1-C6 alkylene))-O-, C3-C7 cycloalkyl, 4-8 membered heterocyclic, NHR 9 NR 9 R 10 ; R 9 and R 10 Each group is independently selected from the following group, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, (C3-C6 cycloalkyl)C1-C6 alkylene, (4-7 membered heterocyclic)C1-C6 alkylene, or R 9 and R 10 The N atom attached to it forms a substituted or unsubstituted 4-8 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R atoms; Better, Selected from group B1, which includes:

6. The compound according to claim 1, characterized in that, U1 is selected from the following group, either substituted or unsubstituted: -OR a -NR a R b Each R a R b Whether identical or different, each is independently selected from the substituted or unsubstituted lower group: H, C1-C 10 Alkyl, C4-C 14 Cycloalkyl, 4-14 membered heterocyclic, and 4-14 membered heterocyclic alkyl, or R a and R b And the atoms connected to them form substituted or unsubstituted 4-14 membered heterocyclic groups; wherein, the substitution refers to being substituted by one or more R; Preferably, U1 is selected from group B2, which includes:

7. The compound according to claim 1, characterized in that, U2 is a substituted or unsubstituted 11-13 membered tricyclic heterocyclic group, or a substituted or unsubstituted 7-9 membered bicyclic heterocyclic group; wherein the substitution is by one or more groups selected from the group consisting of: deuterium, halogen, hydroxyl, cyano, oxo (=O), -NH2, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 ester group, Amino (-NR'R"), amide, sulfone, urea, sulfonamide, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclic-O-, -NH- (C1-C6 alkyl), -NH- (C3-C6 cycloalkyl), hydroxyl-substituted C3-C6 cycloalkyl, hydroxyl-substituted 4-6 membered heterocyclic; wherein the heterocyclic group contains 1, 2, 3, 4 or 5 heteroatoms independently selected from the group consisting of S, N or O; and wherein the heterocyclic group is a spirocyclic and / or bridged ring and / or fused ring structure: Preferably, U2 is selected from group C1, group C2, or group C3; Group C1 includes: Group C2 includes: Group C3 includes: More preferably, U2 is independently selected from the following group:

8. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of: Or select from: Or select from: Or select from: Or select from: Or select from: Or select from: Or select from: Or select from:

9. A pharmaceutical composition, characterized in that, It comprises one or more of the compounds as described in any one of claims 1-7, or their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; And pharmaceutically acceptable carriers.

10. Use of a compound as described in any one of claims 1-7, or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition as described in claim 8, characterized in that, This is used to prepare a drug for the prevention and / or treatment of diseases related to the activity or expression level of KRAS mutations, preferably, the diseases being tumors or disorders.

11. A method for suppressing KRAS mutations, characterized in that, Applying a therapeutically effective amount of any one of claims 1-7, or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition as described in claim 8, to a person in need.

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