Benzopyrimidine compounds

Abstract

The present application belongs to the field of pharmaceutical chemistry and relates to a benzopyrimidine compound, the structure of which is shown in formula (I); specifically, it also relates to a preparation method of the compound, a pharmaceutical composition and its use in treating diseases.

Description

Technical Field

[0001] The present disclosure relates to a benzopyrimidine compound, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating diseases. Background Art

[0002] Ras The gene is an important proto-oncogene, named after the rat sarcoma virus found in it. The Ras protein it encodes is located on the inner side of the cell membrane, can bind to GTP / GDP and hydrolyze GTP with the assistance of GTPase activating protein (GAP). By converting between active (GTP-bound) and inactive (GDP-bound) conformations, Ras protein controls the "on" and "off" of signal transmission processes such as growth factors and cytokines, and plays an important role in life processes such as cell proliferation, differentiation, aging and apoptosis (Bos JL et al., Cell , 2007, 129(5): 865-877). Ras The gene family has three members: Harvey rat sarcoma virus oncogene homolog ( HRas ), neuroblastoma rat sarcoma viral oncogene homolog ( NRas ) and Kirsten rat sarcoma viral oncogene homolog ( Kras ),in Kras Mainly expressed in intestine, lung and thymus (Rajalingam K et al., Biochim Biophys Acta , 2007, 1773(8): 1177-1195).

[0003] Studies have shown that more than 30% of human tumors have Ras Gene mutations, including Kras Mutations account for approximately 86% (Riely G J et al., Proc Am Thorac Soc , 2009, 6(2): 201-205). Kras Mutation, glycine 12 (G12) mutation accounts for about 80%, and G12D mutation (glycine 12 mutates to aspartic acid) is the main mutation form of G12 mutation. (Prior IA et al., Cancer Res , 2012, 72(10): 2457-2467). Mutations at G12 reduce the catalytic activity of GAP, ultimately leading to the continuous activation of Ras, making it unable to effectively regulate cell signal transduction, thereby promoting the occurrence and development of tumors.

[0004] Currently, Kras (e.g. Kras G12D ) has become an attractive anticancer target. Summary of the invention

[0005] The present disclosure relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0006]

[0007] in,

[0008] R 1a Selected from deuterium, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0009] R 1b Selected from -H, deuterium, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0010] Or, R 1a , R 1b and the C atoms to which they are attached together form C=O, or form a C=O optionally substituted by one or more R 1c Substituted as follows: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;

[0011] Each R 1c independently selected from deuterium, oxo, halogen, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0012] Ring A is selected from optionally substituted with one or more R A Substituted benzopyrazolyl;

[0013] Each R A are independently selected from deuterium, halogen, -OH, oxo, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0014] R 2 , R 3are each independently selected from -H, deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl;

[0015] Ring B is selected from optionally substituted with one or more R B Substituted 3-12 membered heterocycloalkyl;

[0016] Each R B are independently selected from deuterium, halogen, -OH, oxo, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, or di-C 1-6 Alkylamino;

[0017] X is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-;

[0018] R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 Alkylene;

[0019] Each R 4a are independently selected from deuterium, halogen, -OH, oxo, -NH 2 , -CN, or optionally one or more R 4b Substituted groups: =NH, =CH 2 =N(C 1-6 alkyl), =CH(C 1-6 alkyl), =C(C 1-6 alkyl) 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, or di-C 1-6 Alkylamino;

[0020] Each R 4b are independently selected from deuterium, halogen, -OH, oxo, -NH2 、-CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0021] Ring C is selected from optionally substituted with one or more R C Substituted as follows: 6-10 membered aryl or 5-10 membered heteroaryl;

[0022] Each R C independently selected from deuterium, halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0023] L is selected from a single bond or C 1-6 Alkylene, the C 1-6 One or more -CH 2 - are each independently optionally replaced by the following atoms or groups: -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -CH=CH-, -C≡C-, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the C 1-6 Alkylene, -NH-, -CH=CH-, 3-12-membered cycloalkyl, 3-12-membered heterocyclyl, 6-10-membered aryl, or 5-10-membered heteroaryl are each independently optionally substituted by one or more R L replace;

[0024] Each R L are each independently selected from deuterium, oxo, halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C1-6 Alkylamino;

[0025] Ring D is selected from optionally one or more R D Substituted as follows: 6-10 membered aryl or 5-10 membered heteroaryl;

[0026] Each R D are each independently selected from deuterium, halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0027] R 5a , R 5b are each independently selected from -H, deuterium, halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0028] R 6a , R 6b are each independently selected from -H, deuterium, halogen, -OH, -NH 2 , -CN, or optionally one or more R 6c Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, or di-C 1-6 Alkylamino;

[0029] Each R 6c are each independently selected from deuterium, oxo, halogen, -OH, -NH 2 、-CN、C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, halo 1-6 Alkylamino, or halogenated di-C1-6 Alkylamino;

[0030] Ring E is selected from optionally substituted with one or more R E Substituted as follows: 6-10 membered aryl or 5-10 membered heteroaryl;

[0031] Each R E are each independently selected from deuterium, halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0032] Ring F is selected from F substituted 5-10 membered heteroaryl;

[0033] Each R F are each independently selected from deuterium, halogen, -OH, -NH 2 、-CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, halo C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0034] In some embodiments, the R 1a Selected from deuterium, halogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0035] In some embodiments, the R 1a is selected from deuterium, -F, -Cl, -Br, -I, methyl, ethyl, deuterated methyl, or halomethyl.

[0036] In some embodiments, the R 1a Selected from deuterium, -F, -Cl, -Br, methyl, trideuteriummethyl, or trifluoromethyl.

[0037] In some embodiments, the R 1a Selected from deuterium, -F, -Cl, or methyl.

[0038] In some embodiments, the R 1b Selected from -H, deuterium, halogen, C 1-4Alkyl, deuterated C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0039] In some embodiments, the R 1b is selected from -H, deuterium, -F, -Cl, -Br, -I, methyl, ethyl, deuterated methyl, or halomethyl.

[0040] In some embodiments, the R 1b Selected from -H, deuterium, -F, -Cl, -Br, methyl, trideuteriummethyl, or trifluoromethyl.

[0041] In some embodiments, the R 1b is selected from -H, deuterium, -F, -Cl, or methyl.

[0042] In some embodiments, the R 1a , R 1b and the C atoms to which they are attached together form C=O, or form a C=O optionally substituted by one or more R 1c Substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl.

[0043] In some embodiments, the R 1a , R 1b and the C atoms to which they are attached together form C=O, or form a C=O optionally substituted by one or more R 1c Substituted as follows: cyclopropyl or cyclobutyl.

[0044] In some embodiments, the R 1a , R 1b Together with the C atoms to which they are attached, they form C=O, cyclopropyl, or cyclobutyl.

[0045] In some embodiments, the R 1a Selected from deuterium, -F, -Cl, -Br, -I, methyl, ethyl, deuterated methyl, or halomethyl;

[0046] The R 1b is selected from -H, deuterium, -F, -Cl, -Br, -I, methyl, ethyl, deuterated methyl, or halomethyl;

[0047] Alternatively, the R 1a , R 1b and the C atoms to which they are attached together form C=O, or form a C=O optionally substituted by one or more R 1c Substituted as follows: cyclopropyl or cyclobutyl.

[0048] In some embodiments, the R1a is selected from deuterium, -F, -Cl, or methyl; said R 1b is selected from -H, deuterium, -F, -Cl, or methyl; or, said R 1a , R 1b Together with the C atoms to which they are attached, they form C=O, cyclopropyl, or cyclobutyl.

[0049] In some embodiments, each R 1c independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH 2 、-CN、C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Alkylthio, C 1-2 Alkylamino, di-C 1-2 Alkylamino, deuterated C 1-2 Alkyl, halogenated C 1-2 Alkyl or halogenated C 1-2 Alkoxy.

[0050] In some embodiments, each R 1c independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, methoxy, methylthio, methylamino, dimethylamino, trideuteriomethyl, trifluoromethyl, or trifluoromethoxy.

[0051] In some embodiments, each R 1c are independently selected from deuterium, -F, -Cl, or methyl.

[0052] In some embodiments, the ring A is selected from the group consisting of A Replaced .

[0053] In some embodiments, each R A independently selected from deuterium, -F, -Cl, -Br, -I, -OH, oxo, -NH 2 、-CN、C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Alkylthio, C 1-2 Alkylamino, di-C 1-2 Alkylamino, halo C 1-2 Alkyl or halogenated C 1-2 Alkoxy.

[0054] In some embodiments, the R A independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -NH 2, -CN, methyl, ethyl, methoxy, methylthio, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0055] In some embodiments, the R A are independently selected from deuterium, -F, -Cl, or methyl.

[0056] In some embodiments, the ring A is selected from .

[0057] In some embodiments, the R 2 , R 3 are each independently selected from -H, deuterium, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, 3-5 membered cycloalkyl, or 3-5 membered heterocyclic group.

[0058] In some embodiments, the R 2 , R 3 Each is independently selected from -H, deuterium, -F, -Cl, -Br, -I, -CN, C 1-2 Alkyl, C 1-2 Alkoxy, halogenated C 1-2 Alkyl, halogenated C 1-2 Alkoxy, 3-4 membered cycloalkyl, or 3-4 membered heterocycloalkyl.

[0059] In some embodiments, the R 2 , R 3 Each is independently selected from -H, deuterium, -F, -Cl, -Br, -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyclopropyl.

[0060] In some embodiments, the R 2 is selected from -H, deuterium, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyclopropyl.

[0061] In some embodiments, the R 2 Selected from cyclopropyl.

[0062] In some embodiments, the R 3 is selected from -H, deuterium, -F, -Cl, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0063] In some embodiments, the R 3 Selected from -H.

[0064] In some embodiments, the ring B is selected from the group consisting of BSubstituted 3-10 membered heterocycloalkyl.

[0065] In some embodiments, the ring B is selected from the group consisting of B Substituted 5-9 membered heterocycloalkyl.

[0066] In some embodiments, the ring B is selected from the group consisting of B Substituted 7-8 membered heterocycloalkyl.

[0067] In some embodiments, the 3-10 membered, 5-9 membered, or 7-8 membered heterocycloalkyl contains one or two N atoms.

[0068] In some embodiments, the 3-10 membered, 5-9 membered, or 7-8 membered heterocycloalkyl is selected from bridged heterocycloalkyl.

[0069] In some embodiments, the ring B is selected from the group consisting of B Substituted with the following groups: , , ,or .

[0070] In some embodiments, each R B are independently selected from deuterium, halogen, -OH, oxo, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0071] In some embodiments, each R B independently selected from deuterium, -F, -Cl, -Br, -I, -OH, oxo, -NH 2 、-CN、C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Alkylthio, C 1-2 Alkylamino, or di-C 1-2 Alkylamino.

[0072] In some embodiments, each R B independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -NH 2 , -CN, methyl, methoxy, methylthio, methylamino, or dimethylamino.

[0073] In some embodiments, each R B are independently selected from deuterium, -F, -Cl, or methyl.

[0074] In some embodiments, the ring B is selected from , , ,or .

[0075] In some embodiments, the ring B is selected from or .

[0076] In some embodiments, X is selected from a single bond, -O-, -NH-, or -N(CH 3 )-.

[0077] In some embodiments, said X is selected from -O-.

[0078] In some embodiments, the R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl 1-4 Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 Alkylene.

[0079] In some embodiments, the R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl 1-3 Alkylene, 3-8 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0080] In some embodiments, the R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl group C 1-3 Alkylene, or 3-8 membered heterocyclic group C 1-3 Alkylene.

[0081] In some embodiments, R 4In the definition, the 3-12-membered, 3-10-membered or 3-8-membered heterocyclic group is selected from 3-12-membered, 3-10-membered or 3-8-membered heterocycloalkyl groups, respectively.

[0082] In some embodiments, R 4 In the definition, the 3-12 membered heterocyclic group C 1-6 Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene or 3-8 membered heterocyclic group C 1-3 The alkylene groups are selected from 3-12 membered heterocycloalkyl groups C 1-6 Alkylene, 3-10 membered heterocycloalkyl C 1-4 Alkylene or 3-8 membered heterocycloalkyl C 1-3 Alkylene.

[0083] In some embodiments, the R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkylC 1-3 Alkylene, or 3-8 membered heterocycloalkyl C 1-3 Alkylene.

[0084] In some embodiments, the R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, 5-azaspiro[2.4]heptyl, cyclopropylC 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, tetrahydrofuranyl C 1-3 Alkylene, tetrahydropyranyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, piperazine C 1-3 Alkylene, hexahydro-1H-pyrrolizinyl C 1-3 Alkylene, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, or 5-azaspiro[2.4]heptyl C 1-3Alkylene.

[0085] In some embodiments, the R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0086] In some embodiments, the R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted with the following groups: n-propyl, isopropyl, sec-butyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropylmethylene, or tetrahydrofuranyl C 1-3 Alkylene.

[0087] In some embodiments, the R 4 is selected from -H, deuterium, or optionally substituted by one or more R 4a Substituted groups: n-propyl, isopropyl, sec-butyl, , , , , , , , ,or .

[0088] In some embodiments, the R 4 Selected from optionally one or more R 4a Substituted C 1-6 alkyl.

[0089] In some embodiments, the R 4a The substituted position is R 4 The cyclic part and / or alkylene part in the

[0090] In some embodiments, each R 4a are independently selected from deuterium, halogen, -OH, oxo, -NH 2 , -CN, or optionally one or more R 4b Substituted groups: =NH, =CH 2 =N(C 1-4 alkyl), =CH(C 1-4 alkyl), =C(C 1-4 alkyl) 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-6 Alkylamino.

[0091] In some embodiments, each R 4a independently selected from deuterium, -F, -Cl, -Br, -I, -OH, oxo, -NH 2 , -CN, or optionally one or more R 4b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0092] In some embodiments, each R 4a independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -NH 2 , -CN, or optionally one or more R 4b Substituted: methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, or dimethylamino.

[0093] In some embodiments, each R 4a independently selected from deuterium, -F, -Cl, -OH, -NH 2 , methyl, methoxymethylene, hydroxymethylene, methoxy, or dimethylamino.

[0094] In some embodiments, each R 4bare independently selected from deuterium, halogen, -OH, oxo, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0095] In some embodiments, each R 4b independently selected from deuterium, -F, -Cl, -Br, -I, -OH, oxo, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0096] In some embodiments, each R 4b independently selected from deuterium, -F, -Cl, -OH, -NH 2 , methyl, or methoxy.

[0097] In some embodiments, the R 4 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0098] In some embodiments, the ring C is selected from optionally substituted with one or more RC Substituted as follows: phenyl or 5-6 membered heteroaryl.

[0099] In some embodiments, the ring C is selected from optionally substituted with one or more R C Substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0100] In some embodiments, the ring C is selected from optionally substituted with one or more R C Substituted as follows: phenyl or pyridyl.

[0101] In some embodiments, the ring C is selected from optionally substituted with one or more R C Replaced .

[0102] In some embodiments, each R C independently selected from deuterium, halogen, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0103] In some embodiments, each R C independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0104] In some embodiments, each R C independently selected from deuterium, -F, -Cl, -OH, -NH 2 , methyl, or methoxy.

[0105] In some embodiments, each R C are independently selected from deuterium, -F, or -Cl.

[0106] In some embodiments, the ring C is selected from .

[0107] In some embodiments, L is selected from a single bond or C 1-4 Alkylene, the C 1-4 One or more -CH 2- are each independently optionally replaced by the following atoms or groups: -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -CH=CH-, -C≡C-, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein C 1-4 Alkylene, -NH-, -CH=CH-, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl are each independently optionally substituted by one or more R L replace.

[0108] In some embodiments, L is selected from a single bond or C 1-4 Alkylene, the C 1-4 One or more -CH 2 - are each independently optionally replaced by the following atoms or groups: -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -CH=CH-, -C≡C-, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, wherein C 1-4 Alkylene, -NH-, -CH=CH-, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl are each independently optionally substituted with one or more R L replace.

[0109] In some embodiments, the "alkylene" in L is selected from a linear alkylene or a branched alkylene.

[0110] In some embodiments, the "one or more" in L is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the "one or more" involved in L is selected from 1, 2, 3, or 4.

[0111] In some embodiments, L is selected from a single bond or a linear C 1-4 Alkylene, the straight chain C 1-4 1, 2, 3 or 4 -CH 2 - are each independently optionally replaced by the following atoms or groups: -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -CH=CH-, -C≡C-, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, the straight chain C 1-4 Alkylene, -NH-, -CH=CH-, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl are each independently optionally substituted with one or more R L replace.

[0112] In some embodiments, L is selected from a single bond or a linear C1-4 Alkylene, the straight chain C 1-4 1, 2, 3 or 4 -CH 2 - are each independently optionally replaced by the following atoms or groups: -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, the straight chain C 1-4 Alkylene, -NH-, -CH=CH-, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl are each independently optionally substituted with one or more R L replace.

[0113] In some embodiments, each R L are each independently selected from deuterium, oxo, halogen, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0114] In some embodiments, each R L are each independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0115] In some embodiments, each R L are each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0116] In some embodiments, each R L independently selected from deuterium, oxo, -F, -Cl, -OH, -NH 2 , methyl, or methoxy.

[0117] In some embodiments, L is selected from a single bond or a linear C 1-4 Alkylene.

[0118] In some embodiments, said L is selected from a single bond.

[0119] In some embodiments, the ring D is selected from the group consisting of D Substituted as follows: phenyl or 5-6 membered heteroaryl.

[0120] In some embodiments, the ring D is selected from the group consisting of D Substituted 5-membered heteroaryl.

[0121] In some embodiments, the ring D is selected from the group consisting of D Substituted: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, or isothiazolyl.

[0122] In some embodiments, the ring D is selected from the group consisting of D Substituted: pyrrolyl, pyrazolyl, imidazolyl, or triazolyl.

[0123] In some embodiments, the ring D is selected from the group consisting of D Replaced , optionally, the The left or right side of the fragment is connected to L.

[0124] In some embodiments, each R D are each independently selected from deuterium, halogen, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0125] In some embodiments, each R D independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0126] In some embodiments, each RD independently selected from deuterium, -F, -Cl, -OH, -NH 2 , methyl, or methoxy.

[0127] In some embodiments, each R D are independently selected from deuterium, -F, or -Cl.

[0128] In some embodiments, the ring D is selected from , The left side of the fragment is connected to L.

[0129] In some embodiments, the R 5a , R 5b are each independently selected from -H, deuterium, halogen, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0130] In some embodiments, the R 5a , R 5b Each is independently selected from -H, deuterium, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0131] In some embodiments, the R 5a is selected from H or deuterium; said R 5b Selected from C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0132] In some embodiments, the R 5a Selected from H or deuterium.

[0133] In some embodiments, the R 5b is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0134] In some embodiments, the R 5b Selected from isopropyl or tert-butyl.

[0135] In some embodiments, the R 6a , R 6bare each independently selected from -H, deuterium, halogen, -OH, -NH 2 , -CN, or optionally one or more R 6c Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0136] In some embodiments, the R 6a , R 6b Each is independently selected from -H, deuterium, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, or optionally one or more R 6c Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0137] In some embodiments, the R 6a , R 6b Each is independently selected from -H, deuterium, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, or optionally one or more R 6c Substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, or diethylamino.

[0138] In some embodiments, the R 6a , R 6b are each independently selected from -H, deuterium, or optionally substituted by one or more R 6c Substituted C 1-4 alkyl.

[0139] In some embodiments, the R 6a , R 6b are each independently selected from -H, deuterium, or optionally substituted by one or more R 6c Substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0140] In some embodiments, the R 6a is selected from -H or deuterium; said R 6b Selected from one or more R 6c Substituted C 1-4 alkyl.

[0141] In some embodiments, the R 6a Selected from -H or deuterium.

[0142] In some embodiments, the R 6b Selected from one or more R 6c Substituted methyl.

[0143] In some embodiments, each R 6c are each independently selected from deuterium, oxo, halogen, -OH, -NH 2 、-CN、C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino.

[0144] In some embodiments, each R 6c are each independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH 2 、-CN、C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0145] In some embodiments, each R 6c are each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0146] In some embodiments, each R 6c independently selected from deuterium, oxo, -F, -Cl, -OH, -NH 2 , or methoxy.

[0147] In some embodiments, the R 6b Selected from methyl or hydroxymethylene.

[0148] In some embodiments, the ring E is selected from the group consisting of ESubstituted as follows: phenyl or 5-6 membered heteroaryl.

[0149] In some embodiments, the ring E is selected from the group consisting of E Substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0150] In some embodiments, the ring E is selected from the group consisting of E Substituted as follows: phenyl or pyridyl.

[0151] In some embodiments, the ring E is selected from the group consisting of E Replaced .

[0152] In some embodiments, each R E are each independently selected from deuterium, halogen, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0153] In some embodiments, each R E independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0154] In some embodiments, each R E independently selected from deuterium, -F, -Cl, -OH, -NH 2 , methyl, or methoxy.

[0155] In some embodiments, each R E are independently selected from deuterium, -F, or -Cl.

[0156] In some embodiments, the ring E is selected from .

[0157] In some embodiments, the ring F is selected from the group consisting of optionally substituted with one or more R F Substituted 5-6 membered heteroaryl.

[0158] In some embodiments, the ring F is selected from the group consisting of optionally substituted with one or more RF Substituted: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0159] In some embodiments, the ring F is selected from the group consisting of F Substituted: pyrazolyl or thiazolyl.

[0160] In some embodiments, the ring F is selected from the group consisting of F Substituted with the following groups: or .

[0161] In some embodiments, each R F are each independently selected from deuterium, halogen, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halo C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0162] In some embodiments, each R F Each independently selected from deuterium, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0163] In some embodiments, each R F Independently selected from deuterium, -F, -Cl, methyl, ethyl, methoxy, or trifluoromethyl.

[0164] In some embodiments, each R F Independently selected from methyl or ethyl.

[0165] In some embodiments, the ring F is selected from , ,or .

[0166] In some embodiments, the heterocyclic group disclosed herein is selected from heterocycloalkyl. In some embodiments, the heterocyclic group disclosed herein is selected from heterocycloalkenyl.

[0167] In some embodiments, the C 1-12 Selected from C1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 .

[0168] In some embodiments, the C 1-6 The alkyl group is selected from C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0169] In some embodiments, the C 1-6 The alkylene group is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0170] In some embodiments, the halogen is selected from -F, -Cl, -Br, or -I.

[0171] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0172] In some embodiments, the "one or more" described in the present disclosure may refer to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine or ten; or, "one or more" refers to one, two, three, four, five or six; or, "one or more" refers to one, two, three or four.

[0173] In some embodiments, the 3-12-membered is selected from 3-10-membered, 3-8-membered, 3-6-membered, 4-10-membered, 4-8-membered, 4-6-membered, 5-10-membered, 5-8-membered, or 5-6-membered.

[0174] In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

[0175] In some embodiments, the heterocycloalkyl contains 1 N atom.

[0176] In some embodiments, the heterocycloalkyl contains 1 O atom.

[0177] In some embodiments, the heterocycloalkyl contains 1 N atom and 1 O atom.

[0178] In some embodiments, the heterocyclyl or heteroaryl contains 1 or 2 heteroatoms selected from N, O, or S.

[0179] In some embodiments, the heterocyclyl or heteroaryl contains 1 or 2 N atoms.

[0180] In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 O atom.

[0181] In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 S atom.

[0182] In some embodiments, the heterocyclyl or heterocycloalkyl includes a monocyclic, spirocyclic, fused or bridged ring. In some embodiments, the heterocyclyl or heterocycloalkyl includes a monocyclic, fused or spirocyclic ring. In some embodiments, the heterocyclyl or heterocycloalkyl includes a bridged ring.

[0183] The present disclosure relates to a compound of formula (I-1), (I-1a), (II), (II-1), (II-1-1), (II-1-1a), (II-1-1b), (II-1-1c), or (II-1-1d), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0184] , ,

[0185] ,

[0186] , , , , , ,

[0187] Among them, R 1a , R 1b , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , X, L, Ring A, Ring B, Ring C, Ring D, Ring E, or Ring F are as defined above.

[0188] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0189] The present disclosure also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0190] , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0191] , .

[0192] The present disclosure also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0193] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0194] , .

[0195] The present disclosure also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0196] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0197] In another aspect, the present disclosure relates to a pharmaceutical composition comprising the compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0198] In another aspect, the present disclosure relates to a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of the compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure to a mammal, preferably a human, in need of such treatment.

[0199] In another aspect, the present disclosure relates to use of the compound of the present disclosure, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in preparing a medicament for treating a disease.

[0200] In another aspect, the present disclosure relates to use of the compound of the present disclosure, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in treating a disease.

[0201] In another aspect, the present disclosure relates to a compound of the present disclosure, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating a disease.

[0202] In some embodiments of the present disclosure, the disease is preferably a Kras-associated disease.

[0203] In some embodiments of the present disclosure, the Kras-associated disease is preferably a Kras-mutated cancer (eg, pancreatic cancer).

[0204] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12D Related diseases.

[0205] In some embodiments of the present disclosure, the Kras G12D Related diseases are preferably Kras G12D Cancers with mutations (e.g. pancreatic cancer).

[0206] Technical Effects

[0207] The compounds disclosed herein have higher Kras G12D Protein degradation activity and cell proliferation inhibitory activity (such as AsPc-1 cell proliferation inhibitory activity), while showing good drugability in in vitro and in vivo pharmacokinetics (such as in vitro liver microsome stability in humans, monkeys, rats or mice), bioavailability and / or pharmacodynamics studies.

[0208] definition

[0209] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be considered as indefinite or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0210] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.

[0211] Non-limiting examples of “substituents” as described herein include deuterium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, hetero arylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., which are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2 NH 2 、-S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0212] In some embodiments herein, the substituent is selected from deuterium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12-membered cycloalkynyl, halogenated 8-12-membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 ester group, oxo and thio, etc., wherein the substituent is optionally substituted by one or more substituents selected from the following: deuterium atom, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halo C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)O- C 1-12 Alkyl, -OC(O)- C 1-12 Alkyl, -C(O)NH 2 、-C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 alkyl) 2 、-NHC(O)- C 1-12 Alkyl, -C(O)- C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O) 2 -C 1-12 Alkyl, -S(O)2 NH 2 、-S(O) 2 NH-C 1-12 Alkyl, -S(O) 2 N(C 1-12 alkyl) 2 , 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 Alkylene or 6-10 membered aryloxy.

[0213] The term "substituted" means that the specified atom or group can be replaced by another specified atom or group. 2 CH 2 CH 2 -1, 2 or 3 of -CH 2 - can be replaced by O, S, NH to obtain -O-CH 2 -CH 2 -、-O-CH 2 -、-CH 2 -O-CH 2 -、-CH 2 -O-, -CH 2 -CH 2 -O-, -O-, etc.

[0214] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. For example, ethyl is "optionally" substituted with halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely replaced (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group comprising one or more substituents, no substitution or substitution pattern will be introduced that is sterically impossible to exist and / or cannot be synthesized.

[0215] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-12 " means that the group may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. For example, "C 1-6 " means that the group may have 1, 2, 3, 4, 5 or 6 carbon atoms. For example, "C 1-4 ” means that the group may have 1, 2, 3 or 4 carbon atoms.

[0216] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition is independent on each occurrence. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0217] When the number of a linking group is 0, such as -(CH 2 ) 0 -, indicating that the connecting group is a covalent bond.

[0218] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0219] When the listed linking group does not specify its connection direction, its connection direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0220] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. or It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0221] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0222] The term "hydroxy" refers to an -OH group.

[0223] The term "cyano" refers to a -CN group.

[0224] The term "mercapto" refers to a -SH group.

[0225] The term "amino" refers to -NH 2 Group.

[0226] The term "nitro" refers to -NO 2 Group.

[0227] The term "alkylene" refers to a group of the formula C n H 2n A saturated straight or branched divalent hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 "Alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -or-CH 2 CH(CH 3 )-), butylene (-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH(CH 3 )CH 2 -or-CH 2 CH 2 CH(CH 3 )-) etc. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0228] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1 - 6The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted with one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy. Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.

[0229] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms attached thereto) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkyl group contains 1, 2 or 3 heteroatom groups, non-limiting examples of which include O, S, N or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, the term "C 1 - 6 "Heteroalkyl" refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkyl group (e.g., internal or terminal position), including the position that connects the heteroalkyl group to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like. The heteroalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0230] The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0231] The term "alkylamino" refers to -NH-alkyl groups, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0232] The term "dialkylamino" refers to -N(alkyl) 2 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. Wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0233] The term "alkylsulfonyl" refers to -SO 2 -alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0234] The term "alkylthio" refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0235] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc. The alkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0236] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (-CH 2 The alkynyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0237] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 10 rings, 4 to 8 rings, 5 to 8 rings or 5 to 6 rings. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc. The cycloalkyl is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C (O) O-alkyl, -OC (O)-alkyl, -C (O) NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2NH 2 、-S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0238] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring with at least one double bond and which can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 10 rings, 4 to 8 rings, 5 to 8 rings or 5 to 6 rings. Non-limiting examples of cycloalkenyl include but are not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc. The cycloalkenyl is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl,-C (O) O-alkyl,-OC (O)-alkyl,-C (O) NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2 NH 2 、-S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0239] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, cyclic or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is generally 3 to 12, 3 to 10, 4 to 8, 5 to 8, 5 to 6, 3 to 7 or 4 to 6 rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Non-limiting examples of heterocyclic groups include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc. The heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2 NH 2 、-S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0240] The term "heterocycloalkenyl" refers to a non-aromatic ring that is partially unsaturated (but not completely unsaturated heteroaromatic) and can exist as a monocyclic, bridged, cyclic or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12, 3 to 10, 4 to 8, 5 to 8, 5 to 6, 3 to 7 or 4 to 6 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Non-limiting examples of heterocycloalkenyl include, but are not limited to, dihydrofuranyl, dihydropyrrolyl, 2H-pyranyl, dihydrothienyl, etc. The heterocycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2, -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2 NH 2 、-S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0241] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3-12-membered, 3-10-membered, 4-8-membered, 5-8-membered, 5-6-membered, 3-7-membered or 4-6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and cyclonitriles; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl. The heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2 NH 2 、-S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0242] The term "aryl" refers to an aromatic ring group of a full carbon monocyclic or fused polycyclic ring with a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C (O) O-alkyl, -OC (O)-alkyl, -C (O) NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2 NH 2 、-S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0243] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, and the remaining ring atoms are C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7 or 5 to 6 rings. Preferred heteroaryls have a single 4 to 8 ring, especially a 5 to 6 ring, or a plurality of fused rings containing 5 to 14, especially 5 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2, -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2 NH 2 、-S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0244] The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0245] (i) inhibiting a disease or disease state, i.e. curbing its development;

[0246] (ii) the disease or condition is alleviated, even if it is resolved.

[0247] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0248] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0249] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0250] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0251] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0252] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0253] The word “comprise” or “comprises” and its English variations such as comprises or comprising should be construed as having an open and non-exclusive meaning, ie, “including but not limited to”.

[0254] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0255] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F.123 I. 125 I and 36 Cl, etc. In some embodiments, the compounds disclosed herein include compounds in which one or more hydrogen atoms are replaced by deuterium atoms, for example, 1, 2 or 3 hydrogen atoms of any methyl group are replaced by deuterium atoms.

[0256] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0257] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0258] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0259] , .

[0260] The compounds of the present disclosure may have one or more atropisomers, and unless otherwise specified, the atropisomers refer to stereoisomers produced due to the hindered free rotation between single bonds. The compounds of the present disclosure containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation of a single bond of the compounds of the present disclosure containing a chiral axis is high enough, the atropisomers thereof can be isolated in an optically pure form. Non-limiting examples of atropisomers include, but are not limited to:

[0261] , .

[0262] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0263] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0264] In all administration methods of the compounds described herein, the daily dosage is 0.001 to 2000 mg / kg body weight. The compounds disclosed herein can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0265] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0266] When L is selected from a single bond, the compound of formula (I) disclosed herein can be prepared by a person skilled in the art of organic synthesis via route 1, wherein PG is independently selected from a suitable common protecting group, such as tert-butyloxycarbonyl; R 1a , R 1b , R 2 , R 3 ,X,R 4 , R 5a , R 5b , R 6a , R 6b , R 7 , Ring A, Ring B, Ring C, Ring D, and Ring E are as defined above.

[0267]

[0268]

[0269]

[0270]

[0271] Route 1

[0272] Each product obtained by the reaction in the above route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to Adrich or Sigma). These raw materials can be characterized by conventional means, such as physical constants and spectral data. The compounds described in the present disclosure can be obtained as a single isomer or a mixture of isomers using synthetic methods.

[0273] This disclosure uses the following abbreviations:

[0274] Boc represents tert-butyloxycarbonyl; Trt represents trityl.

[0275] Commercially available compounds were given by their supplier catalog names.

[0276] For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0277] All reagents used in this disclosure were commercially available and used without further purification. DETAILED DESCRIPTION

[0278] Example 1

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287] Step 1:

[0288] 1-1 (1.4 g) and 1-2 (2.16 g) were added to a mixed solvent of 1,4-dioxane / water (V / V=4 / 1, 50 mL), potassium carbonate (2.76 g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (730 mg) were added, and the mixture was heated to 90°C and stirred for 3 hours, then the heating was stopped and the reaction solution was directly concentrated to dryness. Column chromatography (dichloromethane / methanol=10 / 1) was performed to obtain compound 1-3.

[0289] LC-MS, ESI: m / z (M+H) + : 232.1.

[0290] Step 2:

[0291] Compounds 1-3 (2.031 g) and 1-4 (1.421 g) were added to N,N-dimethylformamide (40 mL), and N,N-diisopropylethylamine (2.142 mL) was added, and stirred at room temperature for 20 minutes. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.675 g) was added, and stirring was continued for 16 hours. Ethyl acetate (60 mL) was added for dilution, and the organic phase was concentrated to dryness after washing with saturated brine (60 mL). Column chromatography (dichloromethane / methanol = 10 / 1) gave compound 1-5.

[0292] LC-MS, ESI: m / z (M+H) + : 544.3.

[0293] Step 3:

[0294] 1-5 (2.0 g) was added to a trifluoroacetic acid / dichloromethane mixed solvent (V / V=1 / 3, 20 mL), stirred at room temperature for 30 minutes, 7 mol / L ammonia methanol solution was added to adjust the pH to 7, and the system was concentrated to dryness. Column chromatography (dichloromethane / methanol=10 / 1) was performed to obtain compound 1-6.

[0295] LC-MS, ESI: m / z (M+H) + : 444.47.

[0296] Step 4:

[0297] Add 1-6 (1.0 g) to methanol (20 mL) and stir at room temperature. Add water (5 mL), potassium carbonate (1.0 g), copper sulfate pentahydrate (0.10 g) and 1H-imidazole-1-sulfonyl azide hydrochloride (0.70 g) in sequence and react at room temperature overnight. Adjust pH to 2-3 with 1 mol / L hydrochloric acid. Add water (50 mL), extract with ethyl acetate (50 mL), wash the organic phase with saturated sodium chloride aqueous solution (50 mL), and concentrate to dryness. Column chromatography (dichloromethane / methanol = 20 / 1) gives compound 1-7.

[0298] LC-MS, ESI: m / z (M+H) + : 470.35.

[0299] Step 5:

[0300] Add 1-8 (5.0 g) to tetrahydrofuran (100 mL), cool to 0°C, add 3 mol / L methylmagnesium bromide in tetrahydrofuran solution (13.5 mL), and react at 0°C for 2 hours. Add water (200 mL) to quench the reaction, and extract with ethyl acetate (200 mL). Wash the organic phase with saturated sodium chloride solution (100 mL) and concentrate to dryness. Column chromatography (petroleum ether / dichloromethane = 20 / 1) gave compound 1-9.

[0301] LC-MS, ESI: m / z (M-OH) + : 128.9

[0302] Step 6:

[0303] 1-9 (1.0 g) was added to dichloromethane (20 mL), and thionyl chloride (1.6 g) was added, and the mixture was reacted at room temperature for 17 hours. Ice water (100 mL) was added to quench the reaction, and dichloromethane (100 mL) was used for extraction. The organic phase was washed with 5% sodium bicarbonate solution (50 mL) and concentrated to dryness. Compound 1-10 was obtained.

[0304] Step 7:

[0305] Add 1-11 (45.4 g) N , N -Dimethylformamide (195 mL) was added N -iodosuccinimide (65.4 g), heated to 80 ° C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, poured into purified water (650 mL), stirred for 1 hour, filtered, and the filter cake was collected. Acetonitrile (182 mL) was slurried overnight, filtered, and the filter cake was collected and dried under reduced pressure at 50 ° C to obtain compound 1-12.

[0306] LC-MS, ESI: m / z (MH) - : 357.9, 359.9.

[0307] Step 8:

[0308] 1-12 (10 g) and urea (10 g) were added to diphenyl ether (50 mL), and the temperature was raised to 200°C for reaction for 3 hours. After the reaction was completed, the reaction solution was cooled to 100°C and slowly dripped into ethanol (50 mL). After the dripping was completed, methyl tert-butyl ether (100 mL) was added, and the mixture was slurried at room temperature for 1 hour, filtered, and the filter cake was rinsed with a small amount of ethyl acetate. The filter cake was collected and dried under reduced pressure at 50°C to obtain compound 1-13.

[0309] LC-MS, ESI: m / z (MH) - :383.1, 385.1.

[0310] Step 9:

[0311] 1-13 (11.3 g) was added to phosphorus oxychloride (66 mL) and then added dropwise with stirring. N , N -Diisopropylethylamine (26.7 g), after dropping, heat to 100 ° C and react for 5 hours. After the reaction is completed, the reaction solution is cooled to 50 ° C, concentrated under reduced pressure, and the residue is dropped into a mixed solvent of ice water / ethyl acetate (800 mL, V / V=1 / 1), stirred for 5-10 minutes and filtered, the filtrate is separated, the aqueous phase is extracted with ethyl acetate (2*500 mL), the organic phases are combined, washed with 10% brine (800 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to obtain compound 1-14.

[0312] Step 10:

[0313] 1-14 (9.2 g) and 1-15 (5.2 g) were added to 1,4-dioxane (60 mL), and then added dropwise with stirring. N , N -Diisopropylethylamine (5.64 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure, and the filter cake was purified by column chromatography to obtain compound 1-16.

[0314] LC-MS, ESI: m / z (M+H) + : 583.0, 585.0.

[0315] Step 11:

[0316] 1-16 (5.0 g), 1-17 (2.32 g), cesium carbonate (8.25 g), 1,4-diazidebicyclo[2.2.2]octane (189 mg), tetrahydrofuran (50 mL) were added N , N -dimethylformamide (50 mL), argon protection, stirring at room temperature overnight. After the reaction, the reaction solution was poured into purified water (300 mL), stirred and separated, the aqueous phase was extracted with ethyl acetate (2*100 mL), the organic phases were combined, washed with 10% brine (2*150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and column chromatography was performed to obtain compound 1-18.

[0317] LC-MS, ESI: m / z (M+H) + : 637.1, 639.1.

[0318] Step 12:

[0319] Benzyl alcohol (1.42 g) was added to tetrahydrofuran (40 mL), sodium hydride (0.38 g) was added, and the mixture was stirred at room temperature for 10 minutes. Then, a solution of 1-18 (2 g) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (2*100 mL), the organic phases were combined, washed with 10% brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography was performed to obtain compound 1-19.

[0320] LC-MS, ESI: m / z (M+H) + : 725.1, 727.1.

[0321] Step 13:

[0322] 1-19 (1.32 g), cyclopropylboronic acid (235 mg), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (293 mg), potassium phosphate (1.38 g), 1,4-dioxane (15 mL), and water (15 mL) were added to acetonitrile (45 mL), and the mixture was heated to 80°C for 3 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, poured into 150 mL of water, extracted with ethyl acetate (3*100 mL), and the organic phases were combined, washed with 10% brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain compound 1-20.

[0323] LC-MS, ESI: m / z (M+H) + : 639.3, 641.3.

[0324] Step 14:

[0325] 1-20 (320 mg), 1-21 (520 mg), potassium phosphate (382 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (47 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (84 mg), 1,4-dioxane (20 mL), and water (10 mL) were added to 20 mL of acetonitrile, and the mixture was heated to 80°C for 3 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, poured into 150 mL of water, extracted with ethyl acetate (3*100 mL), and the organic phases were combined, washed with 10% brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography to obtain compound 1-22.

[0326] LC-MS, ESI: m / z (M+H) + : 951.6.

[0327] Step 15:

[0328] 1-22 (500 mg) was added to methanol (10 mL), and 10% palladium carbon (Pd 10%) (containing about 55% water) (100 mg) and palladium hydroxide (100 mg) were added in sequence under stirring, and the temperature was raised to 50°C for reaction under hydrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and column chromatography was performed to obtain compound 1-23.

[0329] LC-MS, ESI: m / z (M+H) + : 861.5.

[0330] Step 16:

[0331] 1-23 (500 mg) and cesium carbonate (380 mg) were added N , N -dimethylformamide (10 mL), add 1-10 (190 mg), react at room temperature for 6 hours, add water (100 mL), extract with ethyl acetate (100 mL), concentrate the organic phase to dryness, and perform column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 1-24.

[0332] LC-MS, ESI: m / z (M+H) + : 990.07.

[0333] Step 17:

[0334] 1-24 (200 mg), compound 1-7 (142 mg) and cuprous iodide (10 mg) were added to tetrahydrofuran (8 mL), and triethylamine (204 mg) was added, and the mixture was reacted at room temperature for 17 hours. Water (100 mL) was added, and ethyl acetate was extracted (100 mL). The organic phase was concentrated to dryness, and column chromatography (dichloromethane / methanol = 25 / 1) was performed to obtain compound 1-25.

[0335] Step 18:

[0336] 1-25 (120 mg) was added to ethyl acetate (4 ml), and 4 mol / L hydrogen chloride ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness to obtain the hydrochloride salt of compound 1.

[0337] LC-MS, ESI: m / z (M+H) + : 1116.92.

[0338] Embodiment 2-5

[0339]

[0340]

[0341] Example 1 (200 mg) was separated by preparative liquid chromatography (YMC AQ C18 50*250mm 10μm; A: acetonitrile (gradient elution condition 0~60 min, 15%~50%) B: 0.1% acetic acid, 60 mL / min) to obtain Example 2 (liquid phase retention time: 1.727 min), Example 3 (liquid phase retention time: 1.823 min), Example 4 (liquid phase retention time: 1.893 min) and Example 5 (liquid phase retention time: 1.997 min).

[0342] Example 2: LC-MS, ESI: m / z (M+H) + : 1116.87, liquid phase retention time: 1.727 min;

[0343] Example 3: LC-MS, ESI: m / z (M+H) + : 1116.85, liquid phase retention time: 1.823 min;

[0344] Example 4: LC-MS, ESI: m / z (M+H) + : 1116.92, liquid phase retention time: 1.893 min;

[0345] Example 5: LC-MS, ESI: m / z (M+H)+ : 1116.90, liquid phase retention time: 1.997 min.

[0346] Referring to the preparation method of Example 1-5, Example 6-21 was obtained by separation by preparative liquid chromatography.

[0347] Liquid phase conditions:

[0348] Chromatographic column: waters ACQUITY UPLC BEH C18 (2.1*50mm, 1.7um)

[0349] Mobile phase A: 5 mM ammonium acetate (0.1% acetic acid): acetonitrile = 95:5

[0350] Mobile phase B: acetonitrile

[0351] Flow rate: 0.6 mL / min Wavelength: 254 nm (DAD full scan) Column temperature: 40°C

[0352] Elution gradient:

[0353]

[0354] The chemical structures and characterization data of Examples 6-21 are as follows:

[0355]

[0356]

[0357]

[0358] Experimental Example 1 Nucleotide Exchange Experimental Method

[0359] 1. Reagents: His-KRAS G12D (1-169); SOS1 cat (564-1049); GDP (purchased from Sigma); Anti-6HIS-Cryptate (purchased from Cisbio); EDA-GTP-DY-647P1 (purchased from Jena Bioscience)

[0360] 2. Prepare buffer :

[0361] 1) Assay buffer: HEPES pH 7.4, NaCl, MgCl 2 , DTT, BSA, Igepal;

[0362] 2) KRAS G12D working solution: Prepare KRAS G12D working solution containing 100 nM His-KRAS G12D and 2 nM Anti-6HIS-Cryptate using assay buffer;

[0363] 3) SOS1 cat Working solution: Prepare a 20 nM SOS1 cat and 200 nM EDA-GTP-DY-647P1 for SOS1 cat Working fluid;

[0364] 4) Blank control working solution: Prepare a blank control solution containing 2 nM Anti-6HIS-Cryptate using assay buffer.

[0365] 3. Testing process:

[0366] The entire experimental process was completed at room temperature. Using a black bottom transparent 384-well plate, 5 μL of KRAS G12D working solution was added to each well of the experimental group and the negative group. At the same time, 5 μL of blank control working solution was added to each well of the blank group and incubated at room temperature for 10 min. Then, an ultra-micropipette was used to add a starting concentration of 100 μM to the experimental group, and the compound was diluted in 8 concentration gradients of 1:2 in succession, and incubated at room temperature for 30 min. Finally, 5 μL of SOS1 was added to each well. cat Working solution, incubate at room temperature for 15 min, and use PerkinElmer Envision HTS multi-label reader to detect 665nm / 620nm signal value. Calculate inhibition rate, inhibition rate (%) = (average value of negative control group - average value of experimental group) / (average value of negative control group - average value of blank group) × 100%. With the logarithm of compound concentration as the horizontal axis and inhibition rate as the vertical axis, a four-parameter logistic model was used to fit the curve and calculate IC 50 value.

[0367] Test Example 2 AsPc-1 cell proliferation inhibitory activity assay

[0368] Take AsPc-1 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 3×10 4 / mL, inoculated on a 96-well plate (100 μL / well), and the compound was added using a nanoliter pipette to make the final concentration of the compound 5000 nM - 0.31 nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 72 hours, the detection reagent CCK-8 (manufacturer: Tongren Chemical, 10 μL / well) was added. After incubation in the cell culture incubator for 3 hours, the absorbance value was detected at 450nm using a PerkinElmer Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .

[0369] The above test results of some compounds disclosed in the present invention are shown in Table 1.

[0370] Table 1 Test results of some compounds

[0371]

[0372] Note: A stands for IC 50 <150nM.

[0373] Test Example 3: In vitro liver microsome stability

[0374] Liver microsome incubation samples (species: human, monkey, rat or mouse) were prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / mL), test compound and NADPH + MgCl 2 The solution was incubated at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / mL), and the test compound. The sample was added with acetonitrile solution containing internal standard to prepare the supernatant by protein precipitation, which was diluted for LC / MS / MS determination. The results are shown in Table 2.

[0375] Table 2. In vitro metabolic stability results of mouse liver microsomes

[0376]

Claims

1. The following compound or a pharmaceutically acceptable salt thereof: 。 2. Stereoisomers of the following compounds or pharmaceutically acceptable salts thereof: ， The structure of the stereoisomer is selected from , , ,or .

3. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the stereoisomer according to claim 2 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 3 , further comprising a pharmaceutically acceptable excipient.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, the stereoisomer according to claim 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 3 or 4 in the preparation of a method for treating Kras G12D Use in medicines for related diseases.

6. The use according to claim 5, wherein the Kras G12D Related diseases are Kras G12D Mutation cancer.

7. The use according to claim 5, wherein the Kras G12D Related diseases are Kras G12D Mutations in pancreatic cancer.

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